Def. NMR Studies

Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190 www.elsevier.
nl/locate/pnmrs
NMR studies of cyclophanes

L. Ernst*
Department of Chemistry, Technical University of Braunschweig, Hagenring 30, D-38106 Braunschweig, Germany Received 17 January 2000
Contents 1. Introduction and scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. [n]Phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. [n]Metacyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. [n]Paracyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Other [n]phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. [1.n]Phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. [2.2]Phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. [2.2]Metacyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. [2.2]Paracyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. [2.2]Metaparacyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. [2.2]Orthometacyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. [2.2]Orthoparacyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. [2.2]Naphthalenophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Other [2.2]phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. [2.2]Heterophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. [2.2]- and [3.3]Phanes capable of through-space 19F, 19F coupling . . . . . . . . . . . . . . . . . . . . . . . 4. [3.3]Phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. [3.3]Phane hydrocarbons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. [3.3]Metacyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. [3.3]Paracyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3. [3.3]Metaparacyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4. Other [3.3]cyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Dithia- and diaza[3.3]phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. Dithia- and diaza[3.3]metacyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Dithia- and diaza[3.3]paracyclophanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3. Other dithia- and diaza[3.3]phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. [m.n]Phanes (m 2, n 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Multiply bridged phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Phanes with multiple bridges between different aromatic rings . . . . . . . . . . . . . . . . . . . . . . . . .
48 49 49 55 65 71 73 73 83 95 97 99 99 100 108 115 119 119 119 125 127 127 128 128 133 133 145 159 159
I dedicate this review to my parents on the occasion of my mothers 86th and my fathers 85th birthday in November 1999. * Tel.: 49-531-3915379; fax: 49-531-3915387. E-mail address: l.ernst@tu-bs.de (L. Ernst). 0079-6565/00/$ - see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0079-656 5(00)00022-4
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L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190
6.2. in-Phanes . . . . 7. Multilayered phanes 8. [mn]Phanes . . . . . . . 9. Conclusion . . . . . . . References . . . . . . . . . .
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170 173 174 182 183
Keywords: Cyclophanes; High-resolution NMR; Review
1. Introduction and scope Cyclophanes are bridged aromatic compounds the title of the rst monograph published on this subject [1]in particular, as their name implies, those containing aliphatic bridges, hence the morpheme -ane in cyclophane. While, at rst, the term cyclophanes meant bridged arenes in general, gtle and Neumann [2] suggested reserving this Vo term specically for bridged benzenes. They introduced the general term phanes for what used to be called cyclophanes. Although the title of the present article is NMR studies of cyclophanes, it deals with gtles nomenclature. Later phanes in the sense of Vo important reference books on cyclophanes are the two volumes edited by Keehn and Rosenfeld [3] and the gtle [4] and Diederich [5], the latter treatworks by Vo ing the supramolecular chemistry of cyclophanes. Moreover, three volumes on cyclophanes, edited by gtle [6,7] and Weber [8], have appeared in the Vo series Topics in Current Chemistry. In Ref. [3], the NMR properties and conformational behaviour of cyclophanes were treated in a chapter by Mitchell [9], who covered the literature up to the end of 1981. Mitchell excluded the NMR behaviour of multilayered cyclophanes because this was described by Misumi in his chapter on this particular class of compounds [10]. Further, the same book contains chapters by Rosenfeld and Choe on [n]cyclophanes [11], by Paudler and Bezoari on heterophanes [12] et al. [13] on nonbenzenoid cyclophanes. and by Ito The authors of these chapters also discussed the NMR aspects of their respective classes of compounds. Comparing the status of cyclophane NMR in 1964, the time of Smiths book [1], with that in 1983, Mitchell in the introduction to his chapter [9] predicted: Current easy access to high-eld NMR instrumentation suggests that a rapid expansion of our knowledge
of cyclophane properties will again occur. Not surprisingly, his prophecy has been fullled and the number of papers relating to the subject of cyclophane NMR is so large that complete coverage is very difcult and possibly not even desirable. Therefore, the present article is essentially a follow-up to Mitchells, yet with a number of restrictions in order to limit the vast amount of material to be treated. Firstly, the focus will be directed on the NMR properties of the cyclophanes themselves, not on their changes that occur when the cyclophanes interact with other molecules, neutral, anionic or cationic. So, the inuences of hostguest or supramolecular interactions upon NMR spectra are not covered, which leaves out the crown ether derivatives of cyclophanes and their thio analogues, polyazacyclophanes, calixarenes and analogous compounds, the cavitands, the carcerands or the spherands, etc., the main interest in which consists in their suitability for such interactions. Secondly, I have refrained from including metallocenophane (i.e. mostly ferrocenophane) papers although, for example, the effect of phane complexation by Cr(CO)3 and related groups is covered. Thirdly, cyclophanes possessing only bridges spanning ortho-positions are not considered proper cyclophanes because they mostly do not show the characteristic NMR spectroscopic properties usually associated with cyclophanes such as shielding of protons positioned above/below the planes of aromatic rings. The orthocyclophanes are therefore omitted. Otherwise compounds like indane, tetralin or 9,10-dihydroanthracene would also qualify for being included. It is important to realize that a number of important basic references concerning cyclophane NMR may not be listed in this review because they date from before 1982. Several Chemical Abstracts Online searches were carried out to arrive at the selection of papers included
49
in this review, for the last time on 13 December 1999. The CA File of Chemical Abstracts was searched for literature references later than 1981 with occurrence of both the term (NMR or nuclear magnetic resonance) and the term (cyclophan or phan or names of important aromatic moieties followed by phan, e.g. pyridinophan or metacyclophan) in any of the title, abstract or index term elds. This implied that the author must have considered the NMR-related content of his/her paper important enough to mention it in the title, abstract or keywords. Thus, generally, a paper did not qualify for inclusion if it simply contained undiscussed NMR data of a cyclophane, unless this reviewer learned of it some other way and recognized its contents as of interest. The hits of the search were ltered by eye according to the restrictions mentioned in the preceding paragraph. Another search, carried out in the Registry File, looked for phan as a segment in the names of chemical compounds. The hits were transferred to the CA File and the number of references were reduced by requiring the simultaneous presence of NMR-related terms in the Basic Index. The references remaining were ltered using the above restrictions as the criterion. Finally, between 50 and 60 colleagues known to work in the cyclophane area were asked for reprints of papers they considered relevant in the present context. About half of them responded. The different approaches furnished a total of ca. 500 papers. This number decreased further when the papers were inspected for information interesting enough to be included. The material presented in this article is arranged according to classes of compounds. This makes it easy for the reader to nd information related to particular molecules. Cross-references to other sections are given when papers deal with compounds belonging to different classes.
Table 1 NMR chemical shifts (measured at 47C; solvent: toluene-d8) of the bridge hydrogens in the two conformers of (2) Conformer (2A) (2B)
d (Ha)
0.97 1.32
d (Hb)
1.82 0.65
d (Hc)
0.04 1.48
d (Hd)
1.48 2.31
d (He)
1.85 1.56
d (Hf)
3.39 3.18
are affected. The second reason lies in the mobility of the bridges which is often restricted because of their shortness and therefore brings the rate of existing conformational processes into the range observable by NMR spectroscopy. The main interest in the [n]phanes concerns metacyclophanes and paracyclophanes with short bridges, by which the aromatic ring is forced out of planarity and the chemical and spectroscopic behaviour of the molecule is altered relative to cyclophanes possessing longer bridges. 2.1. [n]Metacyclophanes The shortest-bridged [n]metacyclophanes that are isolable and stable compounds are those with n 5: The 1H NMR spectrum of the parent hydrocarbon (1) is unchanged between 50 and 150C [14]. It was fully analysed and the chemical shifts and coupling constants indicate that, in solution, [5]metacyclophane prefers conformation (1A). The spectra of the halogenated derivatives (2)(4) [15] showed the presence of the same major conformer, e.g. (2A) and of 1115% of a second conformer, e.g. (2B). The interconversion of the conformers was demonstrated by spin saturation transfer experiments, coalescence measurements and full lineshape analysis. The ratio B/A remains constant in the temperature range 50 to 80C. The activation parameters for the conversion of A into B for (2)(4) are DG 23C 55:256:1 kJ mol1 ; DH 48:551:5 kJ mol1 ; and DS 15:0 to 23.0 J K 1 mol 1. Some remarkable chemical shift differences were observed between conformers A and B, the largest ones being those for Ha, which moves by 2.29 ppm (upeld), and for Hc, which moves by 1.44 ppm (downeld), when A changes into B; the numbers quoted refer to (2), see Table 1. These effects are due to the moving of these protons into and out of, respectively, the shielding zone of the aromatic ring by the conformational change. Smaller shift changes were found for Hb
2. [n]Phanes There are two main reasons why phanes are interesting to NMR spectroscopists. The rst consists in unusual 1H chemical shifts which are caused by the magnetic anisotropy of the aromatic system(s) in these molecules and which can only be observed by virtue of the simultaneous presence of the bridges that
50
11
X (1) (2) (3) (4) (5) H Cl Br Br D
Y H Cl Cl Br D
9 12
(CH2)6 H
(6 )
Ha Hb Hc Hd Hf Cl (1A) (2A) He Cl Hc
Hb Ha He Cl (2B) Hd Hf Cl
(1.17 ppm) and Hd (0.83 ppm) which have contributions, in addition to that from the ring current effect, from the release and increase, respectively, of steric compression by the neighbouring chlorine substituent. This interpretation was supported by the result of an X-ray diffraction study of (2). The vicinal H,H coupling constants in the bridges of both conformers could be well tted to a Karplus-type equation although the CCC bond angles deviate considerably from normal values. A remarkable feature in the 13 C NMR spectra of (1)(4) was the deshielding of C11 ( 8 ppm), the carbon atom between the bridge7
heads, in comparison with C-2 of identically substituted m-xylenes [16]. This observation was tentatively ascribed to long-range anisotropy effects of the bridge and to the bending of the aromatic ring. The latter argument is supported by a correlation found between the downeld shifts of C-8 and C-11 in (1) and C-9 and C-12 in [6]metacyclophane (6) on the one hand and the degree of out-of-plane bending of these atoms on the other. Ring bending also produces an increase of the geminal J(C-8,H-7) coupling constant in (1) to 4.0 Hz from the normal value of ca. 1 Hz. The strong bending imposed by the short aliphatic
H
2.18 0.36
RO
11
Cl
NOE
(7), X = Cl (8), X = H, R = Me
11
13
Cl (9 ) R
NOE
H 6.94 Cl H 6.94
Cl
R R
exo -
(10), R = H (11), R = Me
endo-
51
bridge on the benzene ring of (1) raises the question of the aromaticity of the latter. One possibility of answering this question makes use of the determination of the magnetic susceptibility anisotropy from quadrupolar deuterium couplings of molecules in solution aligned by the magnetic eld. This was done by van Zijl et al. [17] who measured high-eld deuterium NMR spectra of some ring-deuterated 1,3dialkylbenzenes as model compounds and of 8,11dideuterio[5]metacyclophane (5). The principle of the technique consists in determining the quadrupolar splitting and comparing it with the splitting calculated for a nonaromatic reference compound from known localized susceptibilities. The results proved beyond doubt that [5]metacyclophane is fully aromatic. In the reaction of (2) with NaOR/DMSO, the chlorine substituent at C-11 (between the bridgehead carbon atoms) was replaced by an alkoxy group to give (7) [18]. The identity of the products followed from a comparison of the chemical shifts of their aromatic carbon atoms with those predicted by increment calculations. Compound (7) and some analogues prefer conformation A (at 53C), but conformer B is also signicantly populated in the 11-alkoxy derivatives, reaching a mole fraction of 0.42 in (8); A and B correspond to formulae (2A) and (2B). The 1H NMR spectra of both conformers were analysed as far as possible with respect to the chemical shifts and J(H,H) coupling constants in the ve-membered bridge. Dichloro[3.0]orthometacyclophane (9), 1 a highly strained biphenylophane, may also be regarded as a [5]metacyclophane with benzoannelation at the bridge [19]. In contrast to (2), which lacks the benzo anneland, it exists exclusively in the endo-conformation shown [corresponding to (2B)]. This causes strong shielding of the endo-proton at C-7 d 0:36 while its geminal partner has a more normal shift of d 2:18: The conformation was conrmed by an NOE experiment: saturation of the H-7(endo) resonance caused enhancements of the signals of H-11 and H-13 which have very similar but not identical
shifts near d 6:94: This value indicates that, in spite of the large molecular distortions predicted by density functional computations, the meta-bridged ring is still fully aromatic. [6]Metacyclophan-3-ene (10) contains a ciscongurated double bond and its 1H and 13C NMR spectra demonstrate the presence of two conformers, exo-(10) and endo-(10), in equal amounts [20]. Spin saturation transfer experiments using the aromatic and the olenic proton resonances proved the reversible interconversion of the conformers. The olenic protons of exo-(10) absorb at d 5:40; those of endo-(10) are shielded at d 4:75: By measuring the coalescence of the olenic proton signals at 90C and 500 MHz observation frequency, the barrier to chemical exchange was estimated to be 69:5 ^ 2:1 kJ mol1 : In the dimethyl derivative (11) the equilibrium ratio of endo-conformer dMe 1:1 to exoconformer dMe 1:8 is 3:1.
(CH2)n Ph N (12), n = 9 (13), n = 8 (14), n = 7 (15), n = 6

Hb
4 1
(CH2)n N (16), n = 9 (17), n = 8 (18), n = 7 (19), n = 6
1.45
Ha
Ph
N
7
Ph
1.45 7
Hb
Ha
(14A)
H
1 1.95 3
(14B)
H H
1.24
1.44
H
4
H
3 1
1.95 4 H
Ph
N (15A)
6
Ph
N
6
(15B) Ph
1 In the present article, decimal numbers in chemical formulae mean NMR chemical shifts, usually 1H, sometimes 13C NMR chemical shifts. In some cases chemical shift differences relative to a particular model compound are given. The exact meaning of the numbers follows from the context and is usually not explicitly stated.
Ph
N
4
N
3
(15C)
(15D)
52
The chemical equivalence of the geminal protons at the benzylic positions of the [7]- to [9](2,4)pyridinophanes (12)(14) indicates rapid ipping of the oligomethylene chains at room temperature [21,22]. On lowering the temperature, the averaged proton signal of H-4a/4b in (14) d 0:16 disappeared due to decoalescence into broad components and at 60C the signal of H-4a in (14A) or H-4b in (14B) reappeared at d 1:45: The geminal counterpart at lower eld was hidden under other signals. Also, all four benzylic protons gave separate signals, which showed that the ipping of the bridge is frozen. The energy barrier (DG ), determined from signal coalescence, is 5055 kJ mol 1 at 20C. The [6]pyridinophane (15) displayed four anisochronous benzylic proton signals at room temperature already, thus indicating slow ipping of the bridge. Signal coalescence was reached at 150C and DG at this temperature was estimated to be 8892 kJ mol 1, signicantly larger than in [6]metacyclophane (72.8 kJ mol 1 at 76.5C) [23]. There was no 1H signal at d 0 for (15) at room temperature. This suggests that the structure is not xed in conformer (15A) or (15B) or their equivalents (15C) and (15D) but that a rapid equilibrium between them is set up by pseudorotation of the hexamethylene chain. At 90C, pseudorotation is frozen as indicated by the presence of two sets of 1 H and 13C signals in the ratio of 2:1 DG 1:1 kJ mol1 : Lineshape analysis of the 13C signals at various temperatures (details not given) furnished DH 41:0 kJ mol1 and DS 4:8 J mol1 K1 for the pseudorotational movement of the bridge. However, DG (30C) was also reported to be 41.0 kJ mol 1, i.e. either DG or DH must be in error. The H-6 signals were distinguished from the H-1 signals by their larger shifts upon addition of Eu(fod)3. 2D shift correlations allowed the assignments of all 1H and 13C shifts of the two conformers. The major conformer is (15A/C), the minor one (15B/ D). Overall, the results bear much resemblance to those of [6]metacyclophane [23] but not to those of [6](2,6)pyridinophane [24]. Nittas group later also studied the azuleno-annelated [n](2,4)pyridinophanes (16)(19), n 9; 8; 7; 6 [25]. These behaved basically like their nonannelated analogues but the barrier DG to bridge ipping in the [7]phane (18), 45 kJ mol 1 (30C), and in the [6]phane (19), 76 kJ mol 1 (90C), are somewhat lower than in (14) and (15),
respectively. It was suggested that the exibility of the pyridine ring is increased by azuleno-annelation.
13
X S
3 4
TsN
(20) Et R
(21a), X = H (21b), X =OMe
(22), R = Me (23), R = OMe
(24), R = H (25), R = OC(=O)Ph
G = 42.7 kJ mol 1 (48 C) bridge flipping
G = 36.4 kJ mol 1 (73 C)
bridge pseudorotation
(24)
Some [7]metacyclophanes (20)(21) with heteroatoms in the bridge and with or without intraannular substituents were studied by variable-temperature 1H NMR [26]. The aliphatic bridges in (20) and (21b) have xed conformations and display chemical nonequivalence of all methylene protons. At room temperature, these two compounds show both restricted bridge ipping, indicated by AB spectra for the benzylic protons, and restricted rotation of the C-3/C-4/C-5 part of the bridge, indicated by geminal nonequivalence of these CH2 protons. One of the hydrogens at C-4 is strongly shielded [dH-4a 1:16 in (20) and 0.90 in (21b)], which points to its position above the m-phenylene
53
S
3
O2 S
3
O2 S R S O2 (28a), R = H (28b), R = Br
R S (26a), R = H (26b), R = F (26c), R = Cl (26d), R = Br O2 S R S O2 (E,Z)-(29a), R = H (E,Z)-(29b), R = Br
R S O2 (27a), R = H (27b), R = Br
O2 S R S O2 (Z,Z)-(29a), R = H
ring, while its geminal partner has a normal chemical shift [dH-4b 1:19 in (20) and 1.40 in (21b)]. No coalescence could be reached up to 180C for these two compounds, thus DG (180C) 92 kJ mol 1. In (21a), lacking an intraannular substituent, the barriers for the bridge ip, DG 36C 47:3 kJ mol1 ; and for polymethylene chain rotation, DG 10C 51:9 kJ mol1 ; could be measured separately. The ipping barrier of thiaaza compound (21a) is very similar to that of [7]metacyclophane itself, 48.1 kJ mol 1 at 28C [23,27]. At room temperature, the averaged shift for the protons at C4 is d 0:15: The [7]metacyclophanes (22) and (23) were obtained as 1:1-diastereomeric mixtures [27]. The 1 H NMR spectra of the bridges are complicated and do not change upon raising the temperature to 150C. Hence, neither pseudorotation nor bridge ipping takes place in this temperature range. The large activation barriers are caused by the bulky intraannular substituent and the ethyl group on the bridge. The 1H NMR spectra of the bridge protons of [8]metacyclophane (24) show four signals of equal intensity at room temperature. The authors claimed to have observed two coalescence points upon lowering the temperature, viz. at 73 and at 48C (270 MHz), but this is difcult to recognize from the spectra published. The estimated DG c values
are 36.4 and 42.7 kJ mol 1, respectively. In analogy to the known behaviour of [6]metacyclophane, the respective conformational processes were assumed to be bridge pseudorotation and bridge ipping. To prove this, 14-benzoyloxy[8]metacyclophane (25) was studied, for which bridge ipping is excluded because of the bulky internal substituent. The only conformational process left, bridge pseudorotation, has a DG value of 37.2 kJ mol 1 at 65C, thus conrming the above assumptions. There are not many examples of [n]cyclophanes with triple bonds in the bridge. In 2,7-dithia[8]metacyclophan-4-yne (26a) the intraannular hydrogen is small enough (and the CH bond short enough) to allow ipping of the bridge from one side of the aromatic plane to the other, as shown by the singlet nature of the 1H NMR signals of CH2-1 and CH2-3 [28]. These did not even broaden when the temperature was lowered to 50C. However, bridge inversion is severely restricted by the presence of an intraannular substituent (F, Cl or Br) in (26b)(26d) as this would cause very unfavourable interactions with the triple bond in the transition state. The methylene protons at C-1/C-8 give an AB spectrum at room temperature and those at C-3/C-6 give an AA 0 BB 0 spectrum because of the sizeable 5J(H,H) couplings through the triple bond. No signal coalescences were observed up to 120C. When (26a) or (26d) were
54

G [kJ mol1]
X
2 8 15 14 10
Tc 58 C 63 C 78 C
OMe (CH2)n (30), n = 815
(31) (32) (33)
N 41.0 N+Me 40.6 O+ 37.2
FSO3 +N CH3 (CH2)n (34), n = 610
.. N + CH3 (CH2)n (34)
oxidized to the bis-sulfones (27), these were in equilibrium with the corresponding allenes (28) [29]. While the sulfones behave conformationally like the suldes, the allenes give three AB spectra for the CH2 groups, even in the case of rapidly inverting (28a), due to the lack of molecular symmetry. The diastereomeric dienes (E,Z)-(29) and (Z,Z)-(29a) were formed by isomerization of (28). For steric reasons, the former dienes cannot be planar and show AB spectra for the different benzylic methylene groups. According to MNDO MO calculations, (Z,Z)(29a) is predicted to exist in two interconverting enantiomeric C1 conformations with a C2 transition state. Only one AB and one AA 0 BB 0 system were observed in the 1H NMR spectrum as expected. The room temperature 500 MHz 1H NMR spectra of the [8]- to [15]metacyclophanes (30) with an internal methoxy group were assigned as completely as possible and the 13C chemical shifts were reported [30]. The equivalence or nonequivalence of the benzylic protons indicates rapid or slow ipping of the alkylene chain. For the [15]metacyclophane the benzylic proton signals had just coalesced at room temperature but activation barriers were not determined. The most stable conformations, as computed by molecular mechanics, agree with the experimental nding that the d -proton on the side of the macrocycle opposite to the methoxy group is the most shielded in the [8]- to [10]phanes, while the protons of the central methylene group(s) absorb most upeld in the higher phanes.
As information on the conformational behaviour of [9]metacyclophanes was scarce, Balaban et al. [31] determined the barriers to ipping of the nonamethylene bridges in (31)(33) from the coalescence parameters of the H-2/H-8 signals in the low-temperature 1 H NMR spectra. For these protons the chemical shift differences and coalescence temperatures could be measured more accurately than for the other protons, which also showed signal splitting. Ample uctuations (pseudorotation) within the bridges, predicted by molecular mechanics calculations, still persisted at 90C. The lower barrier to bridge ipping in (33) with respect to the other two phanes was suggested to be due to the larger bond distances (of the C14C15 and C10C15 bonds?) of about 2 pm in pyrylium relative to pyridinium cations. This would lower the energy of the conformational transitionstate. In all of the N-methyl[n](2,6)pyridinophanium salts (34) with n 610 bridge ipping is restricted until at least 146C as shown by the temperature-invariant 1H NMR spectra [32]. One of the bridge protons, presumably of the central methylene group, in the compound with n 7 is strongly shielded, having a chemical shift of d 2:27: In the 13C spectra, decreased shielding of the pyridinium carbon atoms C-2,6 from d 160:8 to 166.2 was observed as the bridge length was shortened from 10 to 6. According to the authors interpretation, this could be explained by the increased importance of canonical structure (34 0 ) in the order mentioned. However, they did not consider
55
that differences in the bridge conformation would also affect these chemical shifts.
CO2Me (CH2)n R (35) O O Ph OMe CF3
gtles method [33] for estimating the effective Vo size of an intraannular substituent by determining the energy barrier that must be overcome to move a metacyclophane bridge of given length past the substituent was applied by Kang and Chan [34] to metacyclophanes (35). Because of the unsymmetrical substitution pattern of the benzene ring the metacyclophane system has a plane of chirality when passage of the substituent R through the methylene loop is slow. As these compounds also have a centre of chirality in one of the ester substituents, diastereomeric conformers arise under these conditions. In (35), n 11; R Me, doubling of the aromatic proton signal was observed at low temperature. Signal coalescence occurred at Tc 50C at 200 MHz; the barrier DG to bridge ipping is 47.9 kJ mol 1. Shortening the bridge by three methylene groups increased Tc to 133C and DG to 89.9 kJ mol 1 in (35), n 11; R Me. However, keeping the ring size at 11 and omitting the internal methyl group lowers the barrier so much that signal doubling is not observed down to 70C in (35), n 11; R H. 2.2. [n]Paracyclophanes [4]Paracyclophane is the smallest [n]paracyclophane of which a derivative has ever been observed. Okuyama and Tsuji [35] succeeded in preparing phane (36b) by irradiating the Dewar benzene precursor (37b) with 365 nm light in CD2Cl2 solution at 90C. Two new singlets appeared in the 1H NMR spectrum at d 7:97 and 5.85 with an intensity ratio of ca. 2:1. They were attributed to (36b) and correspond to 6% of product vis-a-vis 94% of starting material. To corroborate the identity of the product, high-level ab initio MO calculations were performed of the 1H NMR chemical shifts of hydrocarbons (36a) and (37a). The calculated shift differences between (36a) and (37a), Dd 1:48 for Ha and 1.56 for
Hb agree qualitatively with the experimental differences between (36b) and (37b), which are 1.35 for Ha and 1.04 for Hb. Assuming that the effects of the cyano groups in (36b) and (37b) cancel, the authors took these results as strong evidence that they had indeed observed a [4]paracyclophane. The upeld shift that Ha experienced in the formation of (36b) suggests that relatively strong diatropicity is sustained in the aromatic ring despite its extreme bending. In agreement with this, the nucleus-independent chemical shift (NICS), which has been proposed as an aromaticity/antiaromaticity criterion [36], was computed to be 9.0 at the centre of the C6 ring of (36a) compared with 9.7 for planar benzene. Such large negative NICS values correspond to a high degree of aromaticity. The next smallest [n]paracyclophane described was [5]paracyclophane (38) [37]. It was prepared in THFd8 solution in an NMR tube at low temperature and its 1 H NMR spectrum was recorded at 72C. At this temperature ipping of the pentamethylene bridge is frozen causing the left and right hand sides of the benzene ring to be different so that an AA 0 XX 0 spectrum results with dH 7:44 and 7.38 and 4 J AX 1:1 Hz: The protons within the geminal pairs at the bridge carbon atoms are also different. The highest-eld chemical shifts were found for one of the homobenzylic protons d 0:22 and one of the central methylene protons d 0:01: Coalescence was observed near 0C; line-shape analysis furnished DH 57:3 kJ mol1 and DS 11:3 J K1 mol1 for the ipping of the bridge. Tobe et al. [38] prepared the 7methoxycarbonyl derivative of [5]paracyclophane. At 60C, it is present as two conformers (39A) and (39B) with the chemical shifts given in the formulae. Kostermans et al. [39] described the tetrasubstituted [5]paracyclophane (40a) which, at 53C, exists as conformers (40aA) and (40aB) in a ratio of 53:47. 1H NMR signals hidden by the resonances of the starting material, the corresponding Dewar benzene, could be assigned by decoupling experiments so that all 1H chemical shifts are available, see the formulae. (The chemical shifts in the formulae correspond to the assignments given in Ref. [40]. There the shift-toconformer assignments were reversed with respect to Ref. [39].) The shifts of the methyl groups, d 2:33 and 2.31, were considered good indicators of the aromaticity of the [5]paracyclophane system; the
56
Ha R R R R R R
Ha R R
Hb (36a) (36b)
1.6
Hb R=H R = CN (37a) (37b)
H H H H H H
1.6
H H H H H
3.84
H H H H H
2.16
0.09 0.12
H H H H
3.86
0.35
H H H H
2.11
0.01 0.22
H
0.25
H
2.77
H
2.84
MeO2C (38) (39A)
8.08
MeO2C
H (39B)
8.05
R H3 C (CH2)5 H3C R R (40a) (40b) (40c) (40d) (40e) CO2Me CF3 CN CO2H CO2C6H4-p-NO2
2.44 2.31
3.22 0.44 3.72
2.99
2.87 1.59 0.06 3.73
H3 C H3 C
1.59
0.55
CO2CH3 CO2CH3
2.33
0.33
1.32
H 3C
1.21
CO2CH3 CO2CH3
H 3C (40aB)
(40aA)
olenic starting material has dCH3 1:64: Activation parameters for bridge ipping are DH 46:9 kJ mol1 and DS 45 J K1 mol1 ; DH being somewhat lower than in the parent compound (38), probably because of increased strain in the ground state conformations of (40a). Later, in a full paper [40], the same authors described the 1H NMR spectra of further [5]paracyclophane derivatives, (40b)(40e). For all of these, conformers analogous to (40aA) and (40aB) were observed at low temperature. An important argument in the assignment process of the bridge proton signals is the relative constancy in the series (40a)(40e) of the chemical
shift (d 0:45 to 0.60) of that proton of the central methylene group which in conformer A points downwards on the side of the ar-methyl substituents as opposed to its geminal partner which in conformer B points downwards on the side of the variable substituents. This has a larger shift range, extending from d 0:21 to 0.17. The rst benzoannelated [5]paracyclophane and at the same time the smallest [n](1,4)naphthalenophane is compound (41) [41]. It was observed only in THF solution at 63C and in the presence of its synthetic precursor. Two conformers were present in a ratio of 95:5. They differ by the centre of the pentamethylene
57
H 3C (CH2)5 H 3C (41)
CO2Me CO2Me
1.18 H 1.72 H 1.31
H H H 0.72 H 0.64
0.93
Ha Hb A
Hb
2.33 H
H 1.72 H 3.45 H 2.12
0.43
R B
Ha
2.88 H
R R
7.48 H
(42a), R = CO 2Et (42b), R = CO 2Me
H 7.27 (42b)
R
H
R
H
R (43a)
OH R = CO 2Et
R HO (43b)
bridge pointing towards the second naphthalene ring and away from it, but the major and minor conformer could not be assigned. Activation parameters of the bridge ipping were determined to be DH 47:3 ^ 5:4 kJ mol1 ; very similar to the nonannelated [5]paracyclophanes, and DS 63 ^ 21 J K1 mol1 : Tochtermann et al. [42] described variabletemperature 1H NMR experiments on the [6]paracyclophane derivative (42a). At 50C the two aromatic protons are chemically nonequivalent and there are four different chemical shifts for the four benzylic protons. This is caused by slow interconversion of the enantiomeric conformations (42aA) and (42aB). Inversion of the hexamethylene bridge leads to coalescence of the signals of the aromatic protons Ha and Hb at 4C. This allowed the ring inversion barrier to be determined as 58.3 kJ mol 1. Later, nther and coworkers [43] presented a very detailed Gu 1 H and 13C NMR study of the conformation and dynamics of the dimethyl ester (42b). The spectra were assigned and analysed in the slow-exchange limit (20C) for the bridge inversion process using
various 2D NMR techniques including 2D exchange spectroscopy (EXSY). In this way all the chemical shifts of the individual bridge protons could be determined and also the geminal and most of the vicinal H,H coupling constants. The latter showed a Karplustype dependence on torsional angles and indicated that the solution conformation of (42b) closely resembles that found in the crystal. A complete 1H NMR analysis of a longer cyclophane chain had previously been performed only for [8]paracyclophan-4-ol (see later). The boat-shape of the benzene ring of (42b) does not signicantly change its 1H NMR shielding properties and the 13C chemical shifts of the methylene carbon atoms could be explained without invoking ring current contributions. A line shape analysis for the chemical exchange of the aromatic protons yielded the activation parameters for the inversion of the methylene bridge: DH 43:3 ^ 0:7 kJ mol1 ; DS 51:3 ^ 2:7 J K1 mol1 ; and DG 298 58:5 kJ mol1 : The 3-hydroxy derivative (43) of (42a) occurs in the form of two diastereomers [44]. Their 1H NMR spectra are temperature invariant
58
between 50 and 70C indicating that each exists in one preferred conformation. 1H chemical shift arguments and evaluation of most of the vicinal H,H coupling constants allowed their congurations and conformations to be derived. The hydroxy groups prefer to point towards the outside of the molecule in both diastereomers. Hence their bridge conformations must be different. They are shown in (43a) and (43b).
Hb R
1
Ha R R
Hb
Ha
R H H
H A
(44), R = CO 2Me
O O R H H A
O O R H H
(45), R = CO 2Me
R (CH2)6 (CH2)8
CH3
(46), R = H (47), R = CH 3 (48), R = CH 2OH
(49)
Tobe et al. [45] found two conformers, (44A) and (44B), in a 20:1 ratio, in the low-temperature 1H NMR spectrum of the para-diester of [6]paracyclophane. The value of DG for the inversion of the bridge is 54.0 kJ mol 1 and was determined from the coalescence of the two aromatic proton signals (d 7:94 and 8.04, 20:1) at 24C. Below 50C the most
shielded proton absorbs at d 0:69: The reason for the relative instability of conformer (44B) lies in the severe nonbonded repulsion between the carbonyl oxygens and their syn benzylic hydrogens, e.g. Hb at C-1. Assignments in the proton spectra were based on the careful chemical shift assignments that had been carried out for (42b) [43]. Tobes group also studied methyl [6]paracyclophane-8-carboxylate with two vicinal carbonyl groups in the bridge, (45) [46]. At 30C, conformers (45A) and (45B) were observed. The integral ratio of the signals of the isolated aromatic proton is 4:1. Signal coalescence occurs at 15C, giving DG 54:0 kJ mol1 for the bridge ip. The comparison with (42b) shows that the vicinal dione group has little inuence on the conformational properties of the bridge. Dynamic NMR experiments on the parent [6]paracyclophane (46) ( 13C, coalescence method) and its 8methyl (47) and 8-hydroxymethyl (48) derivatives (both 1H, lineshape analyses) were carried out by Sternhell et al. [47]. They found that the barrier to inversion of the six-membered bridge is rather insensitive to the nature of the substituent at C-8 DG 56:960:4 ^ 1:1 kJ mol1 ; T 10 to 30C). In a 1 H NMR study of possible distorted aromatic systems, Sternhell and collaborators [48] used their previously derived relationship between ortho-benzylic coupling constants involving a methyl group, 4J(HCCMe), and the square of the CC bond order [49], to test electronic distortions in the aromatic rings. No perturbations of electronic structure could be observed with the possible exception of 8-methyl[6]paracyclophane (47), which exhibits a barely signicant deviation from unstrained values. The 4J(H,H) value for (47) is 0.61 Hz, while four less strained cyclophanes, among them 10-methyl[8]paracyclophane (49), have 4 J(H,H) values of 0.65 to 0.66 Hz. Tobe et al. [50] prepared [6](1,4)naphthalenophane (50) and [6](1,4)anthracenophane (51) and fully assigned their 1H NMR spectra at 50C when ipping of the bridges is slow. The preferred conformations are analogous to that of (46), cf. also (44), and the barriers to bridge ipping are in the order (51) DG 5C 56:1 kJ mol1 (50) DG 0C 56:9 kJ mol1 (46) DG 5C 58:2 kJ mol1 ; determined from the coalescences of the signals of H-2 and H-3 (naphthalene and anthracene numbering). A comparison of the chemical shifts of
59
(CH2)6
(CH2)6
(50)
2.79 0.51 0.62 1.06 1.58 1.97 2.79 1.97 1.58 1.06 0.62 0.51 0.71 0.47 1.11 1.58 2.27 3.49 3.01 2.86 1.74 0.79 1.84 0.34
(51)
3.08 0.80 0.31 1.14 1.60 2.36 3.58 3.00 1.77 0.71 1.81 0.38
(46)
(50)
(51)
R (CH2)6 R (52a), R = Ph (52b), R = Me (53) (CH2)6
Ph
Ph
the bridge protons of (50) and (51) with those of (46) shows that, in the former two compounds, the protons located above the interior of the aromatic rings and pointing downwards onto the naphthalene and anthracene system, respectively, are signicantly shielded (d 1:84 and 1.81) with respect to the benzenophane d 0:62: This is due to the combined inuence of the ring currents of more than one aromatic ring. The 13C chemical shifts of (50) and (51) were also reported but no assignments were given. The peri-substituted [6](1,4)naphthalenophanes (52a) and (52b) and the [6](1,4)anthracenophane (53) behave very similarly to their parent compounds, but they all have barriers to ipping of the hexamethylene bridge that are lower than those of (50) and (51) by some 6 kJ mol 1 [51,52]. The free energies of activation are 51.0 kJ mol 1 (10C) for (52a), 50.6 kJ mol 1 (25C) for (52b), and 50.2 kJ mol 1 (25C) for (53). Lowering of the barriers was explained by increased bending of the bridged aromatic rings due to peri-substitution. One feature worth noting are the upeld shifts of the syn-benzylic
protons (Dd 1:2 to 1.9 ppm) due to the periphenyl groups in (52a) and (53) at low temperature. In an attempt to prepare (9,10)anthracenophanes, Tobe and coworkers rst succeeded in obtaining 1,4,5,8-tetramethyl[6](9,10)anthracenophane (54) [53] as the nonmethylated compound is rather unstable. At room temperature, ipping of the hexamethylene bridge in (54) is rapid on the NMR time scale. There are only three different 1H chemical shifts for the bridge, d 3:31; 0.87, and 0.38, at ambient temperature. At 90C, the bridge signals broaden and the most shielded methylene proton appears at d 1:89; comparable to what was found in [6](1,4)anthracenophane (51). The bridge ipping barrier DG (temperature not reported) was determined as 39.7 kJ mol 1, while it is 56.1 kJ mol 1 in (51). The smaller barrier for (54) was attributed to destabilization of the ground-state conformation because of steric repulsion between the methyl groups and the benzyl methylenes. Later, the parent [6](9,10)anthracenophane (55) was also obtained, admixed with 40% of the 9,10-dihydro product [54].
60

3.31 0.87
CH3
CH3
0.38 1 8
(CH2)6
CH3 (54) R
CH3 (55) R
(56), R = H, Me orPh R R
(57), R = H, Me orPh
R (58), R = H or Me
The 1H and 13C NMR spectra were recorded at 50C and signal assignments were made with the aid of H,H-COSY, C,H-HETCOR, and NOE difference experiments. At this temperature, the movement of the methylene bridge is frozen so that six kinds of methylene signals were discerned, the most upeld one at d 1:84; similar to the other [6]anthracenophanes discussed above. The barrier to bridge ipping was determined from a line shape analysis of the H-1 and H-8 signals Tc 5C which appear as two singlets when H-2,7 and H-3,6 are decoupled simultaneously. DG (25C) is 57.3 kJ mol 1, very similar to that of [6](1,4)anthracenophane (51) but distinctly higher than that of (54). In the full paper on this subject [55], the authors additionally reported the 1H chemical shifts at 50C of the diastereomeric diepoxy[6](9,10)anthracenophanes (56)(58). These shifts were compared with those of [6]paracyclophane (46) and discussed in terms of steric compression of the hydrogens by the oxygen
atoms and of shielding by the oxanorbornadiene double bonds. The cis double bond in the bridge of (Z)-[6]paracyclophan-3-ene (59a) [56] entails reduction of its exibility and increase of strain which is expected to lie between that of [5]paracyclophane and of [6]paracyclophane. In the 1H NMR spectra of (59a)(59c), two kinds of aromatic protons were observed irrespective of the temperature (up to 150C), those on the same side (syn protons) and those on the opposite side of the bridge (anti protons). The syn protons are shielded by 0.130.27 ppm relative to the anti protons by the magnetic anisotropy of the double bond. Similarly, the olenic protons appear shielded by ca. 1.0 ppm compared to precursor model compounds, due to the effect of the aromatic ring. In the 13C NMR spectra the carbon atoms of the same side of the bridge are signicantly deshielded Dd 4 ppm relative to the anti carbons by what has been termed p-orbital compression effect [57] due to the
61
R2 R1
R1
R2
H (59a) H (59b) CO2Me H (59c) CO2Me CO2Me
139.0 7.13 136.0 7.07 137.6 7.19 134.7 7.93
132.1 or 132.0 7.20
134.6 7.34 133.7 7.34
136.4 7.69
CO2Me anti (59b) R E syn
CO2Me
(59a)
O R (CH2)7 R O (CH2)7 E
(CH2)7
(60)
R = CO2Me, CH 2OH or CH2OAc
(61)
(62)
E = CO2Me; R = H or Me
S CH3 O H 3C (63) H 3C (63) O H3 C S (64) CH3 CH3
olenic carbon atoms of the bridge. The analysis of the olenic proton signals gave the large vicinal coupling constant of 12.2 Hz across the double bond in (59a). This was interpreted as indicating widening of the CyCC bond angles according to the empirical correlation derived by Cooper and Manatt [58]. An Xray diffraction study of (59c) conrmed this; the bond angles were found to be 130(2) and 132(1) and the double bond is lengthened to 137(2) pm. Because of the substitution pattern of (59b), the two bridge-inversion conformers are diastereomers. They were separated and their isomerization was followed by HPLC. The kinetic parameters were determined to be DH anti ! syn 102:9 kJ mol1 and DS anti ! syn 0:8 J mol1 K1 ; the equilibrium ratio (syn/ anti) is 0.97(1) at 25C.
Tochtermanns group also studied the [7]paracyclophanes (60) and (61) as well as the [7](1,4)naphthalenophanes (62) [59]. Due to the specic conformation adopted by the heptamethylene bridge in these compounds, one proton of the central methylene group is pointing towards the opposite benzene ring and experiences strong shielding by the aromatic ring current. Its upeld shift is larger in the naphthalenophanes (d 2:6 to 3.2) than in the benzenophanes (d 1:7 to 2.3). As other [n]paracyclophanes do not show such a strong upeld shift, the authors suggested that it might be applied as an indicator of 9,10-disubstituted [7]paracyclophanes. Variable temperature 1 H NMR spectra of (60, R CH2OAc) showed no doubling of the aromatic proton singlet down to
62
100C and hence no indication of a second conformer. At room temperature, the 1H and 13C NMR spectra of the 4-oxa[7]paracyclophane (63) [60] indicate apparent C2 symmetry and, hence, fast bridge ipping. This could be stopped at low temperature when the signal of the aromatic protons doubled. Coalescence was observed at 55C (400 MHz, Dv 12:5 Hz), which gave a DG value for the conformational process of 47.9 kJ mol 1. This process is a topomerization reaction with identical educt (63) and product (63 0 ) because these may be interconverted by applying a C2 symmetry operation. A similar case, 9,12dimethyl-2,6-dithia[7]paracyclophane (64), had been studied before and its conformational barrier, 48.5 kJ mol 1 at ca. 30C, is almost identical to that of (63) [61].

12
(65)
-0.28
(66)
H H
5 4
-0.67
O H (68)
1.65
(67) X
5 4
H + X OH CO2H (71)
(69) (70)
Two papers by Hopf and coworkers [62,63] treat the 1H and 13C NMR spectra of [8]paracyclophane (65) and some derivatives. Comparison of the chemical shifts of the aromatic protons of (65) with those of 1,4-di-n-butylbenzene showed that the deformation of the benzene ring by the eight-membered bridge does not decrease the magnitude of the ring current effect upon the chemical shifts of the aromatic protons [62].
By double resonance experiments the chemical shifts of the methylene protons were assigned to be d 2:66; 1.47, 0.91, and 0.19 for the CH2 groups a, b, g and d, respectively, with respect to the aromatic ring, i.e. the g and d protons are shielded relative to CH2 protons in an undisturbed aliphatic chain. No ring current effect upon the 13C chemical shifts of the methylene carbon chemical shifts could be derived by comparing (65) with its saturated counterpart (66). Apparently, other factors such as the conformation of the eight-membered bridge are more important in determining the chemical shifts of the bridge carbon atoms. Also, the magnitudes of the 1J(C,H) coupling constants both for the aromatic and the aliphatic CH bonds in (65) show that no inuence of the transannular bridging upon the degree of hybridization of these carbon atoms can be deduced. Bickelhaupt and coworkers [64] reported the 1J(C-1,C-2) and 1J(C-1,C-12) couplings constants in (65) to be 32.6 and 43.4 Hz, respectively. These values are also very similar to the corresponding values [65] in the strain-free model compounds cyclohexane, 32.7 Hz, and 2-methylnaphthalene, 1J(C-2,C-a) 44.3 Hz. The cyclopropane derivative (67) and epoxide (68) both show characteristic shielding of their protons in positions 4 and 5 [63], viz. dH 0:67 and 1.65, respectively. These values are ca. 1 ppm smaller than in the model compounds trans1,2-dimethylcyclopropane and trans-2,3-epoxybutane. The CH2 protons of the cyclopropane ring in (67) still have dH 0:28 although they are pointing away from the arene ring. The spectrum of the 15 nonequivalent protons of the eight-membered bridge in [8]paracyclophan-4-ol (69) was fully analysed yielding 24 vicinal H,H coupling constants that were correlated with the corresponding torsional angles and yielded a conformation similar to that known for [8]paracyclophane-4-carboxylic acid (70) from an X-ray diffraction study [66]. One of the protons at C-5 is pointing toward the interior of the molecule and experiences substantial shielding dH 0:25; very similar to the corresponding proton in (70). Also, the carbinyl proton has a chemical shift of only dH 2:07 in spite of its position a to oxygen. The assignment of its signal was conrmed through the spectrum of the 4-deuterio derivative of (69). An interesting molecule to compare with [8]paracyclophane (65) is the analogue [8](1,4)tropyliophane
63
(71) [67]. Its aromatic protons absorb as a broad singlet at d 8:83 as do those of the 1,4-dimethyltropylium ion. The methylene protons of the bridge are distinctly less shielded than those of (65) (see above). For the protons in the a-position to the aromatic ring, which show d 3:28 (4 H), this was explained as an effect of the positive charge. The other protons absorb at d 1:98 (4 H) and 1.05 (8 H). This means that the d-protons are deshielded relative to (65) by at least 0.86 ppm. Possible reasons could be a weaker ring-current effect of the tropylium relative to the benzene ring and/or differing conformations of the octamethylene bridges. The assignments of the bridge carbon chemical shifts in (65) have been secured by experiment [62] and the relative shifts are d (C-a) d (C-b) d (C-d) d (C-g). Unsupported by experiments, Thummel and Chayangkoon [67] assigned the bridge carbon signals of (71) in the order d 42:3 (C-a), 31.6 (C-b), 28.1 (C-g), 25.3 (Cd). They argued that the decrease of the one-bond C,H coupling constants which occur in the same order (134, 128, 123, 121 Hz; all ^1 Hz) parallels the expected decrease of ring strain. In the opinion of the reviewer this is unsatisfactory and the question should be resolved by experiment.
Ts N R (CH2)n N
O O
N Ts (72), R = H, n = 510 (73), R = Me, n = 510,12
Two series of (2,5)pyridinophanes with varying bridge length, (72) and (73), were studied by Iwata and Kuzuhara [68] with respect to restricted rotation of the pyridine ring. At ambient temperature, the 1H NMR spectra of (72) with n 7; i.e. a total bridge length m 11; showed geminal proton nonequivalence in the three methylene groups connected to the pyridine ring. This indicates slow rotation of the unsubstituted side of the pyridine ring through the macrocycle. Compounds (73) where additional steric interference is present due to the methyl group on
the pyridine ring, have nonequivalent geminal protons already when n 10 m 14; but from the variabletemperature spectra of (73), n 12 m 16; it was estimated that the largest bridge length causing CH2 nonequivalence at room temperature would be n 11 m 15; although the corresponding compound was not available. Elschenbroich et al. [69] compared the 1H NMR chemical shifts of [10]paracyclophane (74) with those of bis(h 6-[10]paracyclophane)chromium(0) (75). From the chemical shift difference they concluded that the coordination of chromium to the arene ring goes along with a weakening of the ring current but does not abolish it. This approach was criticized by Jenneskens et al. [70] who reported a strong solvent dependence (CDCl3 vs.C6D6) of the 1 H NMR coordination shifts of tricarbonyl(h 6[8]paracyclophane)chromium (76a, n 8). These authors warned that the solvent dependence may act as an obstacle to the use of the coordination shifts as a probe in assessing the quenching of the aromatic ring current due to h 6-complexation. The origin of the solvent dependence of the coordination shifts probably lies in the different solventsolute interactions of the chromium complexes and the parent hydrocarbons. Ref. [70] also reports that Cr(CO)3-complexation of (65) goes along with an increase of 1J(C-a,Ha) from 125.7 to 131.9 Hz. This could be interpreted by an increase in s-character of the carbon orbital involved and would imply a decrease of the C C(a)C(b) valence angle. It is in line with the Xray diffraction results of [2.2]paracyclophane (113.7) and its Cr(CO)3-complex (110.9). Kreindlin et al. [71] determined the complexation shifts in the 1 H NMR spectra of the [10]paracyclophane complexes (77)(81). The downeld shifts of the bto e-protons in the bridge observed in (77)(80) relative to the uncomplexed ligand were explained by a weakening of the paracyclophane ring current and partly by the effect of the positive charge in (78) and (79). In (80), the twofold positive charge was assumed to override the ring current effect. An exceptional effect was observed in the tetranuclear cluster (81), viz. increased shielding of the b- to e-methylene protons upon complexation. This effect was deemed to require further investigation. The complexation shifts in the 13C NMR spectra of
64

0.70 0.90 1.25 1.50
1.08
0.50 0.72
Table 2 Activation barriers DG c to p-phenylene ring rotation determined at coalescence temperatures Tc for the [14]- and [16]paracyclophanes (84)(87) Compound (84a) (84b) (85a) (85b) (86) (87)
1 DG c [kJ mol ]
2.08 4.13
Tc [C] 40 a 18 13 45 1 10
1.54 2.62 7.09
Cr
65 a 51 57 46 55 51 ^ 4
(74)
(75)
a The DG c and Tc values quoted are averages over the values obtained from the H-2 0 /H-6 0 and the H-3 0 /H-5 0 signals.
(CH2)n
M M M (76a) Cr(CO) 3 (76b) (C5H5)Fe + PF6 (76c) Mo(CO) 3 (76d) (C6H6)Ru2+ 2BF4 n = 8, 9, 11, 12, 15 (74) (77) (78) (79) (80) (81) H Cr(CO) 3 Mn(CO) 3+ Ru(C5Me5)+ Rh(C5Me5)2+ Co4(CO)9
([n]paracyclophane)Cr(CO)3 (76a) and ([n]paracyclophane)Fe (C5H5) (76b) complexes (n 8; 9, 11, 12, 15), i.e. the differences Dd between complex and free phane ligand, were reported by Mori and Takamori [72]. The aromatic carbon atoms have complexation shifts that depend on the bridge length n and can be correlated with the interatomic distances between the metal and the ligand carbons; for details see the discussion of the [2.2]phane complexes later. The 1 J(C,H) coupling constants in the p-phenylene rings of the complexes are independent of n and amount to ca. 171 Hz for (76a) and ca. 177 Hz for (76b). 13C complexation shifts were also determined for Mo(CO)3 complexes (76c) of [8][15]paracyclophanes [73] and the conclusions reached were similar to those for the Cr(CO)3- and (C5H5)Fe -complexes, except that the aromatic 1J(C,H) coupling constants vary slightly in (76c) and this variation seems to correlate with the complexation shifts. In a further study Mori and coworkers [74] investigated
complexes of the type [(h 6 C6H6)Ru(h 6 [n]paracy (76d), where n was 8, 9, 12, and clophane)] 22BF4 15, and came to similar conclusions as in the cases of the Mo, Cr, and Fe complexes mentioned above. The pressure dependence of the rate of internal rotation of the p-phenylene ring in the cis-1,12-disubstituted [12]paracyclophane (82) was studied by Yamada et al. [75]. It had been expected that an increase of pressure would slow down the rate of rotation because of compression of the macrocyclic ring structure. In fact, the opposite effect was observed. Simulation of the signals of the aromatic protons showed that at 105C the rate of rotation of the pphenylene ring increases from 33 s 1 at 5 MPa to 52 s 1 at 300 MPa. The corresponding dihydroxy compound behaves similarly. The explanation offered was a negative activation volume DV of the order of 6 to 7 cm 3 mol 1 as the transition state conformation (83) requires less space than the ground state conformation (82). In the [14]- to [16]paracyclophanes (84)(87), the barriers to p-phenylene ring rotation (Table 2) are obviously not only determined by the length of the bridging chain [cf. (84a) with (84b) and (85a) with (85b)] but also by the presence and conguration of the substituents at the pyrrolidine ring. The barriers were determined from the coalescence of the H-2 0 with the H-6 0 signals and of the H-3 0 with the H-5 0 signals. All of these were individually assigned by NOE measurements [76]. In an important paper on the empirical calculation of 1H NMR shielding in cyclophanes, Schneider et al. [77] tested various published methods for calculating ring current effects, viz. those by Haigh and Mallion
65
(CH2)10
(CH2)10
C OAc (82)
H OAc
C OAc (83) O
H OAc
O
5
O
3 2
O R N E (CH2)n E O O (85a), n = 8 (85b), n = 10 O O R N E R N E (CH2)n O O (87), n = 8 R = CH 2Ph, E = CO 2Me E E R N E
(CH2)n O O (84a), n = 8 (84b), n = 10 O O
(CH2)n O O (86), n = 8 E
felin[78], by Johnson and Bovey [79,80], and by Ha ger et al. [81]. The [n]paracyclophanes with n 610 were used as the test compounds. Their geometries were determined by molecular mechanics calculations (MM2 and CHARMm). The best agreement between the calculated ring current effects upon d H on the one hand and the effects determined experimentally on the
Table 3 Comparison of important chemical shifts in the troponophane series (88)(90) and in the series (92), (88), (91) Compound (88) (89) (90) (92) (88) (91) Bridge(s) [4] [4 2] [4 1] [5] [4] [3]
other (i.e. chemical shifts with respect to suitable reference compounds) was found for the Johnson Bovey model, the double loop model parameterized with a radius of 139 pm and a separation of the loops from the aromatic plane of 64 pm. This gave a small mean deviation of 0.1 ppm. Thus, the model and parameters were used to calculated ring current effects in in-cyclophanes (Section 6.2), adamantanophanes and other phanes (Section 3.7). 2.3. Other [n]phanes Increasing strain in the series of (2,7)troponophanes (88)(90) [82] leads to reduced conjugation of the carbonyl group with the triene system in the order mentioned. This is visible from the decreasing chemical shifts of H-b and C-b and the increasing shift of the carbonyl carbon atom (Table 3). The lower and higher homologues of (88), the [3]phane (91) and the
d (H-b)
6.21 6.07 6.04 6.48 6.21 5.96
d (C-b)
118.3 116.5 114.3 121.5 118.3 113.7
d (CyO)
203.7 210.1 214.0 202.5 203.7 210.6
66
O (88)
O (89) (90)
O (CH2)n O
1
(CH2)n HO
(CH2)n
(91), n = 3 (92), n = 5
(93), n = 7 (94), n = 9
(95), n = 7 (96), n = 9
[5]phane (92) [83], behave in an analogous manner. The shorter the bridge, the more severely the tropone ring is bent and the less effective is the carbonyl/triene conjugation as shown by the series [5]phane (92), [4]phane (88), [3]phane (91). In this order, the chemical shifts of H-b and C-b decrease and that of CyO increases (Table 3). In the [n](3,5)troponophanes (93) and (94), decreasing the bridge length from n 9 to 7 produced small changes of 13C and 1H chemical shifts, which were thought to possibly reect decreased carbonyl triene conjugation [84]. In view of the minor deshielding of C-1 (0.7 ppm), this may be over-interpreted. Changes in the 1H shifts are 0.11 ppm or less for H-2, H-6, and H-7, but 0.24 ppm for H-4, probably a consequence of altered ring strain and/or bridge conformation. By a coalescence measurement the barrier DG to ipping of the seven-membered bridge in (93) was determined to be 34.7 kJ mol 1 at 93C. This is distinctly lower than the barrier of 48.1 kJ mol 1 found in [7]metacyclophane [23] and reects the larger CCC bond angles in the tropone relative to the benzene ring. The properties of the tropyliophanes (95) and (96) differ strongly from those of the troponophanes: C-3 to C-6 are deshielded by 1221 ppm, C-1 is shielded by 7 ppm and the olenic protons are deshielded by 1.21.7 ppm. The differences between the [7]- and the [9]tropyliophane, however, are again very small with the exception of H-4 which is deshielded by 0.40 ppm in (95) with respect to (96). A paper by Paquette et al. [85] describes the reduction of 13-methyl[10](1,5)cyclooctatetraenophane
(97) (called 14-methyl- in the paper) to its dianion (98). The diatropic 10p aromatic system formed caused characteristic shieldings of some bridge protons (dH 0:44 and 0.72; number of protons not specied) and deshielding of the methyl protons dH 2:86: The corresponding shifts of (97) are dH 1:37 (8 CH2) and 1.76 (CH3). The dianions (99a) and (99c) of [9](1,3)cyclooctatetraenophane (100a) and of [7](1,3)cyclooctatetraenophane (100c), respectively, were mentioned in a related paper [86]. At 60C in ND3, the triplet nature of the allylic proton signal (4 H) of (99a) at d 3:06 indicates rapid ipping of the nonamethylene chain from one side of the 10p ring to the other whereas this process is slow for the heptamethylene chain in (99c) at the same temperature as shown by the broadened allylic proton signal at d 3:17: The [n](1,3)cyclooctatetraenophanes (100a c) are chiral and can racemize either by ring inversion or by double bond shifting. These processes could be distinguished by 2D-NMR exchange spectroscopy (EXSY) because ring inversion in (101) exchanges the geminal protons, HA with HC and HB with HD, to give (101 0 ), whereas bond shifting exchanges HA with HB or HD and HC with HB or HD, to give (101 00 ). It was found that in (100c) ring inversion is the sole process operating below 37C, with bond shifting setting in only above this temperature. The rate constants of the ring inversion processes in (100a c) were determined from the cross-peak volumes in the 1H 2D EXSY spectra at six to seven different temperatures. The rate constants of bond shifting were extracted from 13 C 2D EXSY spectra at four temperatures. Table 4
67
CH3
CH3 2
(CH2)10 (97) 2
(CH2)10 (98)
(CH2)n (CH2)n (99a), n = 9 (99c), n = 7 (100a), n = 9 (100b), n = 8 (100c), n = 7 HB HD (CH2)n2

3
ring inversion
HA HC
HA HC (CH2)n2
1
(101)
HB
3
HD
bond shift
HA HC (CH2)n2
1
(101)
HB
3
HD
(101")
Table 4 Activation parameters for the enantiomerization of the [n](1,3)cyclooctatetraenophanes (100a c) Compound Ring inversion (100a) (100b) (100c) Bond shifting (100a) (100b) (100c) DH [kJ mol 1] DS [J K 1 mol 1] 58.6 ^ 10.5 9.2 ^ 7.1 7.9 ^ 5.9 28.0 ^ 10.0 39.3 ^ 12.1 32.2 ^ 5.9 DG 25C [kJ mol 1]
50.2 ^ 2.9 65.7 ^ 2.1 78.2 ^ 1.7 66.5 ^ 3.3 65.7 ^ 3.8 92.0 ^ 1.7
67.86 ^ 0.46 68.41 ^ 0.21 75.69 ^ 0.13 74.77 ^ 0.21 76.99 ^ 0.29 82.68 ^ 0.13
68
shows the activation parameters obtained. In all cases the rate of ring inversion exceeds the rate of bond shifting.
H
6
N
6
H N N9
N N N (104) N H N N N N
N N (102) H N
N N
N N
anti-(103)
syn-(103)
In order to explore the diamagnetic anisotropy of 0 the adenine system, N 6 ,N 9-octamethylenepurine (102) was studied by 1H NMR [87]. Its ninemembered bridge is short enough to permit only minimal motion of the methylenes but not so taut as to cause signicant bending of the purine ring. At a measuring frequency of 500 MHz, the chemical shifts of all 16 nonequivalent methylene protons are resolved. The shifts of the NCH2 protons are between d 4:7 and 3.4, those of the CH2 groups not bound to nitrogen are between d 1:8 and 0.6. The 13C chemical shifts were assigned by 2D heteronuclear correlation [88]. The next higher homologue (103) [89] occurs as two conformers, anti and syn, that differ by the torsional angle about the C6N6 0
bond. Their H-2 and H-8 signals coalesce at ca. 25C (500 MHz), giving DG 25C 50:2^ 2:5 kJ mol1 : Two-dimensional H,H-COSY and C,H-HETCOR experiments at 75C and at 60C allowed the assignment of all 13C and 1H resonances apart from the pro-R/pro-S 1H assignments within methylene groups possessing diastereotopic protons. The spectra of the decamethylene compound (104) [90] are very broad at room temperature and could only be assigned at 90C by the usual 2D correlation techniques. At 77C, several isomers, again likely due to anti syn isomerization about the N6 0 C6 bond, appear in the spectra. The anti conformer is preferred by ca. 4:1 over the syn. Variable temperature proton NMR measurements revealed a DG (20C) of 59.4 ^ 5.5 kJ mol 1 associated with the interchange between the two major conformers. The large error in the barrier is caused by a number of signals of minor conformers coalescing about the peaks of interest, which made it difcult to accurately match simulated spectra with the actual peaks. The chemical shifts of the methylene protons of (102) and (103), apart from the benzylic ones, were calculated by adding to the standard methylene shift of d 1:3 the effects of ring currents [91] and local atomic magnetic anisotropies [92]. The relative chemical shifts were roughly reproduced and the purinophanes were found useful in the assessment of the chemical shift calculation procedure. The enantiomerizations, by the jump rope mechanism, of several dioxa[n](1,5)naphthalenophanes (105) with n 1618 (i.e. containing 1416 methylene groups) were studied by dynamic NMR spectroscopy [93,94]. These enantiomerizations go along with interconversion of the diastereotopic protons of each
O D2 D2
O (CH2)m O O D2 (105) m 14 15 16 [n ] 16 17 18 D2 (106) D2 D2
L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190 Table 5 Activation parameters for the jump rope enantiomerization of (105, n 1618) Compound (105, n 16) (105, n 17) (105, n 18) DH [kJ mol 1] 43:47 ^ 0:42 32:01 ^ 0:25 36:94 ^ 0:59 DS [J K 1 mol 1] 97:9 ^ 1:2 80:8 ^ 0:9 13:8 ^ 2:7
69
methylene group in the chain except the central one in the odd-numbered bridge. As the protons in the CH2 groups positioned g to the oxygen atoms have the largest chemical shift differences, their signals were used to follow the kinetics. The b-, d-, and h-CH2 groups were deuterated as in (106) to simplify the spectra. A complete lineshape analysis (CLSA) at 500 MHz was performed for (105, n 18) in the temperature range 87 to 39C. To obtain maximum possible accuracy, complete lineshape analyses at 90 and 500 MHz observation frequencies in the range T 35 to 15C were carried out for (105, n 17), and both CLSA and saturation transfer experiments were applied to (105, n 16). For the latter compound, this allowed a determination of the rate constants over a very large temperature interval
from 30 to 144C. The activation parameters obtained for the jump rope movement of the chains are given in Table 5. The important nding is that large, negative entropies of activation are observed when n 16 or 17 and that DS is rather small when n 18: The results of molecular mechanics calculations explain this by unrestricted and conformationally very exible polymethylene chains in the ground state of all three compounds and by a very restricted chain in the enantiomerization transition state when n 16 or 17 as opposed to a relatively unrestricted chain when n 18: The bridged porphyrins (107a)(107f) with varying bridge lengths from 14 to 20 show increased shielding of their amide protons H-g and methylene protons H-d and H-e relative to the open chain model compound (108). Shortening of the bridges leads to higher-eld shifts of these protons as they cannot evade the shielding zone of the diamagnetically anisotropic porphyrin macrocycle [95] (Table 6). In an attempt to test the tolerance of pyrene towards distortions from planarity Bodwell and coworkers synthesized 1,8-dioxa[8](2,7)pyrenophane (109) [96] and 1,7-dioxa[7](2,7)pyrenophane (110) [97]. The strain imposed on the molecule by the short bridges
N Zn N
N N NH (CH2)n n 4 5 6 7 8 10 O NH Zn (108) HN O O O NH Zn (107a-f) (CH2)n
HN
HN
[m]Cyclophane (107a) (107b) (107c) (107d) (107e) (107f) [14] [15] [16] [17] [18] [20]
70
Table 6 1 H NMR chemical shifts of the g-, d-, and e-hydrogens in the porphyrins (107a)(107f) and in the model compound (108) Compound Bridge length H-g H-d H-e (107a) [14] 5.94 2.01.6 1.4 2.1 2.7 (107b) [15] 6.64 3.02.3 1.0 2.5 3.4 (107c) [16] 7.27 3.22.8 1.2 to 2.6 (107d) [17] 7.81 2.90 0.2 1.0 1.4 (107e) [18] 8.00 2.90 0.2 0.5 1.0 1.4 (107f) [20] 8.20 3.43.2 0.70 0.10 0.4 (108) 8.28 3.20 1.20
is distributed evenly over the polycyclic aromatic system as shown by X-ray diffraction. Increasing deformation leads to slight upeld shifts of the aromatic protons relative to model compound (111). The most shielded bridge protons have dH 1:47 and 2.10 in (109) and (110), respectively, which compares with dH 0:6 for [6]paracyclophane. By taking the synthetic precursor (112) as an open chain reference compound, one arrives at upeld shifts of up to almost 4 ppm for the methylene protons (see formulae) caused by the large ring current effect of the extended pyrene system.
3.02 1.72 0.40
In the dihydropyrenophane (113) the 2,7-positions of the [14]annulene are bridged by an 18-membered chain which is long enough for the annulene ring to spin freely [98]. As a consequence both the bridge and the annulene protons give symmetrical spectra. Free rotation on the NMR time scale is maintained even at 600 MHz and 100C. The bridge protons were assigned by a DQF-COSY experiment, starting at the CH2C(yO) group with its characteristic shift. When the chemical shifts were compared with those of the reference compound 1,14-tetradecanedioic acid, the resulting Dd values gave an idea of the
O
0.25 0.13
MeO
OMe
(109)
3.77
BrCH2
1.89 0.68
(111) (CH2)n
n = 5, 6
CH2Br O CH2Br
O
0.47 0.25
O BrCH2
(112)
(110)
(H values)
CH3
O O CH3
0.68 0.48 0.39
O O
0.24 0.05
0.26
(113)
values, see text
71
annulene ring current effect upon the bridge proton shifts. The largest shielding effect was not observed at the central methylene groups 7 and 8 but at the adjacent ones 6 and 9. The order of the induced shifts (H-6 H-7 H-4 H-5) agrees with the order of observed signal intensities in a gradient-selected NOE experiment when the methyl signal was saturated. It also agrees with the order of distances between the methylene carbons and the centre of the ring current, averaged over the 10 most populated conformers, as computed by molecular mechanics. The 13C NMR spectrum of (113) was fully assigned by the use of 2D heteronuclear shift correlations. A large number of compounds are known of the type of myricanone (114), a natural product from the bark of Myrica cerifera L. [99]. These compounds may be considered as [7](3,3 0 )biphenylophanes or [7.0]metacyclophanes. The parent hydrocarbon (115) has also been described [100]. As such compounds do not show the NMR properties that
Ph H n 5 6 7 8
are usually associated with phanes they are not considered in this review.
HO OMe OMe OH
O (114) (115)
2.4. [1.n]Phanes Staab and coworkers [101] assigned the 1H NMR spectra of the a-phenyl[1.n]paracyclophanes n 58 (116)(119). These are triphenylmethanes in which the para positions of two of the phenyl rings are connected by a (CH2)n bridge. From the relative
(H2C)n
Hc Ha (H2C)5 Hb (116A), parallel H a Hc H Hc
(116) (117) (118) (119)
(H2C)n n 5 6 7
Ph
(H2C)5 Hb
Hc H
(120) (121) (122)
(116B), perpendicular
(H2C)n n 12 11 10 9 8
(123a) (123b) (123c) (123d) (123e)
72
chemical shifts of Ha d 6:94 and Hb d 7:05 and the considerable low-eld shift of Hc d 7:78 in (116), they inferred the preference of the perpendicular conformation (116B) over the parallel conformation (116A). Compounds (117)(119) behave similarly to (116). Conversion of (116)(118) into the triarylmethyl carbanions (120)(122) [102] is accompanied by high-eld shifts of the ortho, meta, and para protons of the phenyl ring of 0.70 to 0.85, 0.65 to 0.75, and 1.35 to 1.50 ppm, respectively, while the aromatic protons of the paracyclophane systems are slightly deshielded (0.1 ppm, H-ortho) with respect to the hydrocarbons or are substantially less shielded [0.27 to 0.31 ppm, H-meta] than the meta protons of the phenyl ring. This is in accord with the averaged
perpendicular orientation of the C-a orbital formally carrying the negative charge and the paracyclophane phenylene rings. In the a-oxo[1.n]paracyclophanes (123a)(123e) with 12- to 8-membered n-bridges [103], the 13C chemical shift of the carbonyl carbon increases slightly with increasing ring strain: d (CyO) 199.1 (123a), 200.4 (123b), 201.3 (123c), 202.1 (123d), 203.5 (123e); solvent CDCl3. In the same order, the carbonyl band in the infrared spectrum is shifted to higher frequencies, from 1675 (123a) to 1710 cm 1 (123e), similar to the well-known trend in the smaller cycloalkanones. The rst two [2.1]paracyclo(1,7)naphthalenophane derivatives, (124) and (125), were described by Buchholz and de Meijere [104]. In these compounds, H-8
4.54
4.49
(124)
7.60 3.94
(125)
HA H H
CO2Me H? HC H
4.44
CO2Me HA
h
HC HB
HB
6.95
7.14
MeO2C
H (126)
CO2Me (127) X
3.38 7.67
H H
6.94
H H
H H
Y Y H
Y Y X (129)
H H
3.67, 3.61
(128)
X = CONMe 2, Y = CH 2SiMe3
73
(naphthalene numbering) is strongly shielded. It is not exactly centred over the p-phenylene ring because, as shown by X-ray diffraction of (124), C-8 is bent out of the plane of the atoms C-6/C-7/C-8a/C-4a by 11. Otherwise, even stronger shielding might have been expected. The rst [1.1]paracyclophane, (126), was prepared photochemically from the bis(Dewar benzene) compound (127) [105]. It could not be isolated but only characterized in the reaction mixture by 1H NMR at 70C. It shows the normal coupling constants between aromatic protons, J(HA,HB) 2.5 Hz and J(HB,HC) 8.8 Hz, while those of the starting material are J(HA,HB) 1 Hz and J(HB,HC) 2.4 Hz. The chemical shifts of the aromatic ring protons are ca. 0.450.50 ppm downeld from the values in the corresponding [2.2]paracyclophane derivative [106]. The chemical shift of one of the methylene protons was not found, probably because the signal is covered by the much stronger methoxyl absorption. Later, the parent [1.1]paracyclophane (128) was also prepared in solution [107]. Its 1H NMR spectrum consists of two singlets at d 6:94 and 3.38 (THF-d8, 80C). The hexasubstituted derivative (129) is so stable that a crystal structure could be obtained. The bridge and the aromatic protons have chemical shifts d 3:67=3:61 and 7.67, respectively [108].
D
14
D D
D
12
(130)
4 16 60 106 7 7
7 59 6 81 305 112 108 283 362
(131a)
D (131b)
(131c) D
333
86 7 112 307
84 108 289
(132a)
D (132b)
Isotope effects [ppb]
(132c)
3. [2.2]Phanes 3.1. [2.2]Metacyclophanes The basic facts on NMR of [2.2]metacyclophanes are found in Ref. [9]. More recent material is presented here, roughly in the following order: substituted anti- and syn-[2.2]metacyclophanes, [2.2]metacyclophanes with heteroatoms in the bridges, metal complexes of [2.2]metacyclophanes, and partially saturated [2.2]metacyclophanes. A paper by Tsuzuki et al. [109] reported 1H and 13C NMR data of [2.2]metacyclophane (130) with one aromatic ring fully deuterated. The results do not provide new insights and the quality of the 1H spectral analysis of the nondeuterated ring is questionable as, for example, a value for J(H-12,H-14) is reported although this coupling should not be detectable, if, as expected, the protons involved are magnetically
equivalent. Later, the same group measured deuterium isotope effects D on 13C chemical shifts in 4-D(131a), 5-D- (131b), and 8-D-[2.2]metacyclophane (131c) [110]. These effects are dened as D dRD dRH; are usually negative (shielding) and are given in ppb ( 0.001 ppm) in the formulae. The deuterated meta-xylenes (132a)(132c) were used for comparison. The authors pointed out that the isotope effects over one and two bonds in the cyclophane isotopomers (131a) and (131b) are very similar to the effects in the corresponding xylenes (132a) and (132b), whereas substantial differences existed between the effects in (131c) with its intraannular deuteron and the effects in xylene (132c). As the 1 J(C,D) coupling in (131c) is also larger (24.4 Hz) than in its isotopomers or in the xylenes (23.6 24.1 Hz), the authors assumed higher than normal scharacter in the C-8 orbital involved in bonding the deuteron. For such a situation they expected a decrease in the one-bond isotope effect. That this was not found in (131c) was attributed to structural strain and/or through-space electronic interaction
74

7.107.05 7.68 2.96 H 2.63 7.25 7.16
*
6.80 6.39
6.78
MeS H F
0.67 2.56 H
H
2.72
CH3 H
2.95 7.13
H
3.79
0.91
CH3
1.61
6.59 6.16
CH3
H
2.80
* *
* (134)
6.82
6.91
* : 7.17 6.94
7.01
(133) F F F F
(135)
F F F
(136)
(137)
(138)
(139)
tBu F F
3.47 H
0.73
tBu Hi
(140)
(141), anti
(141a)
which originates from the unique metacyclophane skeleton. Lai and Zhou [111] achieved a rather complete assignment of the 1H NMR spectra of the 8-uoro16-methyl derivatives of anti-[2.2]metacyclophane (133), -cyclophan-1-ene (134), and -cyclophane-1,9diene (135) by 500 MHz 1D NMR, including NOE measurements, and 2D H,H-COSY. Their assignments also include the individual protons of the saturated bridges. They noted an increasing downeld shift of the methyl protons in the above series (d 0:67; 0.91, 1.67), i.e. with increasing unsaturation in the bridges, and explained this by the sliding of the benzene rings relative to each other due to the change in bond angles of the bridges with the effect of moving the methyl group towards the periphery (C8) of the opposite ring. They further suggested that due to the increased steric hindrance in the order mentioned between the inner substituents and the respective opposite rings, the uorine bearing ring may tilt in order to decrease its interaction with the
methyl group. (This movement would, however, increase the interaction of the uorine with the methylated ring.) The trend found for the methyl proton shifts was also observed for the shifts of the uorine nuclei. However, this is probably not due to the geometrical changes but only fortuitous, as shown by consideration of other model compounds. Mitchell et al. [112] synthesized syn-8,16-diuoro[2.2]metacyclophane (136) and its diene (137) and showed that the compounds previously claimed [113] to have these structures are, in fact, the anti isomers (138) and (139), respectively. The aromatic protons of both syn isomers are shielded by ca. 0.7 ppm relative to those of the anti isomers. Syn-phane (136) is conformationally extremely stable. Five minutes of heating to 300C was necessary to convert it to the anti isomer (138). However, when syn-diene (137) was warmed to 35C, it underwent valence isomerization to cis-10b,10c-diuoro-10b,10c-dihydropyrene (140). Through-space 19F, 19F spinspin coupling in (136) is discussed in Section 3.9.
75
MeO Y
OMe X X Y CO2Me CO2Me H NO2 H H H1 H4 H2 H3 (143A)
MeO
OMe
MeO2C
CO2Me
anti-(142) anti-(144) anti-(145)
syn-(142)
H4
H2
H1 H3 (143B)
In a study of anti- and syn-dithia[3.3]metacyclophanes (see Section 4), Mitchell et al. [114] also obtained a [2.2]metacyclophane possessing a tertbutyl group as the internal substituent (i.e. bound to C-8). The 1H chemical shifts of the tert-butyl group d 0:73 and of the remaining internal proton d 3:47 clearly show the compound to have the anti conformation (141) because of the shielding by the magnetic anisotropy of the opposite aromatic ring. The d value of 3.47 corresponds to the strongest shielding of an aromatic proton in a [2.2]metacyclophane, at least at the time of the original publication. It was explained by a distortion of the molecule into a conformation like (141a), in which unfavourable interactions with the tert-butyl group are somewhat relieved but the internal hydrogen Hi is pushed into the cavity of the opposite benzene ring. Restricted rotation of the tert-butyl group was observed not to occur down to 90C. The synthesis of [2.2]metacyclophane (142) [115] furnished a 6:1-ratio of anti and syn isomers. These can easily be assigned from the large 1H chemical shift differences between the two methoxy Dd 0:95 and the two methyl ester signals Dd 0:55 in anti-(142) as opposed to the very similar shifts, Dd 0:02 for both OMe and CO2Me signals, in syn-(142). Also the aromatic protons in the syn are distinctly shielded relative to the anti isomer (Table 7). Support of the isomer assignment comes from the magnitudes of the vicinal H,H coupling constants in the cyclophane bridges. Ideally, the vicinal CH
bonds in the bridges form a staggered (143A) and an eclipsed conformation (143B) in the anti and the syn isomers, respectively. Hence, in the anti isomer one of the four vicinal coupling constants should be large (for the anti orientation of CH bonds) and three should be small (for the gauche orientations). In contrast, the syn isomer should show two large (eclipsed orientation) and two small (gauche orientation) vicinal couplings as borne out by experiment (Table 7). The coupling constant criterion was also applied to prove the anti structure of (144) and (145). Conrmatory evidence comes from the
Table 7 1 H NMR chemical shifts d and H,H coupling constants J(H,H) [Hz] in the isomers of (142) anti-(142) syn-(142) 3.48, 3.46 3.81, 3.79 7.08, 5.94 4.21 3.42 2.80 2.50 13.1 9.6 3.7 5.1 9.5 12.8
d (OMe) d (CO2Me) d (H-aryl) d (H-1) a d (H-2) d (H-3) d (H-4) J(H-1,H-2) J(H-1,H-3) J(H-1,H-4) J(H-2,H-3) J(H-2,H-4) J(H-3,H-4)
3.79, 2.84 3.92, 3.37 7.85, 6.63 3.70 3.05 2.59 2.72 12.3 12.0 5.5 5.4 2.1 12.0
a For the numbering of the bridge protons, cf. formulae (143a) and (143b).
76

15 17 13
3.92
4.26
4 6
(146) H
6.41 6.62 3.13
(147)
2.93
3 5
H H
6.63
(148)
(149)
(150), X = Y = CH 3 (151), X = CH 3, Y = CHO (152), X = Y = CHO
chemical shifts of the intraannular proton(s) in these two compounds: d 4:39 and 4.14, respectively. The anion of [2.2](4,6)indenometacyclophane (146) was investigated by 1H NMR in order to probe through-space charge transfer from the indenide moiety to the benzene ring [116]. A comparison of the chemical shifts of H-13,14,15 in (146) with those of the neutral 4-H-indenophane (147) or its 6-H isomer shows that the shifts are in the normal range for aromatic protons d 7:37:0 in both the anion and the reference compounds. Thus, charge transfer does not take place. However, H-17 experiences increased shielding d 3:92 in (146) relative to (147) and its isomer (d 4:26 and 4.22, respectively). This demonstrates the increased diatropicity of the indenide anion with respect to its indene precursors. Syn-[2.2]metacyclophanes without internal substituents are not stable at room temperature. The parent compound (148) was described by Mitchell et al. only in 1985 [117]. It was prepared at 45C and its 1H chemical shifts were determined at 30C. The external protons, H-4/6/12/14 and H-5/13, are shielded by 0.620.65 ppm relative to the anti isomer (149) by the opposite aromatic ring. H-8/16 is only shielded by 0.3 ppm relative to H-2 of m-xylene, probably due to a superimposed steric deshielding of the internal hydrogens. The syn isomer rapidly isomerizes to anti above 0C. Kinetic parameters for the syn ! anti isomerization were disclosed later, in a conference
lecture [118] and a full paper [119]. Due to the scarcity of material, only three runs of kinetic measurements (at 10, 20, and 30C) could be carried out. They led to DH 74:5 ^ 4:6 kJ mol1 ; DS 32 ^ 16 J K1 mol1 ; and DG 298 K 84:1 kJ mol1 : Cr(CO)3-complexation of one of the aromatic rings raises the barriers by about 17 kJ mol 1. The later paper also contains the 1H and 13C NMR chemical shifts of a fair number of other syn- and anti-[2.2]metacyclophanes, mostly synthetic intermediates, i.e. mono- or bis-Cr(CO)3 complexed phanes and/or those carrying SCH3 substituents at the bridges. A 13C NMR spectrum of the parent syn-[2.2]metacyclophane (148) could not be obtained, but spectra of derivatives showed that the internal C-8/C-16 have similar low-eld shifts dC 135 as their counterparts in the anti series. In fact, shortly afterwards the 5,13-dimethyl isomer (150) was reported [120] which shows dC-8=C-16 136:2: Assuming the para-SCS of a methyl group to be about 3 ppm, this translates into dC-8=C -16 139 for (148). Activation parameters for the syn ! anti isomerization were also reported for (150), DH 81:2 kJ mol1 ; DS 36:4 J K1 mol1 ; and DG 298 K 94:6 kJ mol1 : The differences between (148) and (150) are probably not signicant because of the experimental errors involved. Later, Ito et al. repeated the determination of the activation parameters of (150) and also determined those of

4.61
77
Ph Ph
4.68
7.05
Ph Ph
4.39
Ph Ph
6.58
4.56
Ph Ph Ph Ph
4.42 4.42
4.73 7.33
Ph Ph
4.44 6.82 6.79 6.50 6.88 6.77
6.54 6.67
(153)
(154)
(155)
(156)
(157)
(158)
(151) and (152) by following the syn ! anti interconversion kinetics in the 1H NMR spectra at four temperatures (15, 20, 25, and 30C) [121]. If transannular p p interaction contributes signicantly to the stability of the syn conformers, (151) should have the largest energy of activation for ring ipping. The results show that this is not the case. Instead, the following order was found (DH in kJ mol 1, DS in J K 1 mol 1, and DG in kJ mol 1, at 25C): (150s) ! (150a): 85.5, 16.3, 90.4; (151s) ! (151a): 89.9, 6.2, 91.8; (152s) ! (152a): 94.6, 5.1, 93.1. Three isomeric syn-[2.2]metacyclophanes (153) (155) were obtained in a 50:45:5 ratio by photochemical cyclodimerization of 1,3-distyrylbenzene [122]. Their structures were derived from the symmetry of their 1H and 13C NMR spectra and from the NOEs observed between aromatic and cyclobutane protons. The important 1H shifts are given with the formulae. The syn-conguration followed from the upeld shifts of the outer cyclophane protons and from the missing upeld shift of the internal protons. The internal proton in (155) is particularly deshielded due to steric interactions from both sides. Analogous compounds in which the phenyl substituents of (153)(155) are replaced by 2-naphthyl and methoxycarbonyl groups, respectively, were reported later [123]. Nishimuras group derived the structures of (156)(158) [124], the phenyl-free analogues of (153)(155), by the same techniques as used in Ref. [122]. The rst [2.2]metacyclophanes containing a single gtles heteroatom in the bridges were prepared by Vo group, viz. 1-oxa- (159) and 1-thia[2.2]metacyclo-
phane (160) [125,126] as well as 1-tosyl-1aza[2.2]metacyclophane (161) [127]. All of these are characterized by strongly shielded intraannular protons and hence possess the anti conformation: dH 4:46 and 3.86 in (159), dH 4:85 and 4.32 in (160) and dH 4:34 (H-16) and 4.13 (H-8) in (161). The value of 3.86 in (159) is attributed by the reviewer to H-16 by comparison with the data of different isomeric 1-oxa[2.2]metacyclopyridinophanes to be discussed in Section 3.8. This enormous shielding was explained by the authors as being due to the tight bridging of the molecule (probably on account of the shorter CO with respect to CC bond lengths). However, the mesomeric substituent effect of the oxygen upon the chemical shift of its ortho-Hi must not be overlooked. Inspection of the 1H NMR data of 1-oxa-10-thia[2.2]metacyclophane (162) and its diagonal 1-oxa-9-thia counterpart (163) shows that the sulphur atom of the bridge deshields its orthoproton, so in (162) the upeld shift by the oxygen is cancelled by the sulphur atom [128]. An even slightly larger high-eld shift than in (159) was observed in 1,10-diaza[2.2]metacyclophane (164) [129]. Of the two chemical shifts for the intraannular protons at d 4:41 and 3.81, the latter is probably due to H-16. Here also, the ()-M effect of the amino groups should contribute to the shielding, in addition to the tight clamping of the m-phenylene rings invoked by the authors. Takimiya et al. [130] described the diagonally 1,9-dithiasubstituted [2.2]metacyclophane (165). Its intraannular protons absorb at dH 4:90; hence it is anti. The AB spectrum of the CH2 protons (d 3:93 and 3.36,
78
16
4.44* 4.52*
O
5.08
3.93
HN S
3.81 4.41
NH
(159), X = O (160), X = S (161), X = NTs
(162)
(163)
(164)
4.90
S S
16
NTs
(165) R a: H b: Me c: OMe R
(166) R R g: SO 2Me d: SMe h: OCH 2CH=CH 2 e: CN f: CO 2Me i: tBu k: Ph
N O2S
16
NTs
16
NTs
16
NTs
N+ O
16
NTs
(167) R a: Me b: CN
(168) R a: Me b: tBu
(169)
(170)
J 12:2 Hz) do not change up to 170C, indicating difcult ring inversion. The intraannular protons of 8-substituted N-tosyl-1thia-10-aza[2.2]metacyclophanes (166a k), of the Sdioxides (167a b), and of the 5-substituted analogues (168a b) show chemical shifts in the region d 3:784:77 [131]. This proves that these compounds are present in the anti conformation. The t-butyl derivative (166i) possesses the most shielded aromatic hydrogen of all because the repulsive interaction between the bulky substituent and the opposite
benzene ring causes a mutual tilt of the two rings which forces H-16 into the p-cloud of the ring carrying the t-butyl group. This shifts the resonance of H16 in (166i) to d 3:78; cf. the analogous situation in t-butyl[2.2]metacyclophane described earlier. The methyl derivative has only d 4:16: In the latter compound, the methyl protons are shielded to d 0:64: The t-butyl hydrogens in (166i) might be expected to be even more shielded, but d (t-Bu) is only 0.78 because of rotational averaging of the three t-butyl methyl groups. Cooling the sample to
79
70C does not slow down t-butyl rotation on the NMR time scale. The 1H spectrum of the O-allyl derivative (166h) shows decreasing upeld shifts of the substituent hydrogens relative to allyl-2,6-bis(bromomethyl)phenyl ether as one goes outwards from the point of attachment of the substituent. Thus, the CH2 protons in (166h) are shielded by 0.8 ppm, the geminal and cis olenic protons by 0.6 ppm and the trans olenic proton by 0.3 ppm. In the phenyl compound (166k) the anti conformation could not be deduced from the upeld shift of H-16 because such a shift is also to be expected for the syn conformer where Hi lies above the phenyl ring. Instead, the anti conformation is indicated by the high-eld shifts (d 5:33 and 6.46) of the o,o 0 -protons of the phenyl ring which rotates slowly at room temperature. Coalescence of the o- and o 0 -proton signals gave DG 47C 64 kJ mol1 : The paper also included the H-16 chemical shifts in the pyridine analogue (169) d 4:94 and its N-oxide (170) d 5:82: In the series of [2.2]metacyclophanes (171)(173) [132] the rst and third compounds possess the anti conformation as clearly indicated by strong shielding of their intraannular protons Hi: dH 4:66 and 5.36 (Hi ortho to S) (171), dH 4:10 and 4.19 in (173), yet the azadithia element combination in (172) favours the syn arrangement. No high-eld intraannular proton signal was found for this compound. Sakurai et al. [133] prepared octamethyl-1,2,9,10tetrasila[2.2]metacyclophane (174) and reported its 1 H, 13C, and 29Si NMR chemical shifts. The intraannular protons Hi absorb at d 6:43: As there is only one 1H and one 13C signal for the SiMe groups, a fast equilibrium between two conformers probably exists. The rather high-eld shift of Hi indicates substantial participation of the anti conformer, so it is either a syn O anti or an anti O anti 0 equilibrium. The 1H chemical shifts of the aromatic protons would seem to speak for the latter. The deshielding of the intraannular proton Hi relative to anti-[2.2]metacyclophane (149) can be explained partly by the longer SiSi and SiC bond lengths compared to those of CC bonds. They diminish the effect of the ring current of the opposite aromatic ring on d (Hi). (Preceding interpretations by the reviewer.) Tetrasilaphane (174) was also studied by Nishiyama and Sugawara [134] who additionally investigated the trisila compound (175) and the three
Table 8 Free energies of activation for the inversion of the 10-membered ring in [2.2]metacyclophanes (174), (175)(178), and (149) with differing degrees of sila substitution in the bridges Compound Degree of sila substitution Tetra Tri Di Di Di Nil DG [kJ mol 1] Tc [C] 50 17 69 103 131 190
(174) (175) (176) (177) (178) (149)
51 66 75 80 113
isomeric disilaphanes (176)-(178). These authors also discussed the decreasing shielding of the intraannular proton(s) with increasing sila substitution in the bridges. However, when comparisons of chemical shifts are made, the number of silicon atoms in the ortho positions must be taken into account because of their electronic effect upon the shift of the ortho proton(s). Inversely, comparing the chemical shifts of the internal carbon atoms Ci with the same number of ortho silicon substituents, one nds increased shielding of these carbon atoms in the compounds with the higher degree of sila substitution. The larger interring distance diminishes the so-called p-orbital compression effect that had been made responsible for the downeld shifts of Ci in [2.2]metacyclophanes [57]. Concerning the conformational mobility of the sila compounds, Nishiyama and Sugawara found fast ring inversion at room temperature for (174) and (175)indicated by one 1H and one 13C signal per group of equivalent SiMe2 units and one 1H signal per group of equivalent CH2 unitsand slow inversion for the three disila compounds (176)(178). The free energies of activation, determined by the coalescence method, are given in Table 8. The lower barriers for the higher silasubstituted phanes are due to lower energies of the transition states of ring inversion because of the longer Si-containing bonds. The varying barriers for the isomeric disilaphanes were interpreted by the different degrees of Hi/Hi interaction caused by the different arrangements of longer and shorter bonds in the molecules. Swann and Boekelheide [135] studied the 1H NMR chemical shift changes which anti-[2.2]metacyclophanes undergo when one or both aromatic rings are h 6-coordinated with (cyclopentadienyl)iron(II). We
80
X Y X X (171) (172) (173) S S CH2 Y CH N CH

conformation
anti syn anti
Me2Si Me2Si
6.43
SiMe2 SiMe2
Me2Si Me2Si
6.14 5.71
SiMe2
Me2Si Me2Si
5.34
(174)
(175)
(176)
5.38
SiMe2
Me2Si
Me2Si
5.97 4.87
SiMe2
4.27
(177) (C5H5)Fe
-0.68 -0.94 +0.59 +0.17 -1.13
(178) (C5H5)Fe
-0.25 -0.89 +0.19
(149)
Me Me
+0.47
+0.10
+0.17 -0.01
(179)
(180)
report here only the monocomplexation results. These are given in formulae (179) and (180) and are to be read as complexation shift Dd d (cpFe-complex) d (hydrocarbon). The authors put their emphasis on the complexation shifts that occur in the uncoordinated ring and interpret the slight downeld shifts suffered by the protons at the outer end of the ring as being due to a decrease of electron density in the uncoordinated aromatic ring when the other ring is coordinated. The larger downeld shifts of the internal proton (or the corresponding methyl protons) of the uncoordinated ring were explained by an additional deshielding effect due to the reduced ring current in the coordinated ring.
C complexation shifts were studied by Mori and coworkers for tricarbonyl(h 6-[2.2]cyclophane)chromium [136] and (h 6-[2.2]cyclophane)(cyclopentadienyl)iron(II) hexauorophosphate [137]. Here [2.2]cyclophane stands for [2.2]meta- and for [2.2]paracyclophane. These authors compared the complexation shifts Dd d (phane complex) d (phane hydrocarbon) with the complexation shifts of model compounds such as Dd d (m-xylene complex) d (m-xylene). Examples for chromium complexation shifts are shown in (181)(184), where the signs are reversed with respect to the original literature. The differences DDd between phane
13
81
(OC)3Cr 38.7
16.6
Cr(CO) 3
25.8 32.6
(OC)3Cr 6.1
+9.2
(181)
values
(182)
values
(181)
values
Cr(CO) 3 (OC)3Cr
36.2 31.6 23.4 41.5 30.8 34.1 34.3 24.9 5.4
Cr(CO) 3
7.2
+2.5 +1.5
(183)
values
(184)
values
(183)
values
M EtO2C
Cr(CO) 3
CO2Et M Mo(CO) 3 (C6H6)Ru2+ 2BF4

1
Cr(CO) 3 (186)
(185a) (185b)
complexation shifts and model compound complexation shifts, cf. (181 0 ) and (183 0 ), were correlated with phane ring deformations which, in turn, were presumed to reect the variations in the metalligand carbon distances. Carbon atoms bent towards the outside of the phane skeleton thus have negative DDd values (i.e. stronger, more negative complexation shifts), those bent inwards have positive DDd values. Unfortunately, actual geometrical data were available only for the paracyclophane complexes. The authors conclusion was that DDd is likely to be related to orbital interaction between chromium (iron) and carbon and that this interaction should be dependent on the Cr(Fe) C distance and the orientation of the 2pz orbital axis with respect to the Cr(Fe) atom. 13C data of the Mo(CO)3-complex of [2.2]metacyclophane (185a) are described in Ref. [73], those of the ruthenium sandwich complex (185b) in Ref. [74]. Schulz et al. [138] interpreted the 13C complexation shifts of (186) along the same lines as Mori [136].
H and 13C NMR data were reported [139] for the methylated [2.2]metacyclophan-1-enes (187) and (188) and for their mono-Fe (C5H5) complexes (187-Fe) and (188-Fe), their mono-Cr(CO)3 complexes (187-Cr) and (188-Cr), and their bisCr(CO)3 complexes (187-Cr2) and (188-Cr2). The chemical shifts of the bridge hydrogens were discussed in terms of the reduction of the ring current of the adjacent ring by the complexation, of the ring current of the opposite ring, and of the magnetic anisotropy of the Cr(CO)3 group of the adjacent ring. In some cases these effects cancel each other so that no net effect is observed upon bis-complexation. The chemical shifts of the protons bound to the nonmetal-coordinated carbon atoms in bis([2.2]metacyclophane)chromium(0) (189) were used to study the spatial dependence of the coordination shift Dd d (complex) d (free ligand) [140]. A positive value above the plane of the complexed metacyclophane rings (H-4, 0.76 ppm) and negative values at their
82
L1
L1
L2
L2
(187) (187-Fe) (187-Cr) (187-Cr2)
L1 = L2 = nil L1 = Fe +(C5H5); L 2 = nil L1 = Cr(CO) 3; L 2 = nil L1 = L2 = Cr(CO) 3
(188) (188-Fe) (188-Cr) (188-Cr2)
H4 H12
1
Cr Cr
(189) H H H H
(190) H
(191)
(192)
(193)
side (hydrogens at C-1: equatorial, 0.61 ppm; axial, 0.26 ppm) are in accord with the notion of ring current reduction by complexation. A comparison of the shift difference d (H-7) d (H-4) in the free ligand (2.85 ppm) and in the complex (2.05 ppm) led to the qualitative estimate that the ring current of the complexed metacyclophane rings is reduced by about 25%. The combined effects of h 6-arene coordination and shielding by the ring current of the outer metacyclophane ring resulted in the unusual chemical shift of d 1:98 for the arene(!) proton H-12. Further
points on the map that correlates Dd values with the polar coordinates (r, r ) of protons (with respect to the centre of the coordinated arene ring) were dened by the 1H NMR spectrum of bis(h 6-[2.2.2]paracyclophane)chromium(0) (190) [141]. In metacyclophane (191), in which one ring is a cis1,4-cyclohexanediyl moiety, the most upeld shift observed is d 0:25 [142]. The authors attributed this to the bridging protons being far away from the benzene ring current cone. The same authors also reported [2.2]metacyclophanes in which one of

1 8 15 12 9
83
3 4
CHD2 (204)
(194) (195) (196) (197) (198)
X H CN NO Br CH3
2a
(199) (200) (201) (202) (203)
X CHO NO2 CH2D CHD2 CD3
1a
1s
2s
2a
1a
2s
1s
NO2
4
NO2
(200A)
1s 2a 1a 2s 2a
(200B)
1a 2s 1s
the m-phenylene rings is replaced by cis- (192) or by trans-1,3-cyclohexanediyl (193) [143]. These compounds show a number of interesting 1H NMR chemical shifts at high eld, viz. (192) at d 1:62; 0.65, and 0.24 (1 H each) and (193) at d 1:68 and 0.24 (1 H each). Unfortunately, no attempts were made to assign the spectra. 3.2. [2.2]Paracyclophanes This section will rst treat [2.2]paracyclophanes substituted at the aromatic rings, approximately in the order of increasing number of substituents, then bridge-modied derivatives, and nally anions, cations, metal complexes and partly saturated [2.2]paracyclophanes. Inspection of molecular models of [2.2]paracyclophane (194) may give the impression that the molecule is rather rigid. From the 13C-satellites in the 1H
NMR spectrum the vicinal H,H coupling constants were determined [144] to be 3 J H; Hcis 10:6 Hz and 3 J H; Htrans 4:1 Hz: These values could be due to a xed eclipsed conformation of D2h symmetry with torsional angles u [C(sp 2)C(sp 3)C(sp 3) C(sp 2)] of 0 or to an equilibrium between two conformations of D2 symmetry which are twisted away from the eclipsed form by torsional angles of a and a; respectively. When a substituent X is introduced at an aromatic position, the 3J(H,H)cis values in the orthobridge remain rather constant, but the 3J(H,H)trans values change, one value increasing (up to 7.2 Hz for X NO2) and one value decreasing (down to 1.5 Hz for X NO2) [145]. This behaviour cannot be explained by a simple change of the torsional angle of a single conformer because in this case one 3 J(H, H)cis coupling should increase and the other one should decrease. Instead, the behaviour can be explained by a shift of the equilibrium so as to favour
84
Table 9 Vicinal H,H coupling constants J(H,H) [Hz] in the ortho-bridge of monosubstituted [2.2]paracyclophanes [145] Compound Substituent J(1a,2a) J(1a,2s) J(1s,2a) J(1s,2s) (194) H 10.6 4.1 4.1 10.6 (195) (196) CN NO 10.7 2.9 4.5 10.5 10.5 2.6 5.4 10.6 (197) (198) Br CH3 10.7 2.2 6.0 10.3 10.7 2.1 6.2 10.2 (199) (200) CHO NO2 10.3 1.8 6.8 10.3 10.1 1.5 7.2 9.9
one of the skew conformers over the other, yet both conformers still equilibrating rapidly, as shown for (200A)/(200B). This averages the cis-couplings J(1a,2a) and J(1s,2s) (1 and 2 indicate the number of the carbon atom to which a proton is bound; a and s indicate its anti or syn relationship with respect to the substituent at C-4) over the torsional angles a and a , so their averages are more or less independent of the conformer populations because the Karplus function is symmetrical with respect to 0. The trans-couplings behave differently. They are averaged over the torsional angles 120 a and 120 a: Hence, if one conformer is preferred over the other, e.g. population p(200B) p(200A), J(1a,2s) will decrease relative to its value in [2.2]paracyclophane because 3J(H,H) decreases from u 120 towards u 90 and J(1s,2a) will increase because 3 J(H,H) increases from u 120 towards higher values. This is indeed what is observed: the bigger the substituent, the larger J(1s,2a) and the smaller J(1a,2s) (Table 9), i.e. the more strongly conformer B is preferred over conformer A. Molecular mechanics computations indicate that the main reason for the increased preference of B with increasing size of the substituent is the unfavourable interaction in A of the substituent at C-4 with H-2s, which lies approximately in the plane of the aromatic ring. The 13 C-NMR spectra of (195)(200) have also been completely assigned [145]. 4-Methyl[2.2]paracyclophane, mono- through trideuteriated in the methyl group [(201)(203)], was the rst example for which a through-space deuterium isotope effect upon 13C chemical shifts could be demonstrated [146]. The chemical shift of C-15, the carbon atom pseudo-geminal with respect to the CHnD3n group, is increased by 12 ppb (0.012 ppm) per deuteron in the methyl group. This is particularly
interesting as deuterium isotope effects are usually expected to be shielding and not deshielding. A possible inuence of the deuteration upon an existing conformational equilibrium in 4-methyl[2.2]paracyclophane could be ruled out by studying the CHD2 derivative (204) of the rigid [24](1,2,4,5)cyclophane which showed an even slightly larger isotope effect of 30 ppb on the chemical shift of the pseudo-geminal carbon, i.e. 15 ppb per deuteron. As monosubstituted [2.2]paracyclophanes are chiral, molecules containing two [2.2]paracyclophanyl moieties bound, for example, to a common atom Z can exist as a meso-diastereomer (R-pc)-Z-(S-pc) with heterochiral paracyclophanyl (pc) groups or as a pair of chiral enantiomers in which the paracyclophanyl groups are homochiral, (R-pc)-Z-(R-pc) and (S-pc)-Z-(S-pc). Bis([2.2]paracyclophan-4yl)methane (205), Z CH2, and the analogues with Z CO (206), SiMe2 (207), S (208) and P(O)(OMe) (209) were investigated by Ernst and Wittkowski [147], mainly with the aim of determining the differences in chemical shifts between the diastereomers. Generally rather small shift differences were found DdH 0:3 ppm; DdC 1:0 ppm; with somewhat larger ones only for some protons in the ketones (206). These were interpreted as due to the different preferred orientations in the diastereomers of these protons with respect to the magnetically anisotropic carbonyl group. When suitable ligands (H or Me) are bound to the central atom, the chiral diastereomers can easily be distinguished from the meso-isomers because the former have a twofold axis of symmetry rendering the ligands chemically equivalent (single line absorptions for the protons of the central CH2 group in (205), dH 3:58; and for the methyl protons and carbons in (207), dH 0:79; dC 1:09). In the meso-isomers these ligands lie in a plane of symmetry which does not render them equivalent, hence meso(205) gives an AX system (dH 3:85 and 3.27; J 15:9 Hz) for its central methylene group and meso-(207) gives two 1H lines (dH 0:79 and 0.57) and two 13C signals (dC 1:86 and 0.56) for its SiMe2 group. Compound (209) is interesting because it possesses a pseudoasymmetric phosphorus atom. There are two meso-diastereomers with r- and s-congurations, respectively, of the phosphorus centre each giving a set of 16 13C signals for the paracyclophanyl groups which are enantiomorphic. By way of contrast,
85
R S
4
Z S
Z (205) CH2 (206) C=O (207) SiMe2 (208) S
Z S
chiral
meso
OMe O S
4
O R P OMe
P
4
OMe
chiral
meso-1 (209) O
5 17
meso-2
H O
(210)
the homomorphic paracyclophanyl groups in the chiral diastereomer of (209) are diastereotopic and thus give rise to 32 paracyclophanyl 13C signals with shift differences of up to 1.85 ppm (for C-4) between corresponding carbon nuclei in the two ligands. Rozenberg et al. described diastereomeric (chiral and meso) b-diketones containing two paracyclophanyl groups [148]. These are present as the enolic chelates (210). The differences between the 1 H NMR chemical shifts of the diastereomers are rather small (Dd 0:05; 0.03, and 0.02 for OH, H5, and H-17, respectively) because of the large separation of the chiral subunits.
Reich and Yelm [149] prepared the diastereomeric paracyclophanyl tolyl sulfoxides (211) and (212) and established their congurations chemically. This allowed them to determine the preferred conformations of the sulfoxide groups from the chemical shifts of their surrounding protons, i.e. the ortho (H-5) and pseudo-gem (H-15) protons and the syn proton (H-2s) at the ortho bridge. It was assumed that proximity of the sulfoxide oxygen caused deshielding. As indicated by a deshielded H-5 in (211) and a deshielded H-2s in (212), the sulfoxide oxygen is pointing towards these hydrogens and, consequently, the sulfur lone pair of electrons towards the second cyclophane ring. This is
86
6.97
6.80
H
7.12
S O (211)
3.50
H H
H
6.58
H H O
Tol
S Tol (212)
3.85
Se O (213)
H H
< 3.6 2.69
Se Me (214)
15
H H
4.08
Me
2.40
16
16
15
H
R
Et OR OH
H 1 H 2 O
Hs Hs H H3 C
H
5
H H 4 O Et
1 2
Hs Hs
H H3 C
O CH3
CH H
O CH3
H3 C
(215), R = iPr (216), R = Me
(215a), major, (R,R)
(215b), minor, (R,S)
reasonable in view of the small steric requirement of the lone pair. Assuming analogous conformations for the related selenium compounds (213) and (214), their relative congurations were suggested to be those shown in the formulae. H,H-NOESY was used to determine the congurations of the asymmetric centres in diastereomers (215a) and (215b) with known (R)-conguration of the [2.2]paracyclophanyl moiety [150]. Signicant NOEs found in the major but not in the minor diastereomer are those between H a and one of the i-Pr methyl groups and between H b and 2-Hs. By contrast, the minor diastereomer shows NOEs from the hydroxyl proton to H-15 and H-16, from H a to the synprotons 1-Hs and 2-Hs of the adjacent bridge and also from H a to H-15. If one supposes that the bulky ethyl group tends to avoid the opposite paracyclophane ring (as AM1 computations indicate), then the NOE results lead to the congurations shown in the formulae, i.e. (R,R) for the major (215a) and (R,S) for the minor diastereomer (215b). Some regularities
were found for the relative 1H chemical shifts of the diastereomers of (215) and (216). Protons 15 and 16 are deshielded by 0.4 ppm and 2-Hs by 0.7 ppm in the (R,S)- relative to the (R,R)-isomers. In the (R,S)isomers where intramolecular hydrogen bonding is facile, the hydroxyl proton is deshielded (d 5:04:5 in C6D6) and spin-coupled to H a (J 6:2 Hz) whereas it has a broad singlet at d 1:6 in the (R,R)-isomers. Ernst [151] has detailed a procedure for determining the congurations of the isomeric [2.2]paracyclophanes with two identical substituents, one at each ring, taking the dimethyl [2.2]paracyclophanear,ar 0 -dicarboxylates (217)(220) as the example. The symmetries of the bridge-proton spin systems put the isomers into two groups. In the pseudo-gem (217) and pseudo-meta (219) isomers the two bridges are different, furnishing an AA 0 XX 0 spectrum for the bridge anked by two substituents and a YY 0 ZZ 0 spectrum for the bridge distant from the substituents. So there are two different spin systems with two
87
X
1
A R
15
X
2 8
A R
5 9
A R
12 10
R Y Z A (218)
pseudo-ortho
Z Y (217)
pseudo-geminal
A R
A R
A R
5
16
R Y Z Z Y A Z X Y (221)
(219)
pseudo-meta
(220)
pseudo-para
R = CO 2CH3
R1 R
pseudo-geminal
2
R1 R2 R1 NO2 NO2 NH2 R2 CO2Me CO2H CO2H

pseudo-ortho
(222a) (222b) (222c)
(223a) (223b) (223c)
chemical shifts each. In the pseudo-ortho (218) and pseudo-para (220) isomers the two bridges are in equivalent environments but the four protons of a bridge are chemically nonequivalent giving one AXYZ spectrum. These two possible situations can be clearly distinguished in an H,H-COSY spectrum. The spacings of the intense N lines J AX J AX 0 in the AA 0 XX 0 coupling patterns of the pseudo-gem and the pseudo-meta isomers are characteristically different. In the former, the spacing corresponds to the sum of 2J (ca. 13 Hz) and 3Jtrans (ca. 4 Hz) and in the latter to 2J (ca. 13 Hz) 3Jcis (ca. 10.5 Hz); J values from Ref. [145]. Hence, N values of 9 and 2.5 Hz are expected for (217) and (219), respec-
tively, the experimental ndings being 8.8 and 3.0 Hz. The distinction between (218) and (220) is somewhat more elaborate. It can either be achieved by irradiating the resonance of H-5 (d, J 2 Hz) in (220) and observing a NOE at the signal of H-16 (d, J 8 Hz) or the bridge AXYZ spectrum must be analysed rst (A and Z being the protons at C-2, syn and anti, respectively, relative to the substituent at C-4) and the spatial relationship between protons X, Y and those (or their connected carbon nuclei) of the second benzene ring must be determined by a long-range H,H-COSY or a C,H-COLOC or -HMBC experiment. The procedure is based on the larger H,H coupling of an aromatic proton with the syn-benzylic proton of its
88
ortho-bridge than with the anti-proton and on the larger transoid C,H-coupling of an aromatic carbon atom with the anti-benzylic proton at the ortho-bridge than the cisoid coupling with the syn-proton; see ref. [151] for details. Much earlier, Reich and Cram [152] have distinguished ar,ar 0 -disubstituted isomers of [2.2]paracyclophanes, e.g. the dibromo derivatives, by comparing the experimental chemical shifts and those predicted by assuming additivity of the substituent effects determined from the monosubstituted derivative. This procedure requires, however, that the monosubstituted derivative is available, that its NMR spectrum of the aromatic protons can be analysed and that the transannular substituent effects on the chemical shifts (SCS) are sufciently different (normally: pseudo-gem-SCS q other SCS). This is the case in the bromo derivative (197) [152] but not in the methyl ester (221) [151]. Pelter and coworkers [153] also derived substituent effects (CO2Me, CO2H, NO2, NH2) upon the 1H chemical shifts of [2.2]paracyclophane. Assuming additivity of the effects, they used them to elucidate the stereochemistry of the pseudo-geminal and pseudo-ortho disubstituted derivatives (222) and (223), respectively. Some of the substituent effects were corrected later [154]. In a paper on the synthesis of mono- and diaryl[2.2]paracyclophanes [155], the 1H NMR data of 4-mesityl[2.2]paracyclophane (224) and two dimesityl[2.2]paracyclophanes were reported. Rotation of the mesityl rings is restricted at room temperature, leading to a spectrum with three different methyl signals [d 2:82; 2.36, and 1.80 for (224)] and two signals for the aromatic protons (d 7:08 and 6.68). Unfortunately, no attempts were made to specically assign these chemical shifts although it is clear that the middle methyl shift must belong to the para [156] also methyl group. At the same time, Kus described a number of aryl-[2.2]paracyclophanes, among them (225) and (226). Examination of CPK molecular models suggests that the preferred torsional angle between the aryl and its connected cyclophane ring, dened by the asterisks in formula (225), should be of the order of 4050. Then the exo-methyl group (a) of (224) and (225) resides in the shielding zone of the cyclophane system as shown by the upeld shifts in (224) and (225) of d 1:80 and 1.82, respectively. The endo-methyl group (b) resides at the side of the
paracyclophane unit. This area is the deshielding zone and the endo-methyl protons are shifted to d 2:82 and 2.84 in (224) and (225), respectively. As the methyl group of 2-methylnaphth-1-yl derivative (226) has a shift d 1:99 similar to the exo-methyl groups of the xylyl and mesityl compounds, it is presumably also oriented exo and, hence, the hydrogen in position 8 of the naphthalene moiety should be deshielded beyond the shift of H-8 in 1 reported the phenylnaphthalene (d 7:9 [157]). Kus shift of a single aromatic proton of (226) to be d 8:86; while all the others are in the range d 7:826:37; and he attributed the single low-eld resonance to an unspecied cyclophane proton. However, for the reason given above, this signal should be assigned to H-8 of the naphthyl group and it is not conceivable that one of the cyclophane protons should be deshielded so strongly. In a study directed toward the synthesis of orthodialkylated [2.2]paracyclophanes [158], compound (227) was obtained and its 1H and 13C NMR spectra were fully assigned by the use of 2D H,H-COSY, C,H-HETCOR, and C,H-COLOC techniques. The conguration at C-1 was determined from a phasesensitive NOESY spectrum in which a strong crosspeak between the chemical shifts of H-1 and H-15 was observed. NMR data of sulfonated [2.2]paracyclophanes were reported by van Lindert et al. [159], viz. the 1H chemical shifts of the 4-sulfonic acid (228), of the pseudogeminal (4,15), pseudo-ortho (4,16), pseudo-meta (4,13), and pseudo-para (4,12) disulfonic acids (229) and disulfonates (230), and the pseudo-geminal disulfonic anhydride (231). For the latter compound, the pseudo-geminal disulfonates (230), and the monosulfonic acid (228), the 13C chemical shifts and assignments are also given and the J(H,H) coupling constants in the bridges are tabulated for the pseudogeminal isomer of (230) and for (231). 1H and 13C chemical shifts were also assigned in the N-substituted disulfonimides (232) with alkyl, cycloalkyl, allyl, benzyl and aryl substituents [160]. Rotation of the phenyl ring about the CN bond in the N-phenyl derivative is restricted at room temperature which leads to different chemical shifts of the ortho-protons (d 8:50 and 7.94 at 50C). From signal coalescence at 80C, DG was determined to be 71 kJ mol 1. The N-cyclohexyl derivative shows

(a) (a)
89
H3C *
(b)
H3C
R
1
* H3C
O CH3
15
H (226) (227)
(224), R = CH 3 (225), R = H R
12 13 15 16
O2 S O R S O2 (231)
O2 S NR S O2 (232), R = alky, aryl
SO3H
(228)
(229), R = SO 3H (230), R = SO 3K+
3.02 3.19 2.98
3.83
H
7.63
H
6.75 5.86 6.93 5.24
7.70
6.53 6.51
7.86 8.51 7.52 7.53
H
2.91
2.77
3.37
4.32
(233)
slow rotation below 0C when the AA 0 XX 0 spectrum of the ethano bridge next to the disulfonimide bridge turns into an ABCD spectrum. The preferred conformation of the cyclohexyl system was assumed to have the cyclohexane plane parallel to the planes of the benzene rings in the paracyclophane moiety. [2.2](1,4)Phenanthrenoparacyclophane (233) was the rst unsymmetrical [2.2]paracyclophane derivative for which the spin systems of both CH2CH2 bridges were completely analysed [161]. This was facilitated by the wide spread of the chemical shifts dH 4:322:77 of the bridge protons. The chemical shifts of the aromatic protons are also distributed over a wide range dH 8:515:24 which is due to the different orientations of these protons with respect to the ring currents of the phenanthrene and benzene systems. A rough correlation was demonstrated
between the 1H chemical shift differences of (233) and [2.2]paracyclophane (194) and the ring current effects predicted by the JohnsonBovey model [79] for annelating the outer two phenanthrene rings to (194). Possible reasons for the less-than-perfect correlation were discussed. NOE difference and 2D H,HCOSY experiments helped in the complete assignment of the 1H NMR spectrum of (233) and the 13C spectrum was also fully assigned by the use of 2D one-bond and long-range C,H-correlation spectra. An unexpected feature in the 1H spectrum is an H,H-coupling of 0.6 Hz between the bay proton of the outer phenanthrene ring and the syn-proton of the bay methylene group at the bridged phenanthrene ring. These protons are xed at a very small nonbonding distance, and a through-space mechanism for this coupling was assumed.
90
Br
Br
Br
Br
Br Br (234) (235)
6.84
Br
Br Br (236)
3.07
F
2.98
F (237)
F
trans
H MeO
H MeO Cl R OMe
H H R Cl OMe MeO H
syn
syn
H R
MeO OMe R Cl H H
OMe
Cl H H
H (238a)
H H R = (CH 2)4C6H4(2-CO2Me) H
17 1 2
H (238b)
H3COCO CO2CH3
1 2 17
(E)-(239)
(Z)-(239)
The structures of the rst three ar,ar,ar 0 -tribromo[2.2]paracyclophanes (234)(236) [162] were derived from the J(H,H) values in the dibrominated ring and the substituent effects of the bromine atoms upon the chemical shifts of their pseudo-geminal protons. The assignments were conrmed by the observation of interring H,H-NOEs. Filler et al. [163], in a discussion of the 1H and 19F NMR spectra of 4,5,7,8-tetrauoro[2.2]paracyclophane (237), withdrew their earlier suggestion [164] that the quintet splitting with an apparent coupling constant of 0.8 Hz, observed for the aromatic proton signal at d 6:84; is caused by transannular through-space 19F, 1H
spinspin coupling. Instead, they reported that irradiation of the CH2 resonance at d 3:07 caused the aromatic proton signal to collapse to a singlet. This suggests that the observed coupling is a benzylic one, viz. an average of the coupling of one aromatic proton with two ortho-benzylic and two meta-benzylic protons, one arranged syn, the other anti in each group. In the authors opinion, however, the nature of the interaction is unclear. On the other hand, the authors original interpretation of the quintet splitting would have been very reasonable because throughspace coupling between uorine and the pseudogeminal proton in 4-uoro[2.2]paracyclophane
L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190 Table 10 Some NMR spectroscopic parameters of the isomers of (239) Isomer (E)-(239) 42.29 4.33 6.17 3.83 1% (Z)-(239) 45.95 3.89 6.10 3.64 6%
91
d (C-2) d (H-2) d (H-17) d (OCH3) NOE (H-2 ! H-17)
amounts to 3.1 Hz [165], so the splitting caused by four chemically equivalent but magnetically nonequivalent uorines, of which three have a zero coupling constant would be expected to be a quintet with a spacing of 3:1 0 0 0=4 0:8 Hz as found experimentally. A clarication of this matter seems desirable. Section 3.9 treats compounds in which through-space 19 19 F, F spinspin coupling has been observed, e.g. an ar,ar 0 -diuoro[2.2] paracyclophane. Fischer et al. [166] described the structural elucidation of a fully ring-substituted synthetic [2.2]paracyclophane derivative. The possible isomeric structures were (238a) and (238b) and only one isomer is present. The correct structure was proved by relating each methoxy group, through H,H-NOE and C,HHMBC correlations, with the syn proton of its neighbouring bridge CH2 group. These two syn protons were shown to have a trans orientation. This followed from their mutual coupling constant of 6.5 Hz, which was extracted from a phase-sensitive H,H-COSY spectrum. Consequently, the methoxy groups of the different rings are pseudo-meta to one another as in (238b). Due to the particular geometry of the semicyclic double bond in the isomers (239), these compounds may be regarded as perpendicular styrene derivatives [167]. Their congurations follow from the large (6%) NOE observed at H-17 of the (Z)-isomer when the resonance of H-2 was saturated. The corresponding enhancement in the (E)-isomer is only 1%. Characteristic 13C and 1H chemical shift differences are present between the isomers (Table 10). The upeld shift of the ester protons in (Z)-(239) was attributed to the possibility of its location in the shielding region of the upper aromatic ring. 1 H and 19F NMR spectra of ring-monosubstituted 1,1,2,2,9,9,10,10-octauoro[2.2]paracyclophanes (OFPs) (240) were described by Roche and Dolbier [168]. The parent OFP (240, R H) has dH 7:30
and dF 118:0: Substitution of an aromatic proton destroys all symmetry and renders the eight uorines and the seven remaining protons chemically nonequivalent. Derivatives with the following substituents R were studied: NO2, NH2, NHOH, NHAc, NHCOCF3, OH, Cl, Br, I, Ph, and CF3. All uorine nuclei are generally shifted downeld by the substitution but in a rather unsystematic manner. The overall shift range is approximately dF 100 to 120 but the assignments of most of the 19F shifts to specic uorines are still due. The 19F spectra are governed by the large 2 J(F,F) values of ca. 240 Hz. As the 3J(F,F) are rather small, a typical 19F spectrum of a monosubstituted OFP contains four AB-type absorptions. The inuences of the substituents on the 1H chemical shifts are not equal but similar to the effects known from the corresponding derivatives of [2.2]paracyclophane (194) [145,152]. The triuoromethyl derivative (240, R CF3) is of interest because the CF3 group causes through-space coupling (quartet splittings) at one of the bridge uorines (assigned as F-2syn) with 29.1 Hz and at a second one (assigned as F-1syn) with 12.1 Hz. Further work by the same authors [169] treats heteroannularly disubstituted OFPs (241) (i.e. one substituent per ring), mainly with equal substituents.
F
1
F
2
Fsyn R R
F R
F (241)
(240)
SiMe2 Me2Si
SiMe2 Me2Si (242)
The pseudo-ortho, pseudo-meta, and pseudo-para isomers were available of (241) with R NO2, NH2,
92
Br, I, and CF3, also the para isomers with R Br and CF3. As an NH2 substituent causes the largest spread in the 1H chemical shifts of OFP, the NH2-SCS values derived [168] could be used to conrm the stereochemistry of the isomers of (241, R NH2) from their 1H NMR spectra. In analogy to (240, R CF3), the uorines in the bridges ortho to CF3 in the four isomers of (241, R CF3) mentioned above were assigned from the through-space coupling of CF3 with the proximate bridge uorines and from the geminal relationship of each of the latter with one of the remaining uorine nuclei. The information obtained from these isomers and from the ortho bridge in the monosubstituted compound together with the assumption of SCS additivity allowed the backward calculation of the missing SCS values of CF3 upon the 19 F chemical shifts in OFP.
(243) 4
1.4 22.9
7.7
22.3 +5.6 13.8 48.2 +0.3 7.6 6.4
0.3 15.2
(244), C values
21.7 +5.0 17.6 45.6 11.6 +2.0 7.3
1.6 22.3
6.4
0.3 14.8
(245), C values
Sakurai and coworkers [170] reported 1H, 13C, and Si chemical shifts for a tetrasila analogue of [2.2]paracyclophane, viz. octamethyl-1,2,9,10-tetrasi29
la[2.2]paracyclophane (242). The aromatic protons of this compound d 6:75 are not as strongly shielded as those of [2.2]paracyclophane d 6:48: It would seem logical to attribute this effect mainly to the larger interring distances, which are a consequence of the longer SiSi and SiC relative to CC bonds. However, the electronic effects of the silicon containing groups upon the chemical shifts of the aromatic protons must not be neglected either. Tetrastyryl[2.2]paracyclophane (243) was reduced with Li, Na, and K metals and shown to be converted into its tetraanion from the sum of the induced 13C chemical shift changes, SDd 560 ppm Dd d anion dparent ; i.e. ca. 140 ppm per electron [171]. The 1H and 13C NMR spectra were fully assigned by 2D methods. Nonequivalence of the ortho and of the meta positions of the terminal phenyl rings and a small 3J(H,H) value of 12.3 Hz for the double bond point to substantial charge delocalization, causing bond order decrease and increase of C2 0 C3 0 and C1 0 C2 0 , respectively. The Dd C values given with formula (244) are averages for the Li , Na , and K salts and indicate that the charge is distributed over the entire molecule with the highest charge densities on C-2 0 and at the para and ortho positions of the phenyl groups. Dianion (245), in the form of its Li salt, was used as a reference compound. Its NMR properties are very similar to those of (244), yet the charge densities on the central ring are slightly higher at the expense of the double bonds and phenyl rings. This difference was attributed to through-space interaction of the electrons in the cyclophane system of (244) which causes the charges to shift to the periphery of the molecule. Treatment of [2.2]paracyclophane (194) with FSO3H/SO2ClF at 80C gives the monoarenium ion (246) [172]. Protonation occurs only at the ipso carbon atom. This releases bond angle strain and contrasts with methylsubstituted benzenes that are protonated at unsubstituted positions. The hydrogens in the protonated ring are more highly shielded than the hydrogens of analogous methylbenzenium ions and the hydrogens of the nonprotonated ring are deshielded relative to the parent hydrocarbon (194). Possible reasons are charge transfer and alterations in the magnetic anisotropies of the ring systems. When (194) was treated with FSO3H/SbF5 in SO2ClF at 100C, diarenium ion (247) was formed. The

4.07 4.94 2.88
4
93
H
8.22 7.59 3.63
4 3
H +
3
3.22
3.48
13 7.19 12
3.47
14
11
8.07 9.32
6.86 3.63
H (246) H values (247)

3.45
H
178.3 55.5 142.9 197.4 146.3* 132.4** 147.1* 133.3** 129.6 139.1 6.84
H
181.6 58.7 138.9 200.0
+ F F
138.1
118.8
7.77 7.05 122.1* 135.2** 146.9
F
146.4
F
118.7*
137.1**
(246) C values
(237)
(248)
H, C, and F values
structure was assumed to be the 3,11-diprotonated compound because molecular models showed this to be much less strained than the 3,14-isomer. The latter was, however, not excluded experimentally. The 4methyl and 4,5,12,13-tetramethyl derivatives of (246) and (247) were also investigated and shown to possess analogous structures. In the monomethyl derivative, protonation of the substituted ring occurs at the bridgehead carbon next to the methyl group. In the 13C spectrum of (246), studied by Laali and Filler [173], ipso-protonation led to large deshielding effects at the carbon atoms ortho (45 ppm) and para (58 ppm) to the protonation site. The meta carbon (10 ppm) of the protonated and the bridgehead carbon atoms (ca. 78 ppm) of the nonprotonated ring are also signicantly shifted, see formula (246 0 ). 4,5,7,8-Tetrauoro[2.2]paracyclophane (237) could only be converted to the monoarenium ion (248). It is protonated at the nonuorinated phenylene ring. The effects of protonation upon the 13C shifts of the nonuorinated ring (o, 52; m, 9; p, 61 ppm) are of the same order as in (246), but those upon the 1H shifts (o, 0.9; m, 0.2 ppm) are much smaller than in (246), where they amount to 1.8 ppm (o) and 1.1 ppm (m) [172]. The smaller effects in (248) were tentatively ascribed to transannular interaction (electron
donation) from the uorinated to the cationic nonuorinated aromatic ring. The 19F nuclei (assignment uncertain) in (248) are deshielded by only 1 and 3 ppm relative to (237). The site(s) of complexation in various tricarbonylchromium complexes of 4-aryl[2.2]paracyclophanes were determined from the typical upeld shifts by 1.52.0 ppm of the protons of the coordinated ring [174]. It was found that in substrates (249), which have three potential complexation sites, monocomplexation takes place preferentially at the unsubstituted paracyclophane ring and dicomplexation at each of the two paracyclophane rings. Other substrates for complexation investigated are the pseudo-meta- (250) and the pseudo-para-diaryl[2.2]paracyclophanes (251). 13 C complexation shifts in tricarbonylchromium and (cyclopentadienyl)iron(ii) complexes of [2.2] paracyclophane as studied by Mori et al. [136,137] are included in the section on [2.2]metacyclophanes, see Section 3.1. 13C data of a Mo(CO)3-complex of [2.2]paracyclophane are described in Ref. [73], those of [(h 6-C6H6)Ru(h 6-[2.2]paracyclophane)] 2 2 BF 4 in Ref. [74]. De Meijere and coworkers reported 1H and 13C complexation shifts in tricarbonylchromium complexes of [2.2]paracyclophane-1,9-diene (252) and
94
Ar
Ar
Ar
Ar
Ar (249) Ar = 4-MeC 6H4, 4-MeOC 6H4, or 2,4,6-Me 3C6H2 (250) Ar = 4-MeC 6H4 or 4-MeOC 6H4 (251) Ar = 4-MeOC 6H4 or 2,4,6-Me 3C6H2
(OC)3Cr X X
(OC)3Cr
(252)
(253), X = H; Y = H (254), X = OMe; Y = H (255), X = H; Y = SiMe 3
Cr(CO) 3 (256)
Ru2+
2.95
Ru+
3
2.24
1.87
2 e
28.3* 110.3
4.43
(J = 5.4 Hz)
2.41
14
55.4
27.4*
87.3
45.9 17.6 103.6
Ru2+
Ru+
(257) H H H H H (259) (260)
(258)
H H
H (261)
H (262)
two of its derivatives [175]. In the complexed rings of (253)(255), the protons are shielded by between 1.76 and 1.71 ppm and the carbon nuclei by ca. 39 ppm (tertiary) and 19 to 17 ppm (quaternary). The
electron withdrawing effect of the Cr(CO)3 group is apparent from the deshielding effects upon the 1H and 13 C chemical shifts of the uncomplexed rings. These measure 0.30 0.34 ppm and 0.2 1.9 ppm,
95
respectively. The complexation shift of the aromatic protons in the dinuclear complex (256), 1.45 ppm, agrees well with the sum of the effects of a near (1.74 ppm) and a distant (0.32 ppm) Cr(CO)3 group. An interesting effect was observed for the one-bond C,H coupling constants in (253). While 1 J(C,H) in the complexed ring show the usual increase (16.4 Hz) relative to the chromium-free parent compound, the coupling constant in the uncomplexed ring decreases by a considerable 3.1 Hz (from 161.2 to 158.1 Hz). Boekelheide and coworkers [176] investigated the two-electron reduction of the bis(hexamethylbenzeneruthenium)[2.2]paracyclophane tetracation (257) to give the dication (258). The product has symmetrical 1H and 13C NMR spectra which have the characteristics of a cyclohexadienyl anion complex. Such a structure requires the presence of a bond between C-3 and C-14, which was indeed proved by X-ray diffraction and has the extraordinary length of 196(3) pm. In the upper and the lower half of formula (258) are given the 1H chemical shifts and the 13C chemical shifts, respectively. The symmetry of the molecule in solution is maintained even at temperatures as low as 100 to 120C as shown by its unchanged 1H and 13C NMR spectra. The paper also describes a number of compounds analogous to (258). In these the central [2.2]paracyclophane unit carried methyl groups or was replaced by [2.2]metacyclophane or by [2.2.2](1,3,5)cyclophane. These compounds have properties similar to (258). Two [2.2]paracyclophanes with a cis- (259) and a trans-1,3-cyclohexanediyl unit (260) instead of one of the p-phenylene rings have been reported [143]. These compounds show a number of interesting 1H NMR chemical shifts at high eld, viz. (259) at d 1:82 (1 H), 1.05 (1 H), and 0.46 (2 H) and (260) at d 0:05 and 0.32 (1 H each). Unfortunately, the spectra were not assigned. Perhydrogenation of [2.2]paracyclophane (194) gives the highly symmetrical compound (261) which shows only two CH2 signals and one CH line in its 13C NMR spectrum and, by denition, is no longer a cyclophane because it lacks an aromatic system. On treatment with triuoromethanesulfonic acid (261) was quantitatively converted into a new product which has a highly misleading 13C NMR spectrum,
showing four CH2 and four CH signals of equal intensity at room temperature [177]. Below 5C, however, eight additional lines appear which all correspond to CH2 groups. A 2D C,C EXSY experiment at 25C and a 2D C,C INADEQUATE spectrum taken at 35C proved the new product to be the monoendo-stereoisomer (262). It exists in equilibrium between two conformers of C1 symmetry, which interconvert rapidly at elevated temperatures to give an averaged structure of Cs symmetry. At room temperature, various coalescences between 13C signals of very different chemical shifts (Dn 355804 Hz at 100.6 MHz) occur, which cause the mentioned lack of signals. The coalescence temperatures could only be determined with a rather high degree of uncertainty. They led to a conformational activation barrier DG of 54 ^ 5 kJ mol 1. Molecular mechanics computations show that (262) indeed possesses a lower strain energy than (261), making the isomerization very plausible. 3.3. [2.2]Metaparacyclophanes A careful 1H and 13C NMR study of [2.2]metaparacyclophane (263) was carried out by Renault et al. [178]. Techniques used were iterative analysis of the 1 H NMR spectrum, in particular of the bridge protons, NOE difference experiments to assign the nonequivalent methylene protons, 2D C,H-HETCOR experiments to assign the signals of the proton-bearing carbon atoms, and a 2D INADEQUATE experiment for assigning the quaternary carbon signals. Also, all 1 J(C,H) coupling constants were reported. Surprisingly, the 12,13-dimethyl derivative (264) of [2.2]metaparacyclophane was obtained as a single conformer with a syn arrangement of H-8 and the methyl groups [179]. This is visible from the normal 1H chemical shifts of the methyl groups d 2:34 which are not under the inuence of the ring current of the m-phenylene ring. On the other hand, there is substantial shielding of H-8 d 5:03 by the p-phenylene ring and of H-15,16 d 5:68 by the m-phenylene ring. The molecule appears to be rather rigid as its 1H NMR spectrum does not change up to a temperature of 150C. The parent compound (263) itself has a barrier to ipping of the inner corner of the m-phenylene ring of 84 91 kJ mol 1, determined by different authors. The
96
5.03
H CH3
5.68
2.34 12
CH3
(263)
(264)
R4 R
3
R1 R2 (268)
(265), R1=R3=Me, R 2=R4=H (266), R1=R4=Me, R 2=R3=H (267), R1=R2=R3=R4=Me R

1 15
(269)
(270), R = H (272), R = CH 3
(271)
transition state of the m-ring ip has the two aromatic rings approximately at a right angle, whereas they form an acute angle in the ground state with C-8 pointing towards the para-bridged ring. When two methyl groups were introduced into the p-phenylene ring, in the 12,15- (265) or the 12,16-positions (266), the barrier of (263) is lowered to 76 kJ mol 1 at 120 127C in (265) and to 81 kJ mol 1 at 126C in (266) [180]. As the methyl groups should have little, if any, inuence on the stability of the transition state, lowering of the barrier was ascribed to an increase in energy of the ground states by destabilizing interactions of the methyl groups with the m-phenylene ring. Surprisingly, the barrier is not lowered further in compound (267) carrying four methyl groups at the p-phenylene ring. Instead, DG (127C) was found to be 82 kJ mol 1, about the same value as in (266). The explanation offered consisted in an increase of the bending angle of the p-phenylene ring, which lowers the energy of the transition state, and simultaneous outward bending of the methyl groups (to reduce their mutual interactions), which lowers the energy of the ground state. The combination of both effects
could keep the conformational barrier constant with respect to (266). The conformational behaviour of [2.2]metaparacyclophanes, their annelated derivatives, and of the corresponding dithia[3.3]phanes have been reviewed [181]. Compound (268), a terphenylophane, may also be regarded as a [2.2]metaparacyclophane (263) with benzoannelation at one of the ethylene bridges [182]. As (263) is conformationally mobile DG 84 kJ mol1 ; it is of interest to see to which extent the barrier to ipping of the m-phenylene ring is affected by benzoannelation. The bridge protons of (268) show an ABCD spectrum at room temperature which coalesces to an AA 0 BB 0 pattern at 100 ^ 10C. The barrier to meta-ring ipping was estimated as 75.8 ^ 2.0 kJ mol 1, ca. 9 kJ mol 1 lower than in the parent compound. For the monothia homologue of (268), see Section 5. Wong et al. [183] prepared (269), the didehydro analogue of (268) and the dibenzo derivative (270). These compounds have DG (41C) 44 kJ mol 1 and DG (24C) 57 kJ mol 1. Together with Boekelheides [2.2]metacyclophanediene (271)
L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190 Table 11 Activation barriers DG c to m-phenylene ring ipping and coalescence temperatures Tc in [2.2]metaparacyclophane derivatives Compound Types of central bridge bonds Single/single Single/aromatic Aromatic/aromatic Aromatic/double Double/double DG c [kJ mol 1] 87 75 57 44 35 Tc [C] 146 116 24 41 96
97
(263) (268) (270) (269) (271)
[184] this gives a nice series of [2.2]metaparacyclophanes in which the nature of the central CC bonds of the bridges is varied systematically (Table 11). The lower barrier in (271) relative to (263) has been interpreted by Boekelheide by the lower energy of the transition state of (271) due to the wider CCC angles in the bridges which supposedly outweigh the effect of the shorter CyC bonds. As a result there is believed to be less penetration of the intraannular hydrogen into the p-electron cloud of the p-phenylene ring in (271) than in (263). The relative barrier in (268), i.e. lower than in (263) and higher than in (271), is also in line with this argumentation. However, it was not clear how the barriers of (270) and (269) relative to that of (271) could t into the scheme. In these three molecules the bond angles should be similar (near 120), so the longer bond lengths (aromatic double bond) should go along with lower barriers, yet the opposite gtle suggested a loweris found. On the other hand, Vo ing of the energy of the transition state by conjugation of the unsaturated bridges with the m-phenylene ring, see Ref. [4, p.117]. Such an explanation would agree with the experimental ndings. In their full paper on the subject, Wong et al. [185] extended the series of benzoannelated [2.2]metaparacyclophanes by including the dimethyl derivative (272). This has a DG value of 89.9 ^ 0.4 kJ mol 1 T 140C as determined by a line shape analysis of the 1H NMR signals of the p-phenylene ring. The increased barrier in (272) relative to (270) was explained by unfavourable steric interaction in the conformational transition state between the methyl group at C-1 and the adjacent hydrogen at C-15. The analogous unfavourable H,Hinteractions in (270) and (269), which occur twice and once, respectively, do then account for the observed sequence of barrier heights (270) (269) (271).
The two benzoannelated [2.2]metaparacyclophanes, [2.2]metacyclo(1,4)naphthalenophane (273) and its derivative (274) with an intraannular methyl group, both occur as the anti isomers with the intraannular proton dH 3:95 and methyl group dH 0:30; respectively, over the naphthalene system [186]. Variable temperature 1H NMR studies up to 150C have shown no indication of anti O syn interconversion. The precursor dithia[3.3]metacyclo(1,4)naphthalenophanes are mentioned in Section 4.2.3. The tert-butyl derivatives without a second substituent (275a) or with a methyl group in the para-position (275b) are formed only in the anti-conformation, no matter whether the precursor dithia[3.3]phanes and their sulfoxides were syn or anti [187]. However, both syn- and anti-[2.2]phanes (275c) are produced from the methoxy-substituted precursor. Recording a 1 H NMR spectrum of anti-(275a) at 150C provided no evidence that the syn-conformer was formed.
6.74 7.03 3.95 6.05 8.09 7.55 6.04 6.90 0.30 6.68
Me
8.07 7.48
(273) tBu R R
(274)
tBu
anti
syn
(275a), R = H; only anti; H = 3.77 (275b), R = Me; only anti; Me = 0.27 (275c), R = OMe; anti >> syn; OMe = 2.63 and 3.17
3.4. [2.2]Orthometacyclophanes The synthesis of [2.2]orthometacyclophane lead to a 4:1-mixture of its syn- (276) and anti-isomers (277) [188] which up to 150C interconvert slowly on the NMR time scale. From the line broadening at the highest attainable temperature, the activation barrier was estimated to lie between 84 and 100 kJ mol 1. Because of the magnetic anisotropy of the opposite benzene rings, all protons apart from H-16 are shielded in (276) relative to (277), but the inclination
98
2b 2a
(CH2)n
H16
H
1a 1b
16
(276), syn
6 5 4 12 13 14 7 Ts 9 2
(277), anti
endo Hexo H
(1), n = 5 (6), n = 6 Ts N
5
H Hexo
endo
Ts N
N Ts
H16
N Ts
H16
(278), boat
(278), chair
N Ts (279)
of the rings in (276) places H-16 into the deshielding zone of the ortho-bridged ring. Although the intraannular aromatic protons in anti-[2.2]metacyclophanes are usually strongly shielded (d H 4.2 [189]), this is not the case for H-16 in (277), where dH-16 7:08; because its benzene rings are not in such close proximity as in the case of double meta-bridging. A very strong NOE of 16% is observed at H-2b when the signal of H-16 is saturated although H-2a competes strongly in the dipolar relaxation of H-2b. This is in accord with the very small distance of 210 pm between H-16 and H-2b, which is predicted by molecular mechanics computations (MMX). There was good agreement between the experimental vicinal coupling constants in the bridges of (276) and those predicted by the Haasnoot equation [190] from the geometry estimated by the MMX computations. In the 13C NMR spectrum strong deshielding of C-16 is observed in (276), dC 138:3; relative to (277), dC 129:9: This deshielding effect in the synconformer is similar to that found for the aromatic intraannular carbon atom in [5]metacyclophane (1) and [6]metacyclophane (6), which had been correlated with the degree of nonplanarity of the aromatic ring [16]. This explanation does not seem to hold in (276) as the MMX computations predict very similar geometries for the meta-bridged rings of (276) and (277). The 1H and 13C NMR spectra of the N,N 0 -ditosyldiaza[2.2]orthometacyclophane (278) [191] were fully assigned by the use of a variety of 2D techniques
at room temperature and at low temperatures. The molecule exists as two conformers of approximately equal energy, the boat (syn) and the chair (anti) conformer. At room temperature averaged 1H (and 13 C) spectra are observed in which some broadened signals (of H-16 and H-2,9) indicate restricted intramolecular mobility. At ca. 3C the methylene signal decoalesces DG 52 kJ mol1 into separate signals for exo and endo protons due to restricted CH2 movement, and between 58 and 73C the different aromatic proton signals split, some of them into resonances of widely differing chemical shifts (Table 12). This lower energy process DG 43:5 ^ 2 kJ mol1 is the boat/chair interconversion and the large chemical shift differences between the conformers, e.g. 2.6 ppm for H-16, are caused by the large change of the relative orientation of the aromatic rings. In contrast to (278), no signal doubling could be observed for the [6]metacyclophan-3-ene derivative (279), which has a cis-CyC double bond instead of the ortho-substituted benzene ring. From the lowest temperature reached (93C),
Table 12 1 H NMR chemical shifts of the boat and chair conformers of (278) in CD2Cl2 solution at 83C H-2 endo Boat Chair Dd 4.92 3.40 1.52 H-2 exo 4.97 4.81 0.16 H-4 7.66 5.99 1.67 H-5 7.07 6.64 0.43 H-12 6.24 6.98 0.74 H-13 6.83 7.32 0.49 H-16 7.18 4.59 2.59
99
an upper limit of the barrier to inversion of the ninemembered ring was determined as 30 kJ mol 1. The true barrier was estimated to lie between 20 and 25 kJ mol 1. 3.5. [2.2]Orthoparacyclophanes [2.2]Orthoparacyclophane (280) is the most strained of the [2.2]cyclophanes and was the last one to be synthesized [192]. The vicinal H,H coupling constants in the ethano bridges are nearly identical to those in (Z)-[6]paracyclophan-3-ene (59a) [56], proving the similar geometries of these two compounds.
syn/anti isomerization, which is facile for methoxycarbonyl derivatives of (59a) and takes place at room temperature with DG 25C 103 kJ mol1 ; was not observed for the corresponding derivatives of (280) within 48 h at 50C. Thus, benzoannelation of (59a) brings about a substantial barrier to conformational isomerization. 3.6. [2.2]Naphthalenophanes The 1H NMR spectra of the three constitutionally isomeric [2]naphthaleno[2]paracyclophanes (281) (283) [193] nicely reect the different relative orientations of the benzene and naphthalene moieties. The large shift difference of 1.00 ppm between the protons on the endo and exo sides of the benzene ring in the (1,4)naphthaleno derivative (281) is mainly due to the inuence of the ring current of the unbridged naphthalene ring. The moderate shift difference of 0.51 ppm between the two kinds of benzene protons (AA 0 BB 0 system with C2 symmetry) in the (1,5)naphthaleno compound (282) is caused by the smaller distance of the more shielded proton from the centre of the nearest naphthalene ring. In (283), where the centre of the benzene ring lies over the centre of the naphthalene system, the AB shift difference is very small (0.09 ppm) so that it cannot be used to assign the
6.08/5.99
6.27 7.32
7.07 7.20
(280)
(59a)
The only major difference between the 1H NMR spectra of (59a) and (280) is the shielding effect experienced by the protons on the syn side of the pphenylene ring. These are strongly inuenced by the ring current of the o-phenylene ring so that their chemical shift d 6:27 is about 1 ppm to the higher eld than that of the anti protons d 7:32: Mutual
6.09 5.09 7.55 7.24 7.37 6.99 6.03 5.52
6.44
7.03 6.82 7.22
7.04
(281)
6.08/6.04 6.75
(282)
3.22/2.68 6.43
(283)
7.23 6.90 7.21 7.11
6.80 6.53
7.12
6.87
3.07
6.99
(284)
(285) MeO OMe X A (287) X (288) A
(286)
MeO
OMe
100
two kinds of protons. The spectrum of diene (284) is very similar [194]. The dithia[3.3]phanes corresponding to (281)(283) are dealt with in Section 4. The chiral [2.2](2,6)naphthalenophane (285) with crossed naphthalene units has been known for a number of years [195], and its structure had been assigned on the basis of its wide spread chemical shifts of the aromatic (d1 6:43; d3 6:87; d4 7:12; naphthalene numbering) and of the bridge protons (AA 0 BB 0 , d 3:22 and 2.68). The achiral, eclipsed isomer (286) could only be prepared much later [196]. Its three different aromatic protons d1 6:80; d3 6:53; d4 6:99 show rather similar higheld shifts relative to 2,6-dimethylnaphthalene: Dd 0:73; 0.72, and 0.66, respectively. Moreover, the two kinds of bridge protons reside in similar environments and are accidentally isochronous. Their chemical shift is the same as in [2.2]paracyclophane, d 3:07: The isomeric [2.2](1,3)naphthalenophanes (287) and (288) [197] differ in that the outer naphthalene rings are arranged in a transoid and a cisoid manner, respectively. Both are present in the anti-conformation as indicated by their highly shielded intraannular protons which both absorb around d 4:5: The different symmetries are apparent from the bridge proton patterns. In (287) both bridges are equivalent by symmetry and the protons of a bridge form an AKRX spin system. In (288), the bridges are in different environments and give two different AA 0 XX 0 spectra. The latter were misinterpreted as two AX systems with coupling constants of 10.1 Hz for one system and 9.0 Hz for the other. This means that the weaker outer lines of the patterns were not seen or were neglected. The spacing of each doublet does not correspond to a single coupling constant but corresponds to J AX J AX 0 ; which in this case is 2 J 3 Jgauche and corresponds to approximately 12 3 Hz 9 Hz; in agreement with the above values. Photocyclodimerization of 1,3-distyrylnaphthalene could, in principle, give seven bis(cyclobutano)annelated syn-[2.2](1,3)naphthalenophanes, of which three, (289)(291), were isolated in sufcient amounts to solve their structures by NMR spectroscopy [198]. This was achieved mainly by the use of the 1H chemical shifts, of the symmetry in the 13C spectra, and of the results of H{H}-NOE measurements. A series of other syn-[2.2]naphthalenophanes
with cyclobutane rings annelated to the bridges was prepared by intermolecular [2 2] photocycloaddition of divinylnaphthalenes [199]. The structures and congurations of the products, (292)(299), were determined by H,H-COSY and by H,HNOESY, making use, in particular, of the NOEs between the cyclobutane and the aromatic protons. The [3.2](1,4)naphthalenophan-1-enes (300) and (301) [200] prefer the anti-conformation as shown by the upeld shift of the protons in the naphthalene positions 2 and 3 in (300) (d 5:67 and 5.93) and of naphthalene proton H-3 d 5:81 and its neighbouring methyl protons d 1:57 in (301). The spin coupling pattern of the protons in the three-membered bridge indicate that it makes rapid wobble movements at room temperature. For (300) this was conrmed by the doubling of several signals at low temperature. The coalescence temperature of 75C gives DG 39 kJ mol1 for this process. 3.7. Other [2.2]phanes This section deals with phanes containing aromatic subunits other than naphthalene or heterocycles, such as uorene, higher condensed aromatics, azulene, and ferrocene (three examples). It also contains adamantanophanes. The preparation of the [2.2](2,7)uorenophanes (302) and (304) furnished both the anti and the syn isomers while only the anti isomer was obtained in the synthesis of diketone (303) [201]. In the syn uorenophanes the uorene units are expected to be arranged eclipsed and parallel to one another. They are characterised by moderate shieldings (Dd 0:50 to 0.68) of their aromatic protons compared with the model compound 2,7-dimethyluorene (305). The C C axes of the bridges are presumably perpendicular to the aromatic planes. This makes the chemical environments of the bridge protons very similar, in agreement with their close chemical shifts; only a broad singlet was observed at d 3:14: The 9-endo and 9exo protons are shielded by Dd 0:43 and 0.17, respectively, relative to (305). An X-ray diffraction study of anti-(302) showed that the uorene units lie in parallel planes, but their centres are shifted relative to one another so that C-1 and C-8 lie approximately above the centres of the opposite aromatic rings (step-
101
Ph Ph
Ph Ph
Ph Ph
Ph Ph
Ph Ph Ph Ph
(289)
(290)
(291)
(292)
(293)
(294)
(295) R R
(296)
(297)
Me
R Me R R R
2
(298), R = CO 2Et (299), R = Ph
(300), R = H (301), R = Me
like conformation). For anti-(302) in solution, this leads to strong shielding of H-1/8 Dd 1:24 and only weak shielding of H-3/6 Dd 0:22 and H-4/ 5 Dd 0:27: The protons at the ve-membered ring are also much more shielded than in the syn isomer, DdH-9endo 1:44 and DdH-9exo 0:65: The nonequivalence of these protons allows the direct observation of their geminal coupling: 22.0 Hz in anti-, 20.5 Hz in syn-(302). The X-ray results also show that the axis of the bridges are not perpendicular but skewed with respect to the uorene
moieties. The geminal protons at a bridge carbon therefore reside in different environments, in agreement with their distinct shift difference observed in the AA 0 BB 0 spectrum dA 3:09; dB 2:67: The geometries of anti-(303), anti-(304), and syn-(304) were derived using the same chemical shift arguments as for (302). The uorenophanes (302) were converted to their dianions (306) and their 1H chemical shifts compared with the model anion (307). As for the neutral hydrocarbon, H-1/8 in the anti phane shows the strongest high-eld shift Dd 0:84;
102
Y (302), X = Y = CH 2 (303), X = Y = CO (304), X = CH 2, Y = CO

3.10 6.95 3.09 2.67 7.35
H
6.63 2.31 3.14 (both H)
3.58 6.94
6.09 1 9
6.83
3.32 H
anti-(302)
7.17 7.62
syn-(302)
7.33
3.75
(305)
7.43 6.21 6.09
5.04
7.11 5.76 6.75
5.43
anti-(306)
2 Li+
syn-(306)
2 Li+
7.60 6.09
6.93 5.73
Li+ (307)
followed by H-9 Dd 0:69: Generally, the shift differences between the charged phanes and their model compound are smaller than in the cases of the neutral hydrocarbons. Dianion anti-(306) was reacted with methyl iodide to give a dimethylated phane which must have the exo,exo structure (308, X CH3, Y H) because of the chemical shifts of the 9-H d 2:38 and 9-Me d 1:03 protons. Renewed metalation of (308, X CH3, Y H) followed by treatment with CH3I yielded the tetramethyl-phane (308, X Y CH3), in which, surprisingly, the endo- and exo-methyl protons have very similar shifts d 1:01; 1:03:
This nding was interpreted by a possible twist of C-9 out of the plane of the ve-membered ring to minimize unfavourable steric interactions of the endo-methyl group. This would lead to a high-eld shift of the exo-methyl group because it would be moved more into the shielding area above the uorene unit on the outside of the molecule. At the same time the endo-methyl group would be moved more into the deshielding zone at the side of the aromatic plane. In a series of [2.2](1,8)uorenophanes (309) (311) described by Tsuge et al. [202] ipping of the uorene moiety is restricted as seen from the different chemical shifts of the geminal protons at
103
X
Y X
anti-(308)
0.00, 2.38
0.69, 2.11
tBu (309) O
tBu
tBu (310)
tBu
3.95
3.41, 3.68
tBu tBu (311) tBu (312)
tBu
C-9. Relative to di-tert-butyluorene (312) as a reference compound, for which dCH2 3:95; both methylene protons are strongly shielded in the parabenzenophane (309), the endo-proton d 0:00 more so than the exo-proton d 2:38: As to be expected, the effects are more pronounced in the (2,6)naphthalenophane (310) but only very small in uorenophane (311) containing the nonaromatic pbenzoquinone ring. Coalescence of the signals of the diastereotopic protons at C-9 was not observed up to a temperature of 150C for any of these uorenophanes. The structures and congurations of the bis(cyclobutano)[2.2]phenanthrenophanes (313) and (314) were determined by H,H-COSY and H,H-NOESY and from the deshielding effect of the annelated cyclobutane rings upon the ortho-protons toward which they are pointing [203]. Both series of compounds possess the syn-conformation as is evident from the upeld shifts of the aromatic protons relative to phenanthrene. Yet, these upeld shifts are more remarkable in (313) than in (314). X-ray diffraction
analysis and molecular mechanics calculations show that this is caused by the different arrangements of the phenanthrene units relative to each other. In the isomers (313) the bridges are on opposite sides of the molecule, thus forcing the phenanthrene decks into a parallel arrangement, whereas they are on the same side in (314), so the phenanthrene planes can form an angle and evade each other. This decreases their mutual shielding effect. Hydrogenation of the cyclobutane rings of (314) led to a [4.4]phane which is described in Section 5. Like [2.2]metacyclophanes, the related pyrenophanes (315a)(315e) [204] adopt the anti-conformation although some of their dithia[3.3]phane precursors preferred the syn-arrangement, cf. Section 4.2.3. The anti-conformation is evident from the upeld shifts, caused by the strong ring current of the pyrene system, of the intraannular benzene proton d 3:54 in (315a), of the methyl group d 0:29 in (315b), of the ethyl group dCH2 0:11; dCH3 0:10 in (315c), and of the methoxy group d 2:35 in (315d). Further, the intraannular
104
(313a), exo,exo
(313b), exo,endo
(314a), exo,exo R2 H (315) R1
(314b), exo,endo
(314c), endo,endo R1 a b c d e R H Me Et OMe F R2 H tBu tBu tBu tBu
tBu
3.1
CH3 CH3 (316)

4.19
4.25
(317a), R = CH 3 (317b), R = CH 2CH2CH=CH 2

4.14
pyrene proton is shifted to 4.505.16 in the series (315a)(315e) by the opposite m-phenylene ring. An interesting compound, (316), which incorporates a [2.2]metaparacyclophane into a 10b,10c-dihydropyrene molecule, was apparently synthesized by Lai and Yap [205], although it could not be isolated in a pure form and only a few of its 1H NMR signals could be identied. As the methyl protons of (316) have almost the same shift d 4:19 as in the model compound trans-dimethyldihydropyrene (317a) d 4:25; the authors concluded that the molecule sustains nearly the full ring current (99%) of the model system. The relative deshielding of the
protons of the methylene group bound to C-10b [d 3:1; compared to 4.14 in the but-4-enyl derivative (317b)] was explained by a deection of this CH2 group from the central axis (dotted line) of pdelocalization by the strain in the cyclophane system. The dianion (318) of [2.2](1,4) benzo[g]chrysenoparacyclophane [206] consists of a paratropic 4np dianion interacting with a neutral benzene ring. The 1 H NMR chemical shifts of the disodium salt range from d 10:31 to 0.91, the most interesting part of the spectrum being the signals of the protons of the benzene ring. Hc and Hd were observed at d 8:68 and 10.31, respectively, extremely deshielded with

(b) 7.96 6.46 (a)
105
(d) 10.31 (c) 8.68
2 2 Na+
6.70 (a)
(b) 6.57
(d) 5.08 (c) 5.92
(318)
(319)
(320)
(321)
R R
R R
(322), R = H (323), R = Me
(320)2
R R R R (321)2 (322)1, (323)1
respect to the neutral hydrocarbon (319) where the shifts are d 5:92 (Hc) and 5.08 (Hd). In fact, reducing diatropic (319) to paratropic (318) reverses the order of the chemical shifts of the benzene ring protons. The remaining proton shifts of (318) were not assigned, neither were the 13C shifts, which extend from d 176 to 100 and from d 38 to 33. In a further paper by the same group [207], a series of [2.2]indenophanes and their anions were studied in order to separate the effects of charge transfer and magnetic anisotropy of the negatively charged cyclophane layer upon the 1H chemical shifts of the opposite layer. The authors concluded that the magnetic anisotropy of the (4n 2)p system formed has the largest inuence, but that charge transfer effects from the negatively charged layer to the opposite
one must not be neglected. The systems studied were (320)(323), their (di)anions, and some further neutral model compounds. In [2.2](5,13)dibenzochryseno[c,l]phane (324) [208], the central parts of the two dibenzochrysene subunits are subject to one anothers ring currents. This causes shielding effects Dd of the central protons amounting to 0.87 and 0.90 ppm relative to the corresponding shifts in the reference compound dimethyldibenzochrysene (325) and indicates the obliquely stacking structure of phane (324) as opposed to a structure in which the two halves are eclipsed. Compared to the free ligand dihydro-s-indacenoparacyclophane (326) the 1H NMR chemical shifts in the benzene ring of the rhodium complex (327)
106
7.93 9.12
8.22 7.06
(324)
(325)
6.13 c d b 6.48 a 6.39 6.26
SbF6 (Me5C5) Rh+ (326) (327)
show deshielding of protons a and b by ()0.18 ppm (averaged) and shielding of protons c and d by ()0.13 ppm [209]. This was interpreted by the authors to indicate a decrease of electron density in the benzene ring by complexation of the dihydroinda6 7 1 8 1
cene moiety with (Me5C5)Rh and an overcompensation of the expected downeld shift of H-c,d by the shielding of the magnetically anisotropic rhodiocene substructure. The 1H NMR signals of the aromatic and the bridge protons in anti-[2.2](1,6)azulenophane (328) [210] are well spread out on the d -scale and show doublet and ddd multiplicities, respectively, due to spinspin coupling. Neglecting enantiomers, there are four possible isomers that could have been formed from the precursor 1,6-azulylene: syn and anti conformers of the syn (1,1 0 ;6,6 0 -bridged) and the anti (1,6 0 ;6,1 0 bridged) conguration. The syn congurations were excluded because they would both give rise to two AA 0 XX 0 bridge spin systems whereas one AKMX system was observed. The anti conformation followed from the large upeld shifts of H-7 and H-8 of ca. 2.5 and 2.1 ppm, respectively (relative to 1,6-dimethylazulene), which indicates a step-like structure. Assignments of the individual bridge proton resonances and their coupling constants were reported later [211]. Hafner and coworkers were the rst to prepare syn[2.2](1,6)azulenophane (329). Its conguration is such that the ve-membered rings and the sevenmembered rings are over each other [212], but the question of the preferred conformation needed to be
X M A K
7.36 7.77 7.53 2.53 H 6
10
(328)
3.09 2.48
H12
6.77 6
8.03 8
7.21 7.71 1 2.34
3.35
H12
7.06
8.31
H11
5.17 6.37 (1.90) (1.84)
H10 3.40 H9
2.95
H11
5.64 (1.46)
H94.25 H
4
H H
H H
4
H H
(329)
(330)
2.37
2.04
N H values (331)
N (332)

7.156.80 13 6.93
107
5.34 1.18 2.37 3.75 3.97
6.23
Fe
9 11
Fe
Fe
3.37 3.87
(333)
(334)
(335)
answered. Comparison of the 1H chemical shifts with those of the reference compound 1,6-dimethylazulene shows large upeld shifts of H-7 and H-8 (1.90 and 1.84 ppm, respectively), while the other aromatic protons are affected by less than 0.3 ppm. Consequently, the molecule assumes the stepped conformation (anti-type) as shown in the formula, with H-7 and H-8 over the centre of the opposite seven-membered ring. The proton chemical shifts of the [2.2](4,6)azulenophane (330) were compared with those of 4,6-dimethylazulene. Here, H-5 exhibits strong shielding (1.46 ppm) relative to the reference compound, and the remaining aromatic protons are deshielded by 0.040.19 ppm. Hence, this azulenophane also assumes an anti-type conformation with H-5 over the centre of the opposite seven-membered ring. For both (329) and (330), the proton shifts were fully assigned, the bridge protons from the NOESY cross peaks with their adjacent azulene protons. Increasing the temperature to 130C hardly affects the spectrum of (329) and demonstrates the conformational rigidity of the molecule. The spectrum of (330) shows broadened aliphatic proton signals up to 130C, while the aromatic proton signals, especially those of the deshielded protons, remain sharp. This was interpreted as indicating ipping of the azulene rings. The large upeld shifts of the inner protons in [2.2](1,3)azuleno(2,6)pyridinophane (331) and in [2.2](5,7)azuleno(2,6)pyridinophane (332) [213] relative to the corresponding dimethylazulenes are very similar to the shielding observed earlier for the analogous azulenometacyclophanes [214,215]. Also, the 13 C chemical shifts of the azulene carbon atoms are much the same in the two classes of compounds. These ndings established the conformations of (331) and (332) as anti (step-like). The 1H NMR spectrum of (331) remains unchanged up to 130C, but the CH2 signals of (332) start to broaden at 120C
before the compound decomposes. Since the aromatic proton signals of (332) do not change, the dynamic process observed is an anti O planar O anti and not an anti O syn conformational change. In order to probe the sign and magnitude of the magnetic anisotropy in the region close to the iron atom in ferrocene, [2.2]metacyclo(1,1 0 )ferrocenophane (333) was studied by 1H NMR [216]. The mphenylene ring in this molecule is situated to the side of the ferrocene unit and H-9 is close to the iron atom: 301 pm apart according to an X-ray diffraction measurement. This arrangement causes strong deshielding of H-9, which absorbs at d 8:80; ca. 1.7 ppm to low eld of H-11,12-13. The same group of authors also studied [2.2]metacyclo(1,3)ferrocenophane (334) and the para isomer (335) [217]. The meta compound possesses the anti conformation as is evident from the upeld shifts of the internal protons. With d 1:18; H-2 of the ferrocene moiety is extremely shielded. This represents an upeld shift Dd of 2.82 ppm relative to the shift of H-2 in 1,3diethylferrocence as a model compound. In contrast, the internal proton at the m-phenylene ring d 5:34 is only shielded by Dd 1:58 ppm relative to 1,3diethylbenzene. Hence, the magnetic anisotropy of ferrocene causes considerably less shielding in the area above the centre of the cyclopentadienide ring than does the magnetic anisotropy of benzene at a comparable position. The para compound (335) has a step-like structure similar to [2.2]metaparacyclophane (263) and one side of the p-phenylene ring is shielded relative to the other, as is the case for the H-2 of the ferrocene moiety relative to H-4,5. The [3.3]and dithia[3.3]-analogues of (334) are mentioned in Sections 4.1 and 4.2, respectively. gtle et al. [218] prepared [2.2](1,3)adamantanoVo metacyclophane (336), the construction principle of which has some resemblance to [2.2]metacyclophane (149), but whose stereochemistry is different because
108
+0.06
1.01 4.08
Ho
0.10
Ho Hi
0.35 0.25
Ho Hi
Hi
Hb
7.75
N (338)
R (336) (337a), R = H (337b), R = CO 2H

[H values for ( 337a)]
three intraannular protons are located within the centre of the 10-membered ring. Protons Hi and Ho (d 0:10 and 0.06, respectively) are strongly shielded while Hb absorbs at d 7:75: The 1H NMR spectrum of (336) remains unchanged at high temperature (126C) apart from some chemical shift alterations. This indicates conformational rigidity, in contrast to the exible [7]metacyclophane which has a DG of only 48 kJ mol 1 for the ipping of the bridge [23]. An X-ray diffraction analysis proved the anti conformation of (336). In their calculations of the ring current effects upon 1H chemical shifts, using a model and parameters tested on [n]paracyclophanes, Schneider et al. [77] also treated compound (336) and found that the calculated shift effect upon Hi is off by 1.6 ppm (shielding calculated too high), although good predictions were made in all other cases including (337a). The reason lay in the strong steric compression effect exerted on Hi, which counteracted the ring current shielding. Other effects, in particular a miscalculation of the molecular geometry, were excluded. The dithia-[3.3]phane precursor of (336) is discussed in Section 4.2.3. [2.2](1,3)Adamantanoparacyclophane (337a) [219] is even more strained than the meta-analogue (336). At room temperature, the intraannular methylene protons absorb as a singlet with d 2:35: Their absorption decoalesces at 50C (400 MHz) and gives rise to an AX spectrum at 65C with d 4:08 (Hi) and 1.01 (Ho). The axial proton Hi apparently intrudes deeply into the p-cloud of the benzene ring and experiences an upeld shift of 5.9 ppm (!) relative to the corresponding hydrogen in adamantane itself. The barrier to the chemical exchange of Hi and Ho is surprisingly low, DG 40 ^ 10 kJ mol1 at 50C, probably due to the high strain present in the conformational ground state. This barrier is
much higher in the carboxylic acid (337b) [220]. Here the chemical shifts of the intraannular CH2 protons are d 3:63 and 1.12 already at room temperature and their signals do not coalesce up to 60C. Another adamantanophane, (338), is the (2,6)pyridino analogue of metaphane (336). It has chemical shifts d of 0.25 and 0.35, for Hi and Ho, respectively. Their signals coalesce at 48C (250 MHz), indicating a barrier DG of 62 ^ 10 kJ mol1 at this temperature, distinctly lower than in (336), a consequence of replacing the intraannular hydrogen of the m-phenylene ring by the nitrogen lone pair of electrons. 3.8. [2.2]Heterophanes The phanes treated in this section possess at least one heterocyclic (mostly aromatic) ring. Some phanes containing a g-pyrone moiety are also included. Sixmembered heterocycles are followed by vemembered ones. The results of a number of NMR studies of pyridinophanes, mainly [2.2]pyridinophanes, are contained in a review article by Majestic and Newkome [221]. According to an X-ray diffraction study [222], [2.2](2,6)pyridinophane (339a) prefers the anti conformation. The ring inversion barrier DG has been determined to be 61.9 kJ mol 1 at 80C [223]. Its 7,15-dimethoxy derivative (339b) [224] has the same conformational preference and a signicantly higher basicity than that of the parent. It was of interest to see whether this affects the height of the conformational barrier. DG was determined by a coalescence measurement (AA 0 BB 0 ! A4) as 64.2 kJ mol 1 at 43C. The barrier for (339a) was determined again and this time found to be 58.3 kJ mol 1 at 16C. The evaluation of the rate constants was carried out by using the equation for
109
(339a), R = H (339b), R = OMe

3 18 7.38 6.79
14
(340)
7.12 2.76 6.46 2.39 6.13 3.93 6.80 7.60 7.25
4 5 13 2 11
17
N
4
N
6.14
16 6
2.82
15
7.38 8.15 7.54
12
(341)
7.28 6.79
(342)
(343)
N
6.42 7.01 7.86 7.80 7.20
(344)
(341)
(341)
the coalescence AB ! A2. It is not clear how large an error is introduced by this. Also, the apparently higher barrier in (339b) relative to (339a) cannot be judged properly without knowing the activation entropy because of the different temperatures of the measurements. [2.2](2,6)Pyrazinophane (340) behaves similarly to (339a), showing an AA 0 BB 0 spectrum for its
Table 13 1 H NMR chemical shifts d and H,H coupling constants J(H,H) [Hz] in (341) under slow chemical exchange conditions (measured in CD2Cl2 at 60C) Chemical shifts d (H-2) 6.45 d (H-3) 6.69 d (H-4) 7.14 d (H-6) 7.42 d (H-7) 7.42 d (H-8) 7.83 Coupling constants a J(11,12) 13.1 J(11,13) 8.2 J(11,14) 9.9 J(12,13) 0.0
a
d (H-3 0 ) d (H-4 0 ) d (H-5 0 ) d (H-11) d (H-12) d (H-13)

J(12,14) J(13,14) J(15,16) J(15,17)
6.61 6.98 6.34 2.77 3.91 2.90 9.0 12.1 12.5 5.9
d (H-14) d (H-15) d (H-16) d (H-17) d (H-18)
2.49 3.14 3.40 2.06 2.86
J(15,18) J(16,17) J(16,18) J(17,18)
2.2 12.2 4.5 12.3
Only coupling constants of the bridge protons listed.
bridge protons at 10C which coalesces at 54C (500 MHz). Evaluation by means of the AB approximation gave DG 54C 61:5 kJ mol1 for the anti/anti 0 interconversion [225]. Among [2](1,5)naphthaleno[2](2,6)pyridinophane (341), [2](1,4)naphthaleno[2](2,6)pyridinophane (342) and their dienes (343) and (344), only the rst compound shows temperature dependent 1H NMR spectra in the range between 100 and 80C [226]. These are caused by chemical exchange between two equivalent conformations (341 0 ) and (341 00 ). At 60C, the naphthalene system gives rise to two ABC spectra, the pyridine system to one ABC spectrum, and the ethano bridges to two ABCD spectra. All 1H chemical shifts and H,H coupling constants were assigned at this temperature, including the parameters of the bridges (Table 13). At 83C, the spectrum shows one ABC-type naphthalene, one AB2-type pyridine, and one ABCD-type bridge spectrum. The signal of the pyridine H-4 0 proton remains sharp over the whole temperature range because its chemical shift and coupling constants are identical in the two exchanging conformers. At high temperature, the coupling constants in the bridges are the averages of
110
N N N N N N
(345) N N
(346)
(347)
(348)
(349) H H N H N H
SMe
(350) SMe
MeS X MeS
(351a) (352a) MeS X MeS N H H H
X = CH X=N MeS X N SMe
(351b) (352b) H MeS H N N H SMe
(353a) (354a)
X = CH X=N
(353b) (354b)
(354c)
the low-temperature spectrum according to the exchange pattern. Coalescence measurements of the signals of the naphthalene protons H-4/8 Tc 3C and of the pyridine protons H-3 0 /5 0 Tc 13C gave a ring inversion barrier DG of 51.5 kJ mol 1, very similar to earlier results for [2](2,6)pyridino[2]paracyclophane [227]. An analysis of the full lineshape of the aromatic protons yielded DH 49:5 ^ 0:6 kJ mol1 and DS 7:1 ^ 2:4 J K1 mol1 : Very likely, the dienes (343) and (344) prefer conformations in which the pyridine and naphthalene rings are orthogonal and the nitrogen lone pairs are
pointing towards the naphthalene moiety, while there exists probably a one-sided equilibrium in (342) with parallel pyridine and naphthalene rings favouring the conformer with the pyridine ring oriented exo. The [2]naphthaleno[2]pyrazinophanes (345)(348) give results that resemble those of their pyridino analogues, in particular the ring inversion barrier DG of 52.4 kJ mol 1 for (345) [228]. The 1H NMR spectroscopic properties of [2](1,4)anthraceno[2] (2,6]pyridinophane (349) and its diene (350) are also very similar to those of the naphthalenopyridinophanes (341)(344) [229]. A number of
111
N
5.21 4.33
N
5.33 4.33 5.19 4.20
N
4.52 3.86
N
4.03
5.32 4.38
4.56 3.90
4.45 4.01
(355) N
4.20* 4.32* 4.60
(356) N N
4.34 4.34
(357) N
4.33* 4.48*
(358) N
4.31 4.31
N (359) N (360) N (361) N
N (362)
N (363)
4.55
4.60
N N (364)
4.36 4.41
N
4.39
(365)
(366)
(367)
bridge-bis(methylthio)substituted [2](1,4)- and [2] (1,5)naphthaleno-[2](2,6)pyridino- and [2]pyrazino (2,6)phanes, (351)(354), were investigated by 1H NMR and their conguration determined from the chemical shifts and, in particular, measurements of nuclear Overhauser enhancements [230]. The spectra of (353b), (354b), and (354c) are temperature dependent, which indicates slow ring inversion as observed in (341) and (345). gtle [126] studied the four isomeric 1Vo oxa[2.2]metacyclo(x,y)pyridinophanes (355)(358), for which (x,y) is (2,6), (2,4), (3,5), and (4,2), respectively. These compounds are characterized by strong shielding of the intraannular proton next to the oxygen and somewhat smaller but still rather strong shielding of the intraannular pyridine proton. Comparison of the chemical shifts within this series and with (159) helped the reviewer to specically assign the intraannular protons that had not been done by the authors. The same paper also described [2.2]metacyclo(2,4)pyridinophane (359) and the isomeric [2.2](2,4)pyridino(x,y)pyridinophanes (360)(363), x; y 2; 6; (2,4), (3,5), (4,2). Unfortunately, complete assign-
ments of the proton spectra of these interesting compounds have not been reported. The 1H NMR spectra of (361) and (363) have also been reported by Kawashima et al. [231], who addressed the different symmetries of these compounds, C2 for (361) and Ci for (363). The symmetries are reected in the bridge proton spin systems. While the bridge protons of (363) absorb in the form of one common ABCD pattern, each bridge of (361) gives a separate AA 0 BB 0 spectrum, incorrectly described as a pair of doublets. Kawashima et al. [232] had also reported the aromatic 1H and 13C NMR chemical shifts of (359), (362), of the isomeric [2.2]pyridinophanes (364) and (365), and of the isomeric [2.2]metacyclopyridinophanes (366) and (367). The chemical shifts of the intraannular aromatic carbon atoms and their connected hydrogens were discussed in terms of electron densities and steric compression. A paper by gtle et al. [131], treated in Section 3.1, includes Vo the H-16 chemical shifts of the [2.2]metacyclo(2,6)pyridinophane (169) d 4:94 and its N-oxide (170) d 5:82: The isomeric [2.2](2,5)pyridiniophane diiodides
112

E
+ +
E
+
E N CH3 CH3
N
+
E CH3
E
+
N CH3
+
N CH3 H3C
E (369)
E
(368)
E
+
(370)
E
+ +
H 3C
+ CH3
E
H H
H3 C N
+
E CH3
H3 C N
N H CH3 H
N CH3
CH3
N CH3
E (374)
(371) O Ph Ph
(372) E = CO 2Me O Ph O O O R
(373)
O Ph Ph Ph
O
endo
Ph O (375)
Ph
exo
(376a), R = H (376b), R = OMe O O CO2Et O N EtO2C O N
(377)
EtO2C
CO2Et
(378)
(379)
(368)(371) show only small upeld shifts (Dd 0:15 to 0.20) of their ring protons compared to model compound (372) [233]. In contrast, the uncharged pyridine rings in the analogous pyridinophanes cause mutual shielding Dd of 0.65 to 0.70 ppm. Thus, the positive charge neutralizes about 75% of the usual ring current effect on the 1H chemical shifts in [2.2]paracyclophanes. Partial reduction of (368) forms the 1,4-dihydropyridine (DHP) substructure in (373). This compound is interesting because its two rings constitute a redox pair like NAD /NADH, yet within the same molecule. In fact,
hydride transfer from the DHP to the pyridinio moiety could be monitored by saturation transfer experiments. Irradiation of the N-methyl signal at d 4:20 (CH3N group of the oxidized ring) causes the signal at d 3:12 (CH3N of DHP ring) to lose intensity and vice versa. No such saturation transfer could be observed in (374), so these experiments indicate the orientation dependence of the rate of the redox reaction. Like [2.2](2,6)pyridinophane (339a), the (2,6)gpyronophane (375) lacks intraannular hydrogens and therefore undergoes unhindered inversion of its macrocyclic ring, as evidenced by the sharp singlet
113
absorption of the methylene protons [234]. X-ray diffraction showed that the compound, like [2.2]metacyclophane, prefers the anti conformation in the crystal. The [2]metacyclo[2]pyronophane (376a) with its internal proton does show hindered inversion at room temperature. This results in an ABCD spectrum for the CH2CH2 bridges. The intraannular proton is somewhat shielded by the magnetic anisotropy of the heterocycle d 6:62: The methoxy derivative (376b) is, of course, also hindered conformationally. Its bridge proton spectrum was analysed and the resulting vicinal H,H-coupling constants prove the exclusive presence of the anti conformer. At room temperature, the 1H NMR spectrum of the [2]paracyclo[2]pyronophane (377) shows coalescence phenomena for the CH2 and C6H4 protons in the form of very broad lines. At 55C, the spectra are sharp and the chemical shifts for the p-phenylene protons are d 6:94 (exo) and 7.38 (endo). This indicates a much smaller shielding effect of the pyrone relative to a phenylene ring as the former lacks aromaticity, cf. the corresponding shifts in [2.2]metaparacyclophane (263) which are d 5:79 and 7.13 [178]. At 60C, a singlet was observed for H-exo and H-endo, and broad signals for both types of methylene groups. The conformational process observed corresponds to a ipping of the meta-bridge but no decision could be made whether rotation of the para-ring is also involved. The precursor dithia[3.3]pyronophanes and their sulfones are mentioned in Section 4.2.3. The [2](2,6)pyridino[2](2,6)g-pyronophane (378) and its unsaturated analogue (379) were studied by variable temperature 1H NMR [235]. The bridge proton signals of (378) that are broad at room temperature show coalescence above 55C and give an AA 0 XX 0 spectrum at 180C (solvent: C6D5NO2). The DG value for the conformational interconversion was determined from the linewidth as 59.6 kJ mol 1 at 80C. As in the case of the [2.2](2,6)pyridinophanes, introduction of a double bond into one of the bridges lowers the barrier. It amounts to 50.3 kJ mol 1 in (379). A report on pyrylium analogues of anti-[2.2]metacyclophane describes the [2.2](3,5)pyryliophane dication derivative (380) and the [2.2]metacyclo(3,5)pyryliophane cation derivative (381) [236]. Both are present as the anti-conformers. The methyl protons in (380) have d 2:04; which is an
upeld shift of 0.69 ppm relative to model compound (382) and represents a rather small shielding effect by the diatropicity of the pyrylium ring. In (381), the protons of the methyl group at the pyrylium ring are strongly shielded d 1:08 by the ring current of the m-phenylene ring. The intraannular proton of the latter is shielded d 4:95 by the pyrylium system but not as highly as the corresponding protons of [2.2]metacyclophane d 4:2: Compound (383) [237], claimed to be the rst benzo-fused heterophane, was reported to be conformationally rigid as the multiplet for its bridge methylene groups show no change up to 150C (DMSO-d6, 200 MHz). The multiplet was said to be of the AA 0 BB 0 type. However, the given structure (383) is correct, the compound has Ci symmetry and the two bridges should give rise to a common ABCD spectrum. The synthesis of [2.2](2,5)oxazolophanes (384) can, in principle, give four stereoisomers, in which both the ve-membered rings (rst designation) and the nitrogen atoms (second designation) can be oriented syn or anti with respect to one another. Two isomers, (384a) and (384b), were in fact isolated [238]. By comparison of the chemical shifts of the aromatic protons with the shift of H-4 in the reference compound 2,5-dimethyloxazole (385), the syn forms (with respect to the rings) are ruled out because the aromatic protons in both cyclophanes are slightly deshielded relative to (385). Anisotropic shielding effects would, however, be expected for a syn orientation. The anti anti (384a) and anti syn (384b) isomers formed were assigned from the symmetry of the bridge proton spectra at room temperature and at 150C, where rapid oxazole ring rotation takes place. Compound (384a) displays an eight-proton multiplet at ambient temperature and one singlet at 150C whereas (384b) exhibits a four-proton singlet and a four-proton multiplet at ambient temperature and two singlets at 150C. The elegance of the study suffers somewhat from a number of accidental shift coincidences at the observation frequency of 90 MHz. Coalescence measurements yield oxazole ring rotation barriers DG of 74.5 kJ mol 1 at 80C for both compounds. This compares with a barrier of 70.3 kJ mol 1 in [2.2](2,5)furanophane [223]. The structures of the isomeric [2.2](2,5)thiazolophanes (386a) and (386b) were derived in a similar manner
114
Ph O Ph + Me + (380)
2.04
Ph O Ph + H (381) Me
1.08
Me
2.73
Ph Me O Ph
+ Ph O (382) Ph
4.95
N S S N (383) (384a) X X N (384b) N O O N N O O N
N H 3C O CH3
N N
X (385)
X (386a), X = H (387a), X = D
(386b), X = H (387b), X = D
N O
(388)
as those of the oxazolophanes and accidental shift coincidences also occur. Conrmation was achieved by investigation of the tetradeuteriated derivatives (387a) and (387b). These give a common AB spectrum for the two protons in each bridge of (387a) and a singlet (degenerate AA 0 BB 0 spectrum) for the nondeuterated bridge of (387b). No signal coalescence was achieved by heating the thiazolophanes to 150C, in accord with the behaviour of the corresponding thiophenophanes [223]. The same authors also found [239] that isoxazolocyclophane (388) is conformationally rigid on the NMR time scale, DG being larger than 88 kJ mol 1 [cf. DG 84 kJ mol1 for [2.2]metaparacyclophane (263)].
Sternhell et al. [47] analysed dynamic 1H NMR spectra of 4-methyl[2.2](2,5)furanoparacyclophane (389) by the lineshape method and determined activation parameters DG 31C 49:7 ^ 1:0 kJ mol1 ; DH 46:9 ^ 1:3 kJ mol1 ; and DS 13:8 ^ 5:2 J K1 mol1 : The observed process is believed to be the ipping of the furan ring as had been postulated by Otsubo et al. in their earlier study of the methyl-free compound [240]. Variable temperature 1H NMR spectra were obtained of the [2]metacyclo[2](3,4)thiophenophane (390) [241], a thiophene analogue of [2.2]orthometacyclophane (276/277) [188]. At 27C the ratio of syn to anti conformer is 2:1 (in C6D5NO2). Lineshape analysis of the methyl signals yields free energies
115
Me H3C O S Me Me S Me (389) (390), syn (390), anti
CO2Me
3.97
3.91
3.35
MeN
4.92 H
CO2Me
NOE
(391)
of activation at 27C of DG syn ! anti 85:4 ^ 0:4 kJ mol1 and DG anti ! syn 83:7 ^ 0:8 kJ mol1 : The barrier in (276/277) has been estimated as 84100 kJ mol 1. The conformation of [2.2]metacyclo(2,4)pyrrolophane (391) [242] was recognized as anti from the upeld shift of the intraannular m-phenylene proton d 4:92 and of the ester methyl group d 3:35 that extends over the m-phenylene ring. The normal ester group has d 3:91: When the signal of the shielded ester methyl group was saturated, NOEs were observed for the resonances of the outer protons of the m-phenylene ring. 3.9. [2.2]- and [3.3]Phanes capable of through-space 19 19 F, F coupling The present section is used to describe work on through-space 19F, 19F spinspin coupling in diuoro[n.n]cyclophanes n 2; 3 with one uorine substituent per aromatic ring. In order to avoid fragmenting related material, the section covers both diuoro[2.2]cyclophanes and diuorodithia[3.3]cyclophanes even though the latter do not belong here as far as the general classication by the Table of Contents is concerned. A comprehensive description of the NMR properties of these compounds is given here, in addition to a description of their throughspace spinspin couplings. The relative rigidity of the smaller meta- and paracyclophanes entails relatively well dened geometries which, in turn, offer themselves for studies of
geometry-dependent NMR phenomena. In an NMR study [243] of the syn-diuoro[3.3]metacyclophanes (392) and (393) and the syn-diuoro[2.2]metacyclophanes (136) and (394), a correlation was found between the nonbonded F,F-distances, dFF, (278 248 pm, as estimated by molecular mechanics computations) and the uorineuorine coupling constants, J(F,F) (42.199.2 Hz), which were considered to be due to through-space spinspin coupling because of the large number of bondsseven and eight, respectivelyand the unfavourable geometry and electronic pathway between the interacting nuclei. As the uorines in (392)(394) are chemically equivalent, the J(F,F) values had to be extracted from the 13C satellites in the 19F NMR spectra. Due to the chemical equivalence of the uorine nuclei (or their nearequivalence if the isotope effect of 13C is taken into account) and their magnetic nonequivalence, their mutual spinspin coupling also manifests itself in second-order effects in the 1H and 13C NMR spectra of these compounds. In syn-(393), for example, the protons meta to the uorines do not absorb as a simple doublet by coupling with 19F but as an apparent triplet which represents the X part of an [AX2]2 spin system. Also, the absorption of C-9 in (392) is not a doublet of doublets due to 1J(F,C) and 7J(F,C) but rather the sixline part of an ABX system A; B 19 F; X 13 C with the inner two lines having very small intensities. Previously, the distances of 251.5 and 7.8 Hz between the four intense lines had been mistaken for the F,C coupling constants [244], while a proper analysis yielded 244.7 and 0.3 Hz. In solution, there exists
116
F F
S S
R SF (392), R = H (393), R = tBu
FS R anti
R syn
F F R R F (136), R = H (394), R = SMe F 242 pm
(397)
a conformational equilibrium between syn-(393) and its anti counterpart with a syn/anti ratio of ca. 8:1 at room temperature, where the conformers interconvert slowly on the 1H NMR time scale (400 MHz). The anti-conformer gives a rst-order 1H NMR signal for the aromatic proton as the F,F-distance is large and the J(F,F) value too small to be resolved. The barrier to syn/anti interconversion was determined by observing the coalescence of the t-Bu signals, DG 105C 81:3 kJ mol1 : The sign of the through-space F,F coupling constant in (392) was proven to be positive (42.1 Hz) by triple resonance experiments of the type 13C{ 1Hbb, 19Fcw} (bb broadband decoupling; cw continuous wave selective irradiation) [245]. In a later paper [246], the series of compounds was extended to include both larger and smaller dFF values.
Hanti
1 8 13 15 16 9 2 3 4
The larger values occur in the pseudo-geminal isomers of the diuoro-dithia[3.3]paracyclophane (395) and of the diuoro[2.2]paracyclophane (396) with computed dFF values of 318 and 300 pm, respectively, and observed J(F,F) coupling constants of 7.2 and 13.7 Hz, respectively. Smaller nonbonded F,F distances were achieved by introducing bulky tertbutyl groups into the positions para to the uorine substituents of (136) to give compound (397). The calculations gave 242 pm for dFF and a record J(F,F) value of 110.1 Hz was observed. The data for the compounds mentioned so far plus those of the mono-tert-butyl derivatives of (392) and (136) allowed the authors to derive a smooth function, Eq. (1), describing the dependence of the through-space F,F-coupling constant on the nonbonded F,F-distance expressed in picometres. The ranges of J(F,F) and dFF
3 4 9 15 17 18 13 7 10 5
Hsyn F X
14 1
X
12
S X (396) (398) (399) (400) (401) 15-F 16-F 13-F 12-F H (395) (402) (403) (404) (405) X 17-F 18-F 15-F 14-F H

120 100 J(19F, 19F) [Hz] 80 60 40 20 0 240 250 260 270 280 dFF [pm] 290 300 310 320
J(F,F)=6800*exp( 0.0199* dFF) J(F,F)=275000*exp( 0.03211* dFF)
117
Fig. 1. Experimental J( 19F, 19F) values [Hz] vs. intramolecular F,F distances dFF [pm] in some diuorocyclophanes. The data points are indicated by the triangles. The curves represent the equations J F; F 275 000 exp0:03211dFF derived in Ref. [246] and J F; F 6800 exp0:0199dFF from Ref. [247].
values covered are 7.2110.1 Hz and 318242 pm, respectively. J F; F 275 000 exp0:03211dFF 1
The curve illustrating Eq. (1) and the data points from which it was derived are shown in Fig. 1 together with the curve for an equation postulated earlier by other authors [247]. Evidently, for the smaller distances, the earlier equation predicts coupling constants that are too small by a factor of two. This is caused by underestimating the F,F-distances in the compounds from which the equation was derived. The four possible isomeric diuoro[2.2]paracyclophanes with one uorine substituent per aromatic ring are the pseudo-geminal (396), the pseudo-ortho (398), the pseudo-meta (399) and the pseudo-para isomer (400). The pseudo-geminal isomer has already been mentioned above with respect to its through-space F,F-coupling. Surprisingly, spin coupling between the uorine nuclei is also observed in (398) and (400), and the J(F,F) values obtained from the 13C satellites in the 19F NMR spectrum amount to 0.6 and 2.8 Hz, respectively [165]. Only in (399) is the J(F,F) coupling not resolved, see below, however. As J(F,F) in the nonpseudo-geminal isomers is largest in (400) in spite of the largest F,F-distance, this coupling was assumed to be transmitted through the p-electron system of the [2.2]paracyclophane deck. The four isomers were obtained as a mixture and their 1H, 13 C and 19F chemical shifts were assigned from one-
and two-dimensional spectra of the mixture, including H,H-COSY, C,H- and F,H-HETCOR and C,HCOLOC [165]. The appearance of the H-5 (proton ortho to the uorine) signal for (399), (400) and (396) is instructive because of its dependence on the magnitude of J(F,F). The near-zero J(F,F) value in (399) leads to a rst-order doublet of doublets for H-5 due to 3J(F,H) and 4J(H,H), while a broadened dd is observed for H-5 in (400) with its medium-sized J(F,F) and a second-order multiplet in (396) which has the largest J(F,F) (Ref. [165, Fig. 2b]). The monouoro compound (401) was also studied for comparison. Interesting features here are the through-space couplings between uorine and its pseudo-geminal proton, J F; H 3:1 Hz; and carbon, J F; C 1:6 Hz: The shape of the H-15/C-15 cross peak in the 2D C,H-HETCOR spectrum shows these couplings to have like signs. The through-space F,Ccoupling had not been observed previously [248,249]. Also interesting is the observation that all 13C nuclei of the nonuorinated ring, apart from C-13, show small but observable couplings (0.151.57 Hz) to the uorine, the largest apart from the pseudo-geminal carbon being the one with the most distant, the pseudo-para carbon (0.39 Hz). Here again, spin coupling is probably transmitted through the [2.2]paracyclophane p-electron system. The diuorodithia[3.3]cyclophanes (395) and (402)(404), and the monouoro compound (405), synthetic precursors of the [2.2]phanes (396), (398)(400) and (401), were
118
also studied by the same techniques, the diuoro compounds again as a mixture. Interring F,C coupling constants of 0.30.7 Hz were detectable between uorine and its pseudo-geminal carbon nucleus in (402)(405). In (405) also two small J(F,C) couplings involving the carbon nuclei pseudo-ortho to the uorine substituent were found, having values of 0.19 and 0.09 Hz. The only interring J(F,H) coupling constant observed was the pseudo-geminal one in (405) of 1.3 Hz. The decreased magnitudes of the interring coupling constants in the dithia[3.3]paracyclophanes are in line with the larger interring distances in these compounds relative to the [2.2]paracyclophanes. The 1H, 13C and 19F NMR spectra of the ar,ar 0 diuoro[2.2]paracyclophanes (396) and (398)(400) were studied again by Huang et al. [250], this time, however, of the separated stereoisomers. Basically, their results agree with those of Ref. [165] and, additionally, they report a long-range J(F,F) value of 0.36 Hz in the pseudo-meta isomer (399). Refs. [165,250] differ, however, in the assignment of the chemical shifts of the diastereotopic protons in the bridge CH2 group ortho to a uorine substituent. In (401), the shifts of the protons syn and anti with respect to the uorine differ by 0.72 ppm, one proton
2 3
8
being shielded Dd 0:41; and the other deshielded Dd 0:31 relative to the hydrocarbon, [2.2]paracyclophane. The question was settled in favour of Ref. [165] by reinvestigating (401) by means of 2D H,H-NOESY and further techniques [251] which clearly show that the deshielded proton is the one syn to uorine. Another series of compounds studied [252] with regard to possible long-range F,F spinspin coupling consists of diuoro[2.2]metaparacyclophane (406) and diuorodithia[3.3]metaparacyclophane (407). In solution, both compounds occur as slowly interconverting syn and anti conformers in a 1:1 ratio. The interconversion barrier in (407) was determined from the coalescence of the two pairs of 19F NMR signals to be DG 125C 77:0 ^ 0:6 kJ mol1 : This number is very similar to the value of 76.2 kJ mol 1 found earlier by Boekelheide et al. [184] for the monouoro derivative (408). Hence, the additional uorine substituent at the para-bridged ring in (407) does not signicantly increase the barrier to internal rotation. This appears reasonable as molecular models show that the C-14F-14 moiety is hardly involved when the tip of the meta-bridged ring rotates through the interior of the molecule. The
F
1 9
F F
15
15 12 11
12
syn-(406) (409)
X=F X=H
anti-(406)
(410)
10
S X
14 17
S X
14 9 5
F S 1
F S
syn-(407) (408)
X=F X=H
anti-(407)
119
shorter bridges in (406) increase the rotational barrier such that no coalescence occurs until 150C, so the gtle lower limit of DG 150C is 89 kJ mol 1. Vo has shown long ago [253] that the barrier in 8-uoro[2.2]metaparacyclophane (409) is higher than 95 kJ mol 1 at 190C. J(F,F) coupling constants can be resolved in both conformers of both (406) and (407). They are 1.87 Hz in syn-(406), 0.42 Hz in anti-(406), 0.49 Hz in syn-(407), and 0.66 Hz in anti-(407). The wrong order in (407), i.e. smaller J(F,F) for the compound with the shorter nonbonding F,F distance, speaks against a pure through-space coupling mechanism. Also, the larger coupling constant of 1.87 Hz in syn-(406) is still much smaller than the value of 16.9 Hz predicted by Eq. (1) for the computed F,F distance of 302 pm. The computed F,F distance in syn-(407) is 330 pm, for which Eq. (1) predicts J(F,F) to be 6.9 Hz. The inapplicability of Eq. (1) to these coupling constants may be due to the different geometrical arrangement of the CF bonds in the diuorometaparacyclophanes compared to the diuorometa- and -paracyclophanes from which the equation was derived. Formally, the aromatic rings in (406) and (407) are twisted relative to each other by 30 about an axis joining their midpoints, whereas no such large twist is present in the meta- and paracyclophanes. This could indicate that factors other than the nonbonding distance may contribute to determining the magnitude of throughspace coupling constants. Further investigations along these lines are clearly indicated. All 1H, 13C and 19F NMR signals in both conformers of (406) and (407) and also of the monouoro analogues (408) and (409) were carefully assigned by appropriate 1D and 2D NMR techniques. A feature worth mentioning with regard to the diuorometaparacyclophanes is the observability of relatively large (2.24.3 Hz) through-space J(F,C) couplings from the uorine at the meta-bridged ring to the syn-oriented carbon atoms of the para-bridged ring but not from the uorine at the para-bridged ring to analogous carbon nuclei at the meta-bridged ring. This is due to the particular geometry of the metaparacyclophanes: the uorine-bearing carbon atom of the meta-bridged ring lies over the centre of the para-bridged ring. Thus, its uorine substituent is very close to the syn-oriented carbon atoms of the para-bridged ring. The reverse is not true for the uorine at the para-bridged ring and
its syn-carbons in the meta-bridged ring. The chemical shifts of the aromatic protons and of the 13C nuclei of the uorine-bearing ring of 4-uoro[2.2]metaparacyclophane (410) have been assigned [249].
4. [3.3]Phanes 4.1. [3.3]Phane hydrocarbons 4.1.1. [3.3]Metacyclophanes According to molecular mechanics computations the lowest conformational energy minimum of [3.3]metacyclophane (411) corresponds to the syn(chair/chair) form (411 0 ), which was also found in the crystal by X-ray diffraction [254]. The symmetry of the 1H NMR spectrum at low temperature, the chemical shifts and the H,H coupling constants in the bridges prove that this conformation is also the major one in solution. The signal for the intraannular aromatic proton of a second, minor conformer, presumably the syn(chair/boat) one (411 00 ), can also be observed at 50C. The benzylic protons of (411) are diastereotopic at low temperature and their signals coalesce at ca. 29C (200 MHz). The barrier DG to bridge inversion was determined to be 48 kJ mol 1 at this temperature. As the equilibrium constant K of major to minor conformer could not be measured directly because of signal overlap in the 1H spectrum and crystallization from the solution of the minor isomer, the temperature dependence of the chemical shift of the internal carbon atom C-9 was used to estimate K. The results do not seem very precise. The signal of C-9 was also used in a lineshape analysis over a temperature range of only 18.5C. The Ea and log A values reported convey the impression of limited accuracy. This study implies that the only important dynamic process in [3.3]metacyclophane is bridge wobbling (chair-to-boat interconversion), but Shinmyozu and coworkers [255] had concluded that it is benzene ring inversion. Therefore, the latter group of authors designed (412), a [3.3]metacyclophane with an ethylenedioxy tether that prevented benzene ring inversion [256]. In their low-temperature 1H NMR study of (412) they conrmed the bridge inversion process postulated by Semmelhack et al. [254] and could observe all three possible conformers, chairchair (412cc), chairboat (412cb), and boat
120
(411)
J = 14.7 Hz
(411) D2 H
3.02 2.47 6.71
(411")
J = 14.6 Hz
6.61
2.46 J = 13.8 Hz
D2 H
3.03 6.83
D2
H
J = 13.8 Hz
D2
6.32
H O O (412cc)
D2
H
2.35 6.20 6.29
2.95
H O O (412cb)
D2
H
2.32 6.16
2.95
O O (412bb)
2.50
Hax D2 R R (413) (414), R = H (415), R = OMe D2 Heq
2.97
boat (412bb) which gave a total of four AB spectra for the benzylic protons. At 70C the conformers are present in the ratio of 47:44:9. Signal coalescence was observed at 11C and the barrier to bridge inversion estimated to be 50.651.5 kJ mol 1. As the high-temperature spectrum of the benzylic protons of (412) consists of an AB pattern but that of (411) of only a singlet, the Japanese authors concluded that in (411) benzene ring inversion must occur in addition to bridge wobbling. A further study of the conformational behaviour of a [3.3]metacyclophane derivative was undertaken by Fukazawa et al. [257]. They analysed variable temperature 1H and 13C NMR spectra of 1,1,10,10-tetramethyl[3.3]metacyclophane (413) and, at 96C, observed the presence of the three possible bridge conformers (cc, cb, and bb) with a syn arrangement of the benzene rings. These conformers interconvert by wobble motions of the bridges and aromatic ring ips to give their respective mirror images. The barrier for the benzene ring ip-
ping process was found to be smaller (39 kJ mol 1 at 83C) than the barriers of the wobble motions of the bridges (56 kJ mol 1 at 3C). Benzene ring ipping occurs most easily from the syn-chairboat conformer. A study of the conformational behaviour of [3.3]metacyclophane, rather similar to that of Semmelhack et al. [254], was reported later by Sako et al. [258]. They studied the low-temperature 1H NMR spectra of 2,2,11,11-tetradeuterio[3.3]metacyclophane (414) and its dimethoxy derivative (415) and came to the same conclusions. They also observed the signals of a minor conformer, probably the syn(boat/chair) one, but could not obtain further details because of signal broadening and overlap at low temperature. Compound (415) behaves like its parent. Irradiation of its intraannular proton signal causes a 17% NOE at the axial bridge proton (in the chair conformation), thus proving that the shielded methylene protons are axial d 2:50; while the deshielded ones are equatorial d 2:97:
121
H CH3 R R
H
H Me H (416) R a b c (417)
H Me Ph
CH3 (CH2)n
(418), n = 4 (419), n = 5 H3 C H3C

chair-chair
H3 C H3C cis-(420) tBu

5.94
chair-boat
O
6.77.2 (4 H)
O R R (421) OMe R R (422), R = CO 2Et (anti) (423), R = H ( syn)
A number of 1-methyl-3-(a-R-b-trans-styryl)[3.3]metacyclophanes plus a [4.3]- and a [5.3]metacyclophane were elucidated with respect to their preferred syn/anti conformation and the cis/trans substitution pattern of the three-membered bridges [259]. The methods applied were Lehners d (Hi) d (He) rule [260] (cf. Section 5), variable temperature 1H NMR and NOE difference spectra. The compounds studied were (416a)(416c) with 1,3-cis-disubstitution and preference of the syn conformation, (417a)(417c), with 1,3-trans-disubstitution and preference of the
anti conformation, (418) and (419) (cis anti) and the model compounds cis- and trans-(420). The lowtemperature 1H spectra of cis-(420) shows doubled signals for the internal proton and the methyl group DdMe 0:035; which the authors attributed to slow interconversion of the chairchair and chairboat conformers. DG c was determined by a coalescence measurement to be 48:5 ^ 0:4 kJ mol1 at 42C. The separation of the methyl signals for the trans diastereomer of (420) is much larger DdMe 0:38 1 (Tc not reported). and DG c is 47:7 ^ 1:3 kJ mol
122
[3.3]Metacyclophane-6,9-quinone (421) [261] possesses the syn conformation as evidenced by the signicant shielding of its olenic protons d 5:94 relative to the model compound 2,6-dimethyl-pbenzoquinone d 6:60: Its 1H NMR spectrum does not change with temperature in the range 70 to 200C. The para- and metapara-isomers of (421) are treated in the following sections. In the same reference, the preferred conformations of the [3.3]metacyclophanes (422) and (423) were determined to be anti and syn, respectively, mainly from the 1H chemical shifts of the internal aromatic and methoxy protons. These are d 6:13 and 3.50 (422) and d 7:23 and 3.68 (423). Breitenbach et al. [262] proved the preference of the anti conformation for [3.3]metacyclophanes (424) and (425) by X-ray diffraction and 1H NMR spectroscopy. The chemical shifts of the intraannular protons Hi in these compounds are d 5:53 and 6.52, respectively, caused by the ring current of the opposite ring in the anti conformation. The authors claimed the anti conformation of (424) and (425) to be unprecedented. This needs to be corrected, cf. the work by Krois and Lehner [260]. When diketone (424) is reduced to the diol, product (426) assumes the usual syn conformation with dHi 7:8: A paper by Osada et al. [263] reported the 1H and 13 C NMR data of the 9-halo[3.3]metacyclophanes (427a)(427d), which like the parent compound (411) prefer the syn conformation, and of the corresponding 2,11-diones (428a)(428d), which favour the anti arrangement. The main subject of the discussion is the inuence of the halogens upon the chemical shifts of the intraannular hydrogens and of the carbon atoms (C-18) to which these are bound. Halogenation of C-9 causes upeld shifts of C-18 by 4.05.7 ppm (F I Br Cl) in the [3.3]metacyclophanes and by 1.72.6 ppm (I Cl Br F) in the [3.3]metacyclophanediones, so there are no obvious trends within the halogen series. The chemical shift of H18 in the diones (428) decreases steadily with increasing size of the halogen, being d 5:78 for the parent compound (429) and 5.65, 5.27, 5.20, and 5.12 for the F-, Cl-, Br-, and I-derivatives, respectively. This was attributed to increased tilting of the halogen-bearing ring away from the opposite ring in the anti conformation. At the same time, this movement forces H-18 further into the p-cloud of the halogen-bearing
benzene ring, thereby increasing the shielding of H18. In the syn-metacyclophanes (427), H-18 is directly inuenced by the halogen and its chemical shift decreases in the order d 7:21; 7.15, 7.12, 6.98, 6.87 for the 9-substituents F, Cl, Br, I, and H. In (427a), H-18 shows a through-space J(F,H) coupling of 4.4 Hz. In another study of transannular interactions in uoro[3.3]metacyclophanes, Osada et al. [264] described the diuorophane (430), in which the two uorine substituents approach each other closely. The authors give values of 253 and 10 Hz for J(F-9,C-9) and J(F-18,C-9), respectively, the latter being due to through-space spinspin coupling. Probably, however, these numbers are the result of the neglect of strong F,F spinspin coupling which is expected for this molecule and has been shown to exist in the corresponding diuorodithia[3.3]metacyclophane [243]. A large value of J(F,F) in (430) makes C-9 the X part of an ABX spin system (A F-9, B F-18). The parameters involved cause the X part to have six lines of which two are of rather small intensity and are easily lost in the baseline noise. The line spacings in the remaining apparent doublet of doublets do not correspond by any means to the true J(F,C) values, cf. the analogous situation in (392) (Section 3.9). Fukazawa et al. undertook the conformational analysis of 1,1,10,10-tetramethyl[3.3]metayclophane-2,11-dione (431) [265]. To this end they generated plausible conformers by molecular mechanics calculations, estimated the chemical shifts of protons ad in these conformers [relative to model compound (432)] from contributions expected by the second aromatic ring and the two carbonyl groups (see below) and adjusted the populations of the conformers so as to achieve the best t between calculated and observed shifts, cf. Section 5 for details. Optimum agreement was found when three equilibrating conformers were assumed, viz. a major anti (94%), approximated by (431a), and two minor (3% each) syn conformers. In this way, the differences between tted and experimental incremental shifts for protons ad could be minimized to 0.030.07 ppm. Experimentally, ipping of the benzene rings becomes slow at 65C when the methyl signal starts to split into two DG 41 kJ mol1 ; but no minor signal could be detected even at 110C. The substituent-induced chemical shifts exerted by the carbonyl groups (see
123
tBu
EtO2C
CO2Et
tBu
HO H
OH H
tBu
EtO2C
CO2Et
tBu
(424), anti
(425), anti
(426), syn
X
18
O O O
O
18
(427a), X = F (427b), X = Cl (427c), X = Br (427d), X = I
(428a), X = F (428b), X = Cl (428c), X = Br (428d), X = I
(429)
O
9
O O
a d
18
O (430) (431) (432) (431a)
above) were calculated by the use of new shielding parameters [266]. These were obtained by least rchers squares multiple regression analysis of Zu experimental values of keto-steroids [267] and geometrical factors newly calculated with the MM3 molecular mechanics program. Compound (433) may be considered a [3.3]metacyclophane with two oxazole rings annelated to its trimethylene bridges [268]. The upeld shifts of the outer protons of ring A Dd 0:22 relative to mxylene were taken as indicators of a preferred syn
conformation. The shifts of the inner protons of rings A and B were not taken into account because of potential disturbing shift effects of the oxazole rings. Coalescence of the methylene AB spectrum at 38C gave DG 64:5 kJ mol1 : This is a substantially higher barrier to conformational inversion than in the case of [3.3]metacyclophane (411) where DG is 48.1 kJ mol 1 at 29C. Hence, (433) is conformationally more rigid than (411) due to annelation of the two oxazole rings to the methylene bridges. Compound (434) [269] is the formal product of
124
Br
Br
O N
O N N
N N
A (434) O X N Hi N O N O (437) O N
(433) O
(435), X = O (436), X = S
6.906.50 (4 H)
R R
X N
R R
R R
R R Fe
3.27 3.85 3.83
(438), X = CH; R,R: =O (439), X = N; R,R: =O (440), X = CH; R = H (441), X = N; R = H
(442), X = O; R,R: =O (443), X = S; R,R: =O (444), X = O; R = H (445), X = S; R = H
(446)
annelating two imidazole rings to the bridges of [3.3]metacyclophane and additionally carries two 4bromophenyl groups. The 1H NMR spectrum at 5C shows the presence of the syn and the anti conformer in a ratio of ca. 3:5. All proton signals of both conformers were assigned by means of an H,H-COSY experiment. The signals of the nonequivalent methylene protons coalesce at 80C, which furnished an interconversion barrier DG of 69.3 kJ mol 1, somewhat larger than in both (411) and (433). This was attributed in part to the bulky substituents on the imidazole rings. Further studies along the same lines dealt with furanometacyclophane (435) [270], which has a 2,5-furandiyl moiety instead of the m-phenylene
unit B of (433), and the analogous thiophenophane (436) [271]. At room temperature, the furan protons of (435) are shielded by 0.26 ppm relative to those of the acyclic model (437) which was taken as evidence of the preferred syn conformation. At low temperature, the CH2 protons become diastereotopic while the aromatic 1H signals do not change much. Coalescence of the CH2 signals at Tc 12C gave DG 58:0 kJ mol1 at this temperature. This barrier is lower than that of (433) in line with the less congested transition state due to the furan oxygen compared to an aromatic C-H unit. By contrast, DG for (436) is 69.4 kJ mol 1 at 69C, higher than in both (435) and (433). At low temperature, thiophenophane (436)
125
gives two sets of H signals which, from their chemical shifts, were attributed to the syn- and anti-conformers. At 31C, the syn/anti ratio is 2:5. The signals in the low-temperature spectrum were assigned by H,H-COSY. Important chemical shifts are: thiophene-H, d 7:21 (anti) and 6.46 (syn); m-phenylene-Hi, d 6:18 (anti) and 6.89 (syn). The hetero analogues (438)(445) of [3.3]metacyclophane were reported by Shinmyozu et al. [272]. Comparison of their aromatic 1H NMR chemical shifts with those of m-xylene or 2,6-dimethylpyridine indicates preference of the syn conformation of all compounds containing unsubstituted trimethylene bridges, viz. (440), (441), (444), (445), and of the anti conformation for the diketones (438), (439), (442), (443). The anti preference of [3.3] metacyclophane-2,11-dione (429) had been demonstrated before by Krois and Lehner [260], cf. Section 5. The conformation of the bridges in [3.3](2,6)pyridinophane (441) was studied by low-temperature 1H NMR of the deuterated derivative (441-d4) [273]. Below 110C the benzylic protons and the aromatic protons each give two major and two minor signals that were assigned to the boatboat conformer (441bb) and the boatchair conformer (441bc) as shown in the formulae ( 1H chemical shifts at 135C in CD2Cl2/CBr2F2, 3:2, are given). The main argument was the deshielding observed for the ortho-protons of the bridge in the chair conformation. A rough estimate of the conformer populations at 135C is (441bb):(441bc) 3:2. The barrier to chairboat interconversion was estimated as DG 110C 36:4 ^ 1:7 kJ mol1 : This is lower than the barriers in [3.3]metacyclo(2,6)pyridinophane (440), 45.6 kJ mol 1, and in [3.3]metacyclophane (411), 48.1 kJ mol 1. In the 1H NMR spectrum of [3.3]metacyclo(1,3)-
ferrocenophane (446), the shielding of the ferrocene protons H-4,5 relative to H-2 and to H-1 0 ,2 0 ,3 0 ,4 0 ,5 0 indicates the preferred syn conformation of the molecule [217]. 4.1.2. [3.3]Paracyclophanes Following earlier work by Anet et al. [274] and by Benn et al. [275], the conformational behaviour of [3.3]paracyclophane was reinvestigated by Sako et al. [276]. These authors studied variable-temperature 1 H and 13C NMR spectra of 2,2,11,11-tetradeuterio[3.3]paracyclophane (447). At low temperature, separate signals were observed for the boat and chair conformers, the former being slightly favoured at 70C in CD2Cl2 solution (boat/chair 1.3/1.0; DG 0.4 kJ mol 1). The bridge proton signals turned into AB spectra below 15C and the aromatic proton signals into AA 0 BB 0 spectra below 30C. Boat and chair conformers could be distinguished from their J(A,B) coupling constants, 7.8 Hz (chair) and 1.5 Hz (boat). Assignment of the proton signals relied on NOE measurements (axial benzylic H ! aromatic ortho-H), those of the 13C signals on the different signal intensities for the conformers. The barrier to bridge inversion was determined as DG 15C 50:2 kJ mol1 : The assignment of the aromatic proton shifts was reversed with respect to Ref. [275]. The trimethylene bridge causes deshielding of the ortho proton in the syn orientation (ca. 0.14 ppm) and shielding of the corresponding ortho carbon atom (ca. 2.8 ppm), both with respect to the counterpart in the anti orientation. In the 1-methyl-3-R-[3.3]paracyclophanes (448) (451) [277] the cis or trans conguration of the available diastereomers was inferred from the 1H chemical shifts of the 1-methyl groups. In the cis diastereomers the methyl group always occupies a quasi-equatorial
2.86
3.14
D2 N N
D2
3.25
Hax" Heq" D2
6.63
D2 N N
3.14
D D
N N
Heq D D
2.55
Heq
2.55
Hax
7.01
Ha Hb
6.42
Hax Ha
7.14
Ha" Hb
6.42
(441-d4)
(441bb)
(441bc)
126
D D
D D
D D chair (447) H 3C R H3 C boat D
cis(448) (449) (450) (451) H3C R
transR CH3 styryl -methylstyryl inden-2-yl H 3C R
(452)
(453)
position on the trimethylene bridge while it is fully or partly quasi-axial in the trans diastereomers. As the quasi-equatorial position is outside the plane of the aromatic ring, a methyl group in this position will be shielded relative to one in the trans diastereomer. For example, d H(CH3) is 1.12 in cis-(448) and 1.27 in trans-(448). A safer criterion for the congurational assignment is the low-temperature behaviour of the isomers. A cis isomer is not expected to show a conformational inversion of the disubstituted chain, because both substituents take quasi-equatorial positions, whereas the trans isomer is expected to invert
the chain conformation. Variable-temperature 1H NMR measurements corroborated these expectations. In these experiments, methyl signal coalescence temperatures between 43 and 28C were found. Line shape analyses over limited temperature ranges yielded DH values for bridge inversion of ca. 29 kJ mol 1 and DS values of ca. 67 J K 1 mol 1 for the trans isomers of (448)(450). This corresponds to DG values of ca. 48 kJ mol 1 at 0C. The rather small DH value of 19.7 kJ mol 1 and the very large DS of 111 J K 1 mol 1 for (451), which give a similar DG (0C) as the other compounds, viz.

O O N
6.90
127
6.05
O N N O (455) (456) O N
(454)
49.8 kJ mol 1, do not appear convincing. The equilibrium populations at low temperature are different for the different R groups and reect the relative size of the substituents in the order methyl styryl amethylstyryl p indenyl. Later, the same group studied 1,3-substituted [3.3]paracyclo(1,4) naphthalenophanes (452) and [3.3](1,4)naphthalenophanes (453) carrying a methyl group and the same R groups as above [278]. The structures of the compounds were derived from variable-temperature 1H NMR spectra and NOE determinations. The barriers to bridge inversion are very similar to those of the [3.3]paracyclophanes (448)(451). In the series (452) there exists the additional problem of constitutional isomerism because one substituent can be adjacent to the phenylene and the other adjacent to the naphthylene ring or vice versa. The olenic protons d 6:05 and, to a lesser degree, also the aromatic protons d 6:90 of [3.3]paracyclophane-5,8-quinone (454) [261] are deshielded relative to the [2.2]analogue (d 5:78 and 6.84/6.73, resp.) which was described much earlier by Cram et al. [279]. This shift difference reects the larger interdeck distance in (454). 4.1.3. [3.3]Metaparacyclophanes Phanes (455) and (456) [268] are isomeric [3.3]metaparacyclophanes that differ in the positions
of oxazole annelation. While freezing of conformational exchange could not be observed down to 80C for (455) which has its oxazole rings condensed to the CH2CH2 unit next to the m-phenylene ring, a barrier DG of 47.7 kJ mol 1 was determined for (456), where the oxazole rings are next to the p-phenylene rings. Apart from the [3.3]meta-(421) and the [3.3]paracyclophanequinone (454) discussed in the preceding sections, the paper by Shinmyozu et al. [261] describes the two isomeric [3.3]metaparacyclophanequinones (457) and (458). In the rst one of these, rotation of the p-phenylene ring and ipping of the m-bridged quinone ring are both restricted at room temperature as two 1H chemical shifts are discerned for the p-phenylene ring, see the formula. The single olenic 1H shift in (458) was interpreted as (probably) indicating rapid ipping of the m-phenylene ring. The latter process is also fast in (459) whereas both rotation and ipping are slow in (460) due to the presence of the internal methoxy substituent. 4.1.4. Other [3.3]cyclophanes Staab and coworkers [280] described [3.3]orthoparacyclophane (461). Molecular models show that the planes of the two aromatic rings are likely to be parallel to each other but shifted sideways. As the 1H NMR spectrum at 10C has sharp lines for both aliphatic
tBu 1.30
7.36.5
6.72 5.73
6.80
O O
6.90/7.00
6.55
OMe
3.28 6.06 OMe
O
6.20 6.22 3.54 6.94
OMe (460)
(457)
(458)
(459)
128
6.906.69 6.03 6.92 1.81 1.91 2.70 7.277.15 6.93 7.21 7.15
(461) X
(462)
(463)
X S
6.17 6.41 6.96
X (464), X = H (465), X = CN
[shifts given for (464)]
and aromatic protons, there must be a fast transition between the two possible equivalent conformations. One pair of the benzylic protons is shielded by ca. 0.9 ppm relative to the other. Presumably these are the CH2 protons at the ortho-substituted ring which reside in the shielding zone of the para-ring. At lower temperature (not specied), the 1H NMR signals start to broaden, indicating the slowing down of the conformational interconversion. The [4.4]orthopara analogue (462) shows less signal broadening. This could mean a lower conformational barrier or a different ground state conformation. The 1H NMR spectrum of [3.3]orthometacyclophane (463) shows that the molecule is frozen in an anti conformation at 60C. This is suggested by the chemical shift of the internal proton d 6:03 on the meta-substituted ring. The two sides of the p-phenylene rings in [3.3]paracyclo(2,5)thiophenophane (464) and its tetracyano derivative (465) are nonequivalent in the room temperature 1H NMR spectrum [281]. Signal coalescence was observed at 50 and 98C, respectively, giving free energies of activation for the ipping of the thiophene ring of 66.5 and 76.6 kJ mol 1. H-2 of the indole moiety of [3.3](1,3)indoloparacyclophane (466) [282] has a chemical shift d 5:59: This is 1.36 ppm upeld from the value in the immediate synthetic precursor, a 3-(3-arylpropyl)indole, and shows that the indole hydrogen must lie over the p-phenylene ring. The three-membered bridges of
(466) can assume chair or boat conformations. AM1 calculations predict the Cchair,Nchair-conformer to be the most stable. The resonances of the p-phenylene ring give a slightly broadened AB spectrum (d 6:65 and 6.57) at room temperature indicating rapid conformational averaging. The NCH2 protons have a common shift of d 4:00 and their signals have triplet multiplicity J 6:6 Hz: At 90C, the p-phenylene ring shows four different 1H shifts and a pattern termed two AB systems by the authors (correct: one ABXY system), d 7:04=6:94 and 6.21/6.00. The NCH2 protons are diastereotopic at low temperature with d 4:25 and 3.63. The coalescence of their signals at 37 ^ 3C yielded a conformational barrier DG of 45:6 ^ 0:8 kJ mol1 : As none of the bridge wobble motions that interconvert the various bridge conformers results in a site exchange of the diastereotopic NCH2 protons, the process observed must be a ring ip. This is followed by a two-fold bridge wobble to furnish the enantiomer of the starting conformer. One of several possible conformational pathways is shown in the formulae. 4.2. Dithia- and diaza[3.3]phanes 4.2.1. Dithia- and diaza[3.3]metacyclophanes Mitchell and coworkers [114] have investigated the inuence of large internal substituents upon the relative stability of the syn and anti conformers of 2,11-dithia[3.3]metacyclophanes. When a single
129
(466)
N HA HB Cchair,Nchair
N HB HA HB ent-Cboat,Nboat HA
ent-Cchair,Nchair
7.02 6.60 7.02 6.89
S 1.52 tBu H S 6.26 (467), syn
7.01 6.50 6.83 6.91
S 1.45 tBu Me S 2.29
(468a), syn
7.06 6.95 7.06 7.36
7.15 7.04 1.68 Me
1.04
tBu S S
tBu S tBu S (469), anti
1.06
(468b), anti
tert-butyl group is present as an internal substituent (i.e. connected to C-9), only the syn isomer (467) is formed. A methyl group as the second internal substituent leads to a syn/anti mixture (6:4 at 80C and 7:3 at 50C) of (468a)/(468b) and the presence of two internal tert-butyl groups allows the formation of only the anti conformer (469). The anti isomers were identied by the upeld 1H shifts of the substituents by the second aromatic ring, cf. the tert-butyl shifts of d 1:05 in (468b) and (469) and the methyl shift of d 1:68 in (468b). The syn isomers show chemical shifts which are closer to normal values. However, the authors point to the exceptional shielding of the hydrogens para to the tert-butyl group in
(467) and (468a) which may arise by a sliding of the opposite ring in order to avoid the t-Bu/Me or t-Bu/H interactions. Such sliding should also shield the Me or H in question, which was indeed found: dMe 2:29 and dH 6:26 compared to the dimethyl compound dMe 2:52 and the parent compound dH 6:76: None of the compounds investigated showed signs of hindered tert-butyl rotation in the 1H NMR spectrum down to 90C. For the anti conformer of mono-tert-butyl[2.2]metacyclophane which was also studied by these authors, see Section 3. The conformation of 2,11-dithia[3.3]metacyclophane (470) is syn [283], but syn and anti conformers are known for the derivative which carries two
130
H2 H18 S S S
H6
S H
S H H H (472) (473)
7.19
H H
(470)
4.32 2.45
H
3.63
CH3
H H H
4.18 121.8
3.80 3.75 123.2
7.34
3.76 7.00 6.70
HH
S CH3
1.51
H
6.91 6.67
S
3.32
H
7.23 7.02
3.37
syn S S H (474), cis(e,e) S S H
(471) S S R
anti S S R (474), cis(a,a)

7.06.9
R H
S S
S S R
H S
6.79 3.65 3.97 3.93
(474), trans(e,a)
Fe
(475)
internal methyl substituents, i.e. at C-9 and C-18. Lai and Zhou [111] fully assigned the 1H NMR spectrum, including the signals of the bridge protons, of a mixture of the syn- and anti-isomers of the 9-uoro18-methyl derivative (471). The most signicant difference between the isomers concerned, of course, the chemical shifts of the methyl groups: d 2:45 (syn) and 1.51 (anti). For C-9 monosubstituted derivatives of 2,11-dithia[3.3]metacyclophanes, the conformation is difcult to predict. Mitchell and colleagues [284] investigated the 9-phenyl derivative (472) and found that it is syn both in the crystal and in
solution. Rotation of the phenyl ring is hindered at temperatures below 60C as seen from the different chemical shifts of H-2 0 and H-6 0 . The syn conformation of the cyclophane rings follows from the good agreement between the observed relative chemical shifts of H-18, H-2 0 and H-6 0 and the shielding effects of the three aromatic rings upon these nuclei as predicted by JohnsonBovey-type ring current calculations [79]. The indenometacyclophane (473), a dithia[3.3]metacyclophane with an annelated cyclopentane ring, is interesting because it shows chemical equivalence of the geminal protons within the three
131
methylene groups of the ve-membered ring [116]. This can only be explained by a fast syn/syn 0 equilibrium on the NMR time scale at room temperature, which interchanges the exo and endo hydrogens. It is in accord with the low activation barrier to ring ipping that has been observed in [3.3]metacyclophane [258] and computed for 2,11-dithia[3.3]metacyclophane [285]. The 2,11-disubstituted 1,3,10,12-tetrathia[3.3]metacyclophanes (474) could, in principle, exist as three congurational isomers. In the preferred syn-conformation of the two arene rings, these diastereomers would be trans(ea), cis(ee), and cis(aa). Due to fast ring ipping at all readily accessible temperatures, the two cis-isomers interconvert rapidly, so only two congurational isomers can be isolated. Beer et al. [286] prepared (474), R CH3, isolated one diastereomer, which is cis according to X-ray diffraction analysis, and could thus assign the 1H and 13C NMR spectra of the cis and trans isomers. As the chemical shifts do not differ much, the results do not allow the congurational assignment of the ferrocenyl-substituted phanes (474), R C5 H5 FeC5 H4 : The 1H NMR spectrum of the diastereomeric mixture of (474), R CH3, shows sharp resonances at room temperature and signal broadening but no decoalescence of signals at 62C. In the 1H NMR spectrum of dithia[3.3]metacyclo(1,3)ferrocenophane (475), the shielding of the ferrocene protons H-4,5 relative to H-2 and to H1 0 ,2 0 ,3 0 ,4 0 ,5 0 indicates the preferred syn conformation of the molecule as has already been mentioned for the analogous [3.3]phane hydrocarbon (446) [217]. While the effects of Cr(CO)3 complexation upon NMR chemical shifts have been well studied for [n]and [2.2]cyclophanes (cf. Sections 2 and 3), this is not the case for dithia[3.3]cyclophanes. Since the spacing between the arene rings in these compounds is different from the [2.2]phanes and since syn and anti isomers of dithia[3.3]metacyclophanes are known, this class of complexes promised additional information. Mitchell et al. [287] conducted a thorough study of the 1H and 13C NMR spectra of Cr(CO)3 complexes of substituted syn-dithia[3.3]metacyclophanes (476), of anti-9,18-dimethyl-dithia[3.3] metacyclophane (477), of dithia[3.3]paracyclophane (478), and of the bis-Cr(CO)3 complexes of syn-dithia[3.3]metacyclophanes (479). The chemical shifts of these compounds
were compared with those of the complexes of analogous simple benzene derivatives. The conclusions derived from these data are: (i) the tricarbonyl umbrella in the complexed dithiametacyclophanes favours the conformation in which the carbonyl groups eclipse the cyclophane bridges; (ii) the reduction in ring current in the arene rings is estimated at 40% on Cr(CO)3 complexation (cf. Ref. [140]); (iii) the complexation shifts are 1.62.0 ppm for protons, 3239 ppm for tertiary, and 2629 ppm for quaternary carbon atoms. From the 1H chemical shifts of the methyl groups d 1:31; 9,18-dimethyl-2,11-diselena[3.3]metacyclophane (480) was shown to occur mainly as the anti conformer [288]. The syn conformer, found in the mother liquor but not obtained pure, has dCH3 2:43: These chemical shift values compare well with those of the thia-analogues, which are d 1:30 and 2.54, respectively [9]. Previously, structure (480) had erroneously been assigned to a compound with different properties [289]. The authentic structure was now also proved by X-ray diffraction. Its 77Se and 13C shifts are available. The methyl-free diselena compound (481) was studied by low-temperature 1 H, 13C and 77Se NMR spectroscopy and found to prefer the syn over the anti conformation by a ratio of 3:2 at ca. 100C [285]. The barrier DG to syn ! anti conversion was determined to be 34.4 kJ mol 1 (at 70C) from the 77Se spectra and 34.8 kJ mol 1 (at 86C) from the 1H spectra. Bridge wobbling between chair and boat conformations was not observed and, hence, must have an even lower barrier. Very recently, the conformational analysis of (482), the 2,11-diaza analogue of (392) was reported [290]. The syn and anti isomers could be isolated, the anti isomer slowly converting to syn in solution. Kinetic measurements by 1H NMR gave Ea 104 ^ 4 kJ mol1 for this process in CD3CN solution. Determination of isomer ratios by 1H NMR between 110 and 170C gave DH 5:94 ^ 0:46 kJ mol1 ; DS 8:0 ^ 0:8 J K1 mol1 and DG25C 8:3^ 0:8 kJ mol1 : Below 10C the 1H spectrum of the CH2 groups in the syn-isomer changes from one AB system to four AB systems, one each for the boat boat (bb) and chairchair (cc) conformers and two for the boatchair (bc) conformer of the diaza bridges. In agreement with this, the 19F NMR spectrum shows three signals below 10C. At low temperatures the
132
Cr(CO) 3
6
18
(476)
R H 6-Me 5,7-Me2 9-F 18-F 9,18-F2 9,18-Me2
(CO)3Cr S CH3 H3C S (477) Cr(CO) 3 R

9S 18
(CO)3Cr
S
S
R H 9,18-F2
(478)
Cr(CO) 3
(479)
(1H) 7.1
(13C) 29.5
Se
Se
Se
Se
(77Se) 379.3
5.8
26.3
Se
Se 321.9
(480)
syn-(481)
anti-(481)
F F
F NH
NH NH
HN F
syn (482)
anti
stability of the conformers is bb bc cc, but with increasing temperature the proportion of bb decreases and the proportions of both bc and cc increase. The overall activation energy of boatchair interconversion was estimated as 5054 kJ mol 1 at 10C from the coalescence of the CH2 1H NMR signals. Formally, cyclophane (483) is also a 2,11diaza[3.3]metacyclophane, but with imidazole rings annelated to the bridges [291]. The intraannular hydrogens have chemical shifts d 5:94 and 5.65. This clearly proves the anti conformation. No other conformation was detected when the sample was cooled to 88C. The benzylic protons have a shift difference of 0.49 ppm at room temperature and their
signals coalesce at 102C (300 MHz), so DG is 75.3 kJ mol 1. The 2,11-diaza[3.3]metacyclophanes (484) [292] with three methyl groups per aromatic ring prefer the anti conformation as indicated by the highly shielded protons of the intraannular methyl groups, d 1:041:05: Compound (485) with only one methyl-substituted ring favours the syn arrangement, dMe 2:03: No change of its spectrum was observed up to 180C. An indication of the syn conformation of diaza[3.3](2,6)pyridinophanes (486) was obtained from the upeld shifts, by 0.220.25 ppm, of their aromatic protons with respect to the corresponding trimeric compounds (487).
133
Br
N N
N N RN NR TsN NTs
(483)
(484) R = H, Me or Ts
(485)
N RN N N NR NR
N RN
R N
(486), R = H or Me
(487), R = H or Me
4.2.2. Dithia- and diaza[3.3]paracyclophanes Dissolution of tetrauoro-2,11-dithia[3.3]paracyclophane and -[3.3]metaparacyclophane in superacidic media gave the corresponding acidic bis(sulfonium cations) (488) and (489), respectively [293]. These could not be further (ring-)protonated to give monoarenium-bis(sulfonium) trications. 1H, 13C, and 19F NMR chemical shifts were reported for the dications and compared with those of the nonuorinated analogues and of the nonprotonated precursors. The 2,11-diaza[3.3]paracyclophanes (490) [292] are chiral due to their ring substitution pattern. This was proved by addition of the chiral shift reagent Eu(dcm)3 to the N-unsubstituted cyclophane, which caused doubling of the methyl and aromatic proton signals. The CH2 groups give an AB pattern in the
H S+ F F F H S+ F
H spectrum. This pattern is unchanged up to 180C which indicates that rotation of the p-phenylene rings is not possible even at the high-temperature limit. 4.2.3. Other dithia- and diaza[3.3]phanes The other [3.3]phanes covered in this section are mainly dithiaphanes with only very few examples of diaza- and diselenaphanes. Important types contained are metaparacyclophanes, naphthalenophanes, phanes containing higher aromatic systems, azulenophanes, heterophanes, and adamantanophanes. The dimethyldithia[3.3]metaparacyclophane (491) was isolated as a single conformer which has the methyl groups anti to H-9 [179]. This conformation followed from the considerable upeld shift of the methyl protons
R N
F + S H (488)
F + S H (489) N R (490), R = H, Me or Ts
134

X
1.86
S
5.81 6.92
H3C H3C S
X (491) (492), X = S (494), X = Se
S (493)
S R
S (495)
S (496), R = CH 3 (anti) (497), R = OCH 3 (syn)
d 1:86 and of H-9 d 5:81: They both are under the inuence of the ring current of the opposite aromatic ring and this is not the case for H-17,18 d 6:92: It is of note that the preferred conformation of (491) is opposite to that of its [2.2]analogue, (264), cf. Section 3.3. The protons in both types of methylene groups of (491) are nonequivalent at room temperature and, surprisingly, remained so up to 150C. Thus, there exists a high barrier to conformational inversion in this [3.3]metaparacyclophane. A paper by Bodwell et al. treats the conformational behaviour of dithia[3.3]orthometa- and -orthoparacyclophanes [294]. The internal proton of 2,11dithia[3.3]orthometacyclophane (492) resonates at d 5:92; strongly indicating that the anti-chair,chair conformation is heavily populated. Out of six limiting conformations (plus their mirror images) suggested by examination of molecular models, this is the only one in which the internal proton extends into the shielding zone of the opposite deck. The 1H NMR signals of the two types of methylene groups are singlets at room temperature and decoalesce into two well-resolved AB spectra below 227 K Dn 51:3 Hz and 219 K Dn 21:3 Hz; respectively. The barrier DG to the exchange of the geminal protons was determined to be 45:7 ^ 0:8 kJ mol1 : A very similar result, DG 46:5 ^ 0:8 kJ mol1 ; was obtained for the indanophane (493). Compound (494), the diselena analogue of (492), is also known [295]. The chemical shift of its internal proton at dH 6:00 suggests that it behaves similarly to (492) in solution. The methylene signals
of 2,11-dithia[3.3]orthoparacyclophane (495) are also singlets at room temperature, but upon cooling to the lower temperature limit of the spectrometer (170 K), only a broadening of these signals was observed and an upper limit of the energy barrier of ca. 37 kJ mol 1 was estimated. According to models, the sole conformational process available to (495) is the ipping of the ortho ring from one side to the other of the para ring. Two 9-substituted 2,11-dithia[3.3]orthometacyclophanes, (496) and (497), were reported by Yamato et al. [296]. The methyl group in (496) has a 1H chemical shift of d 1:38 which supports a strong preference for the anti conformer. This was also found for the solid state by X-ray diffraction. In contrast, the methoxy group in (497) has a normal chemical shift of d 3:64; but the aromatic protons are more shielded than those of (496). Hence, (497) strongly prefers the syn conformation. At 150C in solution (DMSO-d6) and at 400C in the solid state, neither compound shows signs of conversion into the other isomer. Lai et al. [186] studied some dithia[3.3]metacyclo(1,4)naphthalenophanes in order to see whether there is the same change of conformational preference between these compounds (syn) and the corresponding [2.2]phanes (anti), cf. Section 3.6, as there is between dithia[3.3]metacyclophanes and [2.2]metacyclophanes. This is indeed the case. While [2.2]metacyclo(1,4)naphthalenophane (273) assumes the anti conformation, dithia[3.3]phane (498) exists exclusively in the syn form which is evident from

1.90 5.51 7.21
135
Me
6.66.3 7.20
6.98 6.62 5.94 6.31 0.86
Me S
7.19
S
7.92 7.32
7.86
7.33
8.11
7.52
syn-(498)
2.09
syn-(499) Me
7.24
anti-(499)
7.11
S
7.96
5.87 5.71 6.75
0.85
Me S
(500), X = F (501), X = Br
syn-(502)
anti-(502)
the absence of an upeld shift of the naphthalene H2,3 protons. As in dithia[3.3]metacyclophane, introduction of an intraannular substituent can alter the conformational preference. Both the syn and the anti conformer of the methyl derivative (499) were obtained in the preparation. The main differences in their 1H NMR chemical shifts concern the methyl group [d 0:86 (anti) and 1.90 (syn)], its para proton [d 6:98 (anti) and 5.94 (syn)], and the naphthalene H-2,3 protons [d 6:31 (anti) and 7.20 (syn)]. The substantial difference between the chemical shift of the proton para to methyl in syn-(499), d 5:94; and the corresponding proton in the methyl-free compound (498), d 6:45 ^ 0:15; was interpreted as being due to a larger tilt of the m-bridged ring in the methyl derivative which forces the proton in question into the naphthalene p-electron cloud thus causing enhanced shielding. Neither (498) nor (499) show any indication of anti O syn interconversion in their 1 H NMR spectra up to 150C. As their parent (498), the halogenated derivatives (500) and (501) exist in the syn conformation exclusively [297]. This follows from the chemical shifts of the protons of the mbridged ring, which are distinctly upeld from their counterparts in the halogenated 2,11-dithia[3.3]metaparacyclophanes [184,298] and from the fact that the uorine nucleus in (500) is not much more shielded dF 118 than in 9-uoro-2,11-dithia[3.3]metaparacyclophane (408) which has dF 117 [184]. MMP2 molecular mechanics computations were in agreement with these interpretations. The syn- and anti-conformers of dithia[3.3]metacyclotriphenyleno-
phane (502) behave much like their naphthaleno analogues (499). They were assigned from the shielded methyl protons in the anti- and the shielded protons of the benzene ring in the syn-isomer [299]. The latter protons are more highly shielded in syn(502) than in syn-(499) because they are inuenced by a more extended diatropic system. A paper has been published describing in detail the conformational behaviour of dithia[3.3]metaparacyclophanes, in particular of methylated and benzoannelated derivatives [181]. Like (498), the tert-butyl derivative (503a) assumes only the syn-form but the methyl and methoxy compounds, (503b) and (503c), respectively, occur as both syn - and anti-conformers [187]. While for the methyl compound anti q syn, the methoxy derivative shows syn q anti, presumably due to unfavourable interactions between the methoxy oxygen and the naphthalene p-electrons in the synconformer. The anti-conformers are characterized by large upeld shifts (1 ppm) of their substituent protons relative to the shifts of the same substituents in 2-R-5-t-Bu-1,3-dimethylbenzenes. No syn anti interconversion processes were observed up to 130C in dynamic 1H NMR studies (solvent: DMSO-d6). The aromatic regions of the 1H NMR spectra of the 2,13-dithia[3]naphthaleno[3]paracyclophanes (504) (506), precursors to the corresponding [2.2]phanes (281)(283) treated in Section 3, can be interpreted in the same way as those of the [2.2]phanes [193]. Only the interannular shift effects are somewhat
136
tBu R S S anti
R S S syn tBu
(503a), R = H; only syn; H = 5.31 (503b), R = Me; anti >> syn; Me = 0.78, 1.92 (503c), R = OMe; syn >> anti; OMe = 3.33, 2.69
3.74 6.74 6.24 6.42/6.27
S
6.61
6.49
5.82
S S
7.28 7.06 7.22
S
7.27
4.31/3.93
7.93
7.46
7.94
7.19
(504)
(505)
(506)
S
5.55
S S (508), syn
S (507), anti
S
5.98
S S
5.13
S (511), anti
(509), anti
(510), syn
smaller than in the [2.2]phanes because of the larger separations between the benzene and naphthalene moieties. The AB systems of the bridges in (505) and (506) are unchanged down to a temperature of 110C. Hence, either the barriers between the different possible bridge conformations are substantially lower than 49 kJ mol 1 or the molecules possess only a single minimum energy conformation. The 1H NMR data of a number of dithia[3.3]metacyclo(x,y)naphthalenophanes (507)(510) and of the dithia[3.3](1,3)(2,3)naphthalenophane (511) were [300]. Only crude data were given reported by Kus
but the highly shielded intraannular protons of the mphenylene rings of (507) and (509) and of the (1,3)naphthylene ring of (511) sufced to prove that these compounds prefer the anti conformation while the remaining two are syn. The following paper by the same author [301] treated, among other compounds, the (1,4)benzenophanes (512) and (513) and also the analogous phanes with a (1,4)naphthaleno instead of the (1,4)benzeno moiety. Here as well, the phanes containing a (1,6)naphthaleno unit are anti, those with a (1,7)naphthaleno unit are syn. Two isomers of dithia[3.3](1,6)naphthalenophane, (514) and
137
S
4.99 5.68
S S
S S (512), anti (513), syn (514)
S S S S S S
(515)
(516)
(517)
S S (514A) S S S S (515A) S
(516A)
(517A)
(515), and of dithia[3.3](1,7)naphthalenophane, (516) and (517), were reported later [302]. Their 1H NMR chemical shifts were interpreted to indicate the respective preferred conformations (514A), (515A), (516A), and (517A). Georghiou and coworkers [197] reported the preparation of four isomeric dimethoxydithia[3.3](1,3)naphthalenophanes. They occur as a transoid isomer (518) and a cisoid isomer (519), both of which exist as stable syn- and anti-conformers. Their 1 H NMR spectra were assigned by 2D correlation methods and ample use was made of NOE difference spectroscopy to derive the stereochemistry of the
isomers. Furthermore, comparisons were made with Mitchells data of the analogous dimethyl compounds [303]. The favoured conformation of the dithia[3.3]metacyclo(1,3)pyrenophanes (520) [204] depend on the nature of the substituents R 1 and R 2. The syn-conformation of the parent (520a) was recognized from the chemical shifts of the two intraannular protons, which are both d 6:85; whereas d 5 would be expected for the anti-conformer. The syn-conformation of (520d) and (520e) was inferred from the upeld shift of one of their tert-butyl groups (d 0:10 and 0.12, respectively). Further, in (520e) a through-space
138
S Me O O Me S (518), transoid
S Me O O Me S (519), cisoid
R2 R
1
R2 S tBu S
R1
S S syn R a d e
6.15 6.44
1
tBu anti R b c
1
(520) R
2
R2 tBu tBu
H OMe F
H tBu tBu
Me Et
S
2.72, 2.84 J = 16.5 Hz 3.97 8.33 3.13, 3.39 J = 16.1 Hz 5.51*
5.38*
S
8.30
tBu S
7.70 4.23, 4.92 J = 11.7 Hz 7.92
tBu
tBu S
7.70 4.22, 4.66 J = 13.0 Hz 8.01
tBu
(521)
8.24
(522)
tBu
8.12 7.87
tBu
(523)
J(F,H) coupling of 2.0 Hz was found for the intraannular pyrene proton; this can only arise in a synconformation. On the other hand, the intraannular proton of (520b) and (520c) shows d 5:85 and 6.08, respectively, and the methyl and methylene groups show d 1:60 and 2.49, respectively. This proves the anti-conformation of these two compounds, which may be preferred because repulsive interactions between the oxygen or uorine lone pairs and the aromatic p-electrons will destabilize the syn-conformers. When the sulfoxides of the synconformers were pyrolyzed, only anti-[2.2]phanes were formed, cf. Section 3.7.
Di-tert-butyldithia[3.3](4,9)pyrenometacyclophane (521) and the corresponding paracyclophane (522) have been described by Yamato et al. [304]. The 1H chemical shifts of the pyrene part of (521) differ very little from those of model compound (523), but the intraannular hydrogen of the m-phenylene ring has the most upeld shift of any dithia[3.3]phane studied so far. Obviously this is due to the large ring current of the pyrene moiety. The methylene protons adjacent to the m-phenylene ring are also highly shielded by the pyrene system, so that their shift is upeld by 1.8 ppm relative to the CH2 protons next to the pyrene group. The absorptions of the methylene protons show no
139
S
2.76
S
2.37
tBu
(524)
tBu
tBu
(525)
tBu
3.95
S
1.57
tBu
(312)
tBu
tBu
(526)
tBu
(527), R = H (528), R = F
(529)
1
(530)
18
S CH3
H 3C
S S
16
(531A)
(531B)
change between 100 and 150C. Much the same is true for the para-isomer (522). The p-phenylene protons are of particular interest. Their chemical shifts are very similar and cannot be specically assigned with certainty, but the protons are highly shielded (d 5:51 and 5.38) and absorb ca. 0.9 ppm upeld from Haenels dithia[3.3]metacyclo(2,6)naphthalenophane (506) [193]. Some dithia[3.3]phanes based on uorene substituted in the 1,8-positions were rst described by
Tsuge et al. [202]. The hydrogens at C-9 of the uorene moiety in (524)(526) are substantially shielded d 2:81:6 by the ring current of the opposite aromatic rings, especially so in the naphthalene derivative. This is evident by comparison of their shifts with that of reference compound (312), which has d 3:95: The internal diameters of the macrocyclic rings (524)(526) are wide enough to permit rapid ipping of the uorene units, as is obvious from the fact that in all three compounds the methylene protons at C-9 are
140
chemically equivalent at room temperature. Decoalescence of the C-9 proton signals was observed at 30, 50, and 50C for (524), (525), and (526), respectively, and the corresponding free energies of activation DG for the uorene ipping process at these temperatures were determined to be 40.9, 38.5, and 39.1 kJ mol 1. Lai et al. [305] studied a series of dithia x 24; [3.3](2,2 0 )biphenylo(1,x)benzenophanes, (527)(530), with a m-, an o-, and a p-phenylene unit as the benzeno part of the molecules. In (527) (529), internal rotation about the C-1/C-1 0 bond of the biphenyl system is restricted on the NMR time scale at room temperature (AB spectra for the CH2 protons) and remains so at the highest temperatures attained. Barriers to atropisomerization were estimated to be 90, 80, and 75 kJ mol 1 for (527), (528), and (529), respectively. At room temperature there is, however, rapid ipping of the m-phenylene ring in (527) and (528) as well as rapid p-phenylene ring rotation in (529). The ortho-bridged compound (530) proves to be the most conformationally mobile one, its AB spectrum coalescing at 43C. Thus, DG is 61.9 kJ mol 1 for biphenyl rotation. As inversion of the m-phenylene ring in (527) and (528) could not be stopped even at 90C, a methyl substituent was introduced to give (531) [306]. This compound assumes a rigid conformation (531A) and the equivalent conformation (531B). Lack of symmetry causes each of the four pairs of methylene protons to be diastereotopic. When the m-phenylene ring inverts rapidly, the two pairs of methylene protons at C-1 and C-18 are exchanged but each pair remains diastereotopic. Hence, two AB spectra should coalesce into one. The same holds true for the C-3 and C-16 methylenes, so overall the four slow-exchange AB systems should turn into two fast-exchange ones. This was, however, not observed up to a temperature of 130C and the lower limit of the m-phenylene ring inversion barrier was estimated as 84 kJ mol 1. Under the prevailing slow-exchange conditions, the eight biphenyl protons are also all nonequivalent. Both their signals and those of the methylene protons were individually assigned by the use of H,H-COSY and NOE difference experiments at 500 MHz. The methyl protons are shielded to d 1:62 as the methyl group resides over one of the biphenyl rings. In dithia[3.3]corannulenoparacyclophane (532)
[307] the endo-hydrogens of the p-phenylene ring are highly shielded by the magnetic anisotropy of the corannulene bowl and show a shift of d 1:89; very remarkable indeed for aromatic protons. Two different dynamic processes are conceivable for this molecule: (1) rotation about the bond between carbons 3 and 4 which would exchange the endoand exo-phenylene protons; (2) rotation about the bond between carbons 1 and 2 which would force the entire bridge to the outside of the bowl with concomitant bowl inversion. The latter process would exchange the environment of the diastereotopic protons within both types of methylene groups. However, at 300 MHz no coalescence or line broadening was observed up to 148C. Hence, the lower limit for the barrier of both processes is 75 ^ 4 kJ mol1 : In simple corannulene derivatives bowl inversion is very rapid at room temperature, having a barrier of the order of 43 kJ mol 1 [307,308]. The 1H NMR spectra of the syn- and anti-isomers of dimethyldithia[3.3](5,7)azulenometacyclophane (533) were assigned by Mitchell and Zhang [309]. In the syn-isomer, H-5 d 5:51 and H-4,6 d 6:29 of the m-phenylene ring are strongly shielded by the opposite azulene unit, whereas the methyl protons are shifted upeld in the anti-isomer. The shift difference Dd dsyn danti is larger for the methyl group at the benzene ring Dd 1:48 than for the one at C-6 of the azulene moiety Dd 1:15; which could be attributed to a larger diamagnetic anisotropy of the azulene with respect to the benzene system. The pyridine protons in dithia[3.3](1,3)azuleno(2,6)pyridinophane (534a) and in dithia[3.3](5,7)azuleno(2,6)pyridinophane (535) [213] show upeld shifts between 0.26 and 0.83 ppm relative to 2,6dimethylpyridine. Hence, both phanes possess the syn conformation. Ring ipping at room temperature is fast as indicated by the singlet nature of all CH2 proton signals. On cooling to 102C, ring ipping in (534a) slows down to give one broad and one AB-type CH2 signal. No signal for an anti conformer was detected. Signal coalescence measurements yielded the barrier to ring ipping DG as 42.7 kJ mol 1 (corrected value, cf. Ref. [310]). The barrier in (535) is lower than 37.6 kJ mol 1 as only signal broadening and no decoalescence occurred down to 102C. The bis(N,N-dimethylcarbamoyl)-

7.19 7.38
6.75
141
2.53
4
1.89 7.62
3.31 2.64
S S
1.52 1.05
S
2 1
S
4.68 4.45 7.73
2.67
5.51
6.29
8.48
7.96
7.91 7.91
7.19 7.73 7.69
7.09
(532)
anti
(533)
syn
S N S R H CONMe 2 CH2OMe
R N R
S (535)
(534a) (534b) (534c)
S N S (536a) (536b) R CONMe 2 CH2OMe
(534b) and bis(methoxymethyl) derivatives (534c) and the derivatives (536a) and (536b) of the corresponding azuleno(3,5)pyridinophane were investigated [310] to probe the suggestion [311] that the syn/anti equilibrium of [3.3]metacyclophanes depends, among other things, on the p p interaction between the two benzene rings and, hence, on the presence of electron-withdrawing and -donating substituents. Electron-donating groups are expected to shift the equilibrium towards the anti form. It was found, however, that all of the compounds mentioned preferred the syn conformation. No traces of anti conformers were found at 100C although the AB
patterns of the 1H NMR absorptions of the bridge CH2 groups indicate that conformational interconversions are slow. Moreover, the exchange barriers DG of (534b) and (534c) are identical (42.7 kJ mol 1) and equal to the value for the parent compound (534a). With 48.5 and 49.0 kJ mol 1, the DG values of (536a) and (536b) are also nearly identical but higher than those of the (2,6)pyridinophanes because of the replacement of the internal nitrogen atom by the CH group. The expected substituent inuence upon the conformational equilibrium was thus not conrmed. The conformational properties of the pairs of isomers dithia[3.3](1,3)- and -(5,7)azuleno(2,5) furanophane
142
S O S (537) S S S (539) N N S S S O
S (538) S
S (540) N N S S
(541) (CO)3 Mo N N Me Me (543)

5.15
(542) (CO)3 Mo N N N N N
Me
Me
O
8 3.37
OMe
9
4.54
H
3.20 3
H H
4.01
H
NOE
MeN
6.94
CO2Me
(544)
(537)/(538) and dithia[3.3](1,3)- and -(5,7)azuleno (2,5)thiophenophane (539)/(540) were studied by Fukazawa et al. [312]. Large upeld shifts of the furan protons in (537) and (538) relative to 2,5dimethylfuran showed that both compounds prefer the syn conformation. At room temperature there is fast ipping of both rings in both compounds (singlets for all CH2 groups) and at ca. 100C the two CH2 signals of (537) become two AB patterns, but those of (538) remain singlets. Thus, the barrier DG for the (undened) conformational process in (537) is
39.3 kJ mol 1 (Tc not reported), and that in (538) is 33 kJ mol 1. No trace of the anti conformer could be found in the low-temperature spectrum of (537). Both thiophenophanes prefer the anti conformation (539) also in the solid state as proved by X-ray diffraction. Barriers DG to thiophene ring ipping were determined to be 75.7 kJ mol 1 (at 70C) for (539) and 74.9 kJ mol 1 (Tc not reported) for (540). The barrier to azulene ring ipping is ca. 38 kJ mol 1 (at 82C) for (539) and could not be measured for (540) because of poor solubility.
143
Like the parent hydrocarbon, the heteraheteroanalogues of [3.3]metacyclophane (411), the dithia(541) and the tetrathia[3.3](2,6)pyridinophane (542) were shown to possess a syn conformation in solution [313]. For (541) this was inferred from the pyridine proton chemical shifts which are shielded by 0.24 0.36 ppm relative to the trimeric trithia[3.3.3]- and the tetrameric tetrathia[3.3.3.3](2,6)pyridinophanes. A syn/anti-equilibrium had previously been assumed for (542) [314], but the invariant pyridine region in the variable-temperature 1H NMR spectrum was now assumed to be more compatible with a mobile syn conformation [313]. N,N 0 -Dimethyl-2,11-diaza[3.3](2,6)pyridinophane forms the tridentate Mo(CO)3 complex (543), not a tetradentate complex as might have been expected [315]. This complex is uxional and switches its coordination from one aza-bridge to the other slowly on the NMR time scale below room temperature. A lineshape analysis of the CH2 proton signals as a function of temperature yielded DH 58:1 kJ mol1 and DS 3:14 J K1 mol1 : DG was given as 59.0 kJ mol 1 for room temperature. The dithia[3.3]metacyclo(2,4)pyrrolophane (544) [242] prefers the syn conformation as shown by the
Se X Se (545) (546) (547) O Ph Ph Ph X N N CH Y N CH CH O Y
chemical shift of the intraannular m-phenylene proton d 6:94 which is similar to that of syn-dithia[3.3]metacyclophane (470) d 6:82: The four CH2 groups all give AB spectra, of which three have chemical shifts in the normal range whereas the fourth has an unusual downeld shift d 5:15 of the axial proton and an unusual upeld shift d 3:20 of the equatorial proton. The latter was assigned from the NOE it experienced when the N-methyl signal was saturated. These unusual shifts, 0.6 ppm downeld and 0.8 ppm upeld with respect to the corresponding shifts of the CH2-9 group, were attributed to a hydrogen bridge between the axial hydrogen at C-3 and the carbonyl oxygen of the ester group at C-8. Variable-temperature NMR measurements of diselena[3.3](2,6)pyridinophane (545) [316] show unchanged 13C and 77Se spectra down to 103C. The 1H spectrum at room temperature is very similar to that of the dithia analogue which is known to prefer the syn conformation [313], so the same conclusion was drawn for the diselena compound. At 90C, the CH2 signal decoalesces and DG was calculated to be 37.4 kJ mol 1 at this temperature. The dynamic processes taking place in (545) were assumed to be bridge wobbling between boat and chair conformations
Se cycle Se (548)
(see text)
cycle
O Ph Ph Ph
O S O S S
O R S S
O S
Ph O (549)
Ph (550a), R = H (550b), R = OMe (551)
144
alternating with pyridine ring ips. The former are the processes actually measured while the latter have too low a barrier to be accessible by NMR in the usual temperature range. The metacyclopyridinophane (546) has a lower barrier, DG 33:9 kJ mol1 at 105C. From the data of (545) and (546) the authors extrapolated the barrier and coalescence temperature in the diselenametacyclophane (547) to be 30.4 kJ mol 1 and 123C, respectively. Inspection of space-lling molecular models reveal that, in the transition state of bridge wobbling, the pyridine rings are horizontal (parallel?) to each other, which increases the electrostatic interaction between the nitrogen lone pairs. This interaction was assumed to account for the difference in DG of 7 kJ mol 1 between (545) and (546). If this is the case, however, it is not logical to assume the same change in the barrier height on going from (546) to (547). In a further study [317], a large number of diselena[3.3]phanes of the general structure (548) were characterized by 1H and 13C NMR and also by 77Se when solubility permitted. The cyclic substructures in (548) are o-, m-, and p-phenylene, pyridine-2,6-diyl, furan-2,5-diyl, thiophene-2,5-diyl, and biphenyl-2,2 0 diyl. The 77Se chemical shifts appear to correlate with the size of the cavity of the phanes as estimated from space-lling models. Steric crowding in the cavity corresponds with increased 77Se shielding. The dithia[3.3](2,6)g-pyronophanes (549), (550a), and (551) are conformationally mobile at room temperature; their methylene protons give singlet absorptions [234]. The intraannular methoxy group in (550b) makes this compound less exible; there are two AB spectra for the methylene groups and one methoxy signal at room temperature, indicating slow inversion of the macrocyclic ring but the presence of only one conformer. It was not possible to decide whether this has the syn or the anti geometry. The sulfones behave similarly. The [2.2]phanes produced from the sulfones have already been treated in Section 3.8. gtles group has studied dithia[3.3](1,3)adamanVo tanometacyclophane (552) and its sulfone (553) [318]. Both compounds show one extremely shielded proton of the intraannular methylene group at d 2:18 and 1.72, respectively. This corresponds to an upeld shift Dd of ca. 4.0 ppm relative to the CH2 protons d 1:78 in adamantane itself. The second proton of
the methylene group in the sulde and the sulfone has d 1:41 and 1.95, respectively. The signals of the intraannular methylene protons of (552) coalesced at 50 ^ 10C (90 MHz), their averaged absorption becoming a sharp singlet with d 0:13 at 154C. The resulting conformational barrier of DG 50C 62 ^ 4 kJ mol1 demonstrates the increased rigidity of the bridge relative to dithia[3.3]metacyclophane (470) which has a DG 90C of less than 38.9 kJ mol 1 [319]. In the crystal, the conformation of (552) is in-between syn and anti so that one of the intraannular methylene protons resides
2.18
Ho
1.72
Ho
SH
+1.41
O2S H
+1.95
S
Hb
SO2
Hb
(552)
(553)
S N
O2S H S N SO2 O (555)
(554)
S
a
H H 0.25
A B b B A
0.40, 0.25
CO2Me (556b)
(556a)
above the plane of the benzene ring while the other one is pointing toward the periphery of the molecule. This is in line with the large chemical shift difference between these hydrogens. The (2,6)pyridino analogue (554) [220] corresponding to (552) has a lower barrier 55 ^ 10 kJ mol1 to the ipping of the aromatic ring because the smaller size of the nitrogen lone
145
pair compared to a hydrogen reduces the energy of the transition state. No highly shielded proton was observed for (554) at room temperature. When (554) was oxidized to the bis-sulfone, the N,S,S,S 0 S 0 -pentoxide (555) was formed. The nitrogen-bound oxygen prevents ring ipping up to at least 160C: no coalescence was observed for the intraannular CH2 protons (d 0:03 and 2.08). In (556a), the para isomer of (552), the internal methylene protons give rise to a sharp singlet at d 0:25: Broadening of many resonances at room temperature indicates conformational mobility. An AA 0 BB 0 spectrum is observed for the aromatic protons, the chemically equivalent ones being para to one another. This implies a C2 axis through and perpendicular to the centre of the benzene ring. Xray diffraction showed that the different chemical shifts of the aromatic protons are caused by the benzylic bridges pointing in opposite directions with respect to a plane through Ca and Cb and perpendicular to the benzene ring. The signals of the benzylic protons coalesce at 35 or 45C (both 35C and 318 K were mentioned [220]) and DG is 64 ^ 10 kJ mol1 : In the methoxycarbonyl derivative (556b), the intraannular methylene protons have d values of 0.40 and 0.25 [220]. It was stated that on warming to 55C the 1H NMR spectra showed no sign of a conformational process. However, a conformational process like the one assumed for (556a), will not make the intraannular protons of (556b) equivalent because the front and the back side of the molecule are different due to the presence of the substituent.
5. [m.n]Phanes (m 2, n 2) The present section deals with [m.n]phanes in which the length of one bridge is greater than 2 and that of the second one is at least 2. It is difcult to maintain a strictly logical order in the presentation because many papers treat whole series of compounds with increasing length of one or both bridges. Generally, however, smaller phanes are presented rst, followed by increasingly larger phanes, and the largest phanes, [8.8] and [10.10], are mentioned at the end of the section. The benzoannelated monothia[3.2]metaparacyclo-
phane (557) was studied by variable temperature 1H NMR [182]. Below 85C, one of the CH2 signals is split indicating a very low ring inversion barrier DG of 37.3 kJ mol 1. Thus, the molecule is much more exible than the analogous [2.2]phane hydrocarbon (268), cf. Section 3. The thia[3.2]metacyclophan-10-ene (558), in which a phenanthrene unit is condensed onto the C-10,C-23double bond, unexpectedly prefers the syn conformation according to its 1H NMR spectrum [320]. There is no upeld resonance for the internal protons (Hi) but the six outer cyclophane protons appear relatively shielded at d 7:16:6: This is in contrast with the preferred anti conformation of the lower benzoannelated homologue (559), dHi 6:08; studied earlier by Hammerschmidt gtle [321]. The reason lies in the high and Vo steric strain that would occur in anti-(558) due to the close proximity of the proton pairs H-7/H12 and H-21/H-25. The deshielding observed for the Hi relative to their para protons in syn-(558) was attributed to the magnetic anisotropy of the nearby double bond, (C-10)y(C-23). Variable temperature spectra of (558) down to 70C and of its sulfoxide up to 150C showed no change over the temperature range and indicate the absence of cyclophane ring ipping, in contrast to (559) where DG is 54.8 kJ mol 1 (at 7C). Krois and Lehner [260] presented a systematic study of the preferred conformations (syn vs. anti) of [2.2]- (149), [3.2]- (560), [3.3]- (411), [4.2](561), and [4.3]metacyclophanes (562) and of methods to determine them. (i) A symmetry criterion is applicable to the metacyclophanes containing a three-membered bridge. At temperatures low enough to stop conformational inversion on the NMR time scale, the protons of the C3 bridges in (560), (411) or (562) form an AA 0 BB 0 CD spin system in the syn conformation, whereas an AA 0 BB 0 CC 0 spin system is present in the anti conformation because the protons of the central methylene group are chemically equivalent. This criterion showed [3.2]metacyclophane (560) to prefer the anti and [3.3]metacyclophane (411) to prefer the syn conformation. Conformational inversion in [4.3]metacyclophane (562) could not be slowed down sufciently to apply the method. (ii) The second way to determine the conformation uses the Rvalue (ratio of vicinal H,H coupling constants)
146

12 7
Hi
12
S
10 23 Hi
S
21 25
Hi 7.36
Hi
25
21
(557)
(558)
syn-(558)
Hi
Hi 6.08
(559)
(560)
(561)
O O O
(562)
(429)
(563)
O O (564) (565)
method [322] which furnishes the torsional angle(s) f about the appropriate CC bond(s). In the C2-bridges of (149), (560), and (561) f is expected near 0 for a syn and near 60 for an anti conformation. Experimentally, f was found to be 57, 57, and 63 for [2.2]-, [3.2]-, and [4.2]metacyclophane, respectively. Hence all these compounds prefer the anti conformation. In the C3-bridges of [3.3]metacyclophane (411), f should be 60 (syn) or 30 (anti). The value calculated from the experimental J(H,H) coupling constants is 70, so the conformation of this compound is again conrmed to be syn. (iii) The third, most widely applicable method is the evaluation of the chemical
shift of an intraannular proton Hi with no orthobenzylic substituents in comparison with its paraproton He. A value of Dd dHi dHe close to zero indicates preference of the syn conformation while a distinctly negative value points to a preferred anti conformation. The Dd values found for [2.2]-, [3.2], [3.3]-, [4.2]-, and [4.3]-metacyclophane are 3.0, 2.1, 0.1, 1.5, and 1.1 ppm, respectively, which translates into a preferred syn conformation for [3.3]metacyclophane and preferred anti conformations for the other phanes, in agreement with results obtained independently by X-ray diffraction and the NMR methods (i) or (ii) mentioned above.
147
14
CH3 H3 C (566) CH3

6
H3C
H3C
6.98
H
2.78 (t) 1.81 (qi) 6.05
CH3
H 3C
CH3
2.12, 1.35 2.87, 2.51
(567), anti H
(568), syn
H H H Hi He Hi (CH2)n He
(CH2)n
(569) n
a 2
b 3
c 4
d 5
e 6
(570) n
b 3
c 4
Substituents at the bridges may cause deviations from these regularities. By the use of methods (i)(iii), such deviations were found for diketones (429) and (563) (565). The rst of these is anti and the others are syn. Krois and Lehner also give a comparison of the barriers DG to conformational interconversion of the basic [m.n]metacyclophanes, determined by NMR or other techniques. These are 133 kJ mol 1 (at 442 K), 73 kJ mol 1 (at 363 K), 50 kJ mol 1 (at 253 K), 60 kJ mol 1 (at 308 K), and 38 kJ mol 1 (at 193 K) for [2.2]-, [3.2]-, [3.3]-, [4.2], and [4.3]-metacyclophane, respectively. Transannular interaction in a series of 6-R-9,17dimethyl[3.2]metacyclophanes (566) was evaluated by plotting the chemical shifts of H-14 against Hammetts s p substituent constants [323]. Substituents R were H, NO2, NH2, F, OMe, CHO, and Me. The range of chemical shifts is relatively small, but an approximately linear correlation with s p was found. The slope is distinctly smaller than for the correspond-
ing correlation of [2.2]metacyclophanes which was also shown. The authors concluded that transannular interaction is less efcient in [3.2]- than in [2.2]metacyclophanes and that this is due, in part, to the different geometries of the two systems. The two [3.2]metacyclophan-10-enes (567) and (568) prefer different conformations [324]. While (567) is present as the typical anti conformer, the bridge-methylated derivative (568) favours the syn arrangement in order to relieve destabilizing interactions between the methyl groups at the ethano bridge and at the aromatic rings. The preferred anti conformer of (567) was recognized by the upeld shift d 6:05 of its intraannular proton. The triplet and quintet multiplicities of the benzylic methylene signals and of the signal of the middle methylene group, respectively, indicate fast interconversion of the two possible anti forms by ring ipping. This process is still fast on the NMR time scale at 80C, so (567) is a very exible molecule. The syn conformation of (568) was
148
Table 14 1 H NMR data for the cyclobutano[n.2]metacyclophanes (569) and (570) Compound (569a) (569b) (569c) (569d) (569e) (570b) (570c)
d (Hi)
4.54, 4.40 6.55 6.46 6.87 6.72 5.49 6.01
d (methine)
3.98, 3.61 4.06 3.94 4.04 4.00 2.08 1.29
Dd 2.86 0.28 0.68 0.08 0.29 1.83 1.28
Conguration cis cis cis cis cis trans trans
Conformation anti anti anti syn anti anti anti
inferred from the chemical shift of its intraannular hydrogen d 6:98: The trimethylene bridge produced a complicated 1H NMR signal pattern with different chemical shifts of the geminal methylene protons which were maintained over the temperature interval from 80C to 100C. This proved the conformational stability (no syn/syn interconversion) of (568). Several cis- (569) and trans-1,2-diphenylcyclobutanes (570) with (CH2)n bridges between the 3-positions of the phenyl rings were obtained by Nishimura et al. [325] through intramolecular [2 2] photocycloaddition of a,v-bis(m-vinylphenyl)alkanes. The products can be regarded as [n.2]metacyclophanes with cyclobutano annelation to the two-membered bridge. The structural questions to be answered concern the cis/trans congurations of the cyclobutane rings and the syn/anti conformations of the metacyclophane units. The congurations follow from the chemical shifts of the cyclobutane methine protons. These are d 4 in the cis series, but d 2:11:3 in the trans series because the geometry of the latter causes shielding of H-1 by the phenyl ring at C-2 and of H-2 by the phenyl ring at C-1. The metacyclophane conformations were determined by applying Lehners method discussed above [260]. All compounds apart from (569d) have distinctly negative chemical shift differences Dd between the internal proton Hi and its para counterpart He, indicating the anti conformation while Dd is 0.08 ppm for (569d), suggesting preference of the syn conformation. Interestingly, due to the cyclobutano annelation, [2.2]metacyclophane (569a) can only have the cis conguration for steric reasons. This renders the two intraannular protons chemically nonequivalent and the anti conformation does the same to the cyclo-
butane methine protons. The important 1H NMR data for (569) and (570) are gathered in Table 14. The 10-oxa-2-thia[3.2]metacyclopyridinophanes (571)(574), their metacyclophane analogue (575) and the 2-thia[3.2]pyridinophanes (576/577, mixture) and (578) were studied by variable temperature 1H NMR [126]. The coalescence temperature Tc of the OCH2 signals of (571) is lower than 55C and the conformational barrier was not determined. The low barrier is due to the absence of an intraannular hydrogen at the pyridine ring. For (572) (89 kJ mol 1 at 38C), (574) (87 kJ mol 1 at 30C) and (575) (89 kJ mol 1 at 35C) the DG values are equal within experimental error but the barrier for (573) (95 kJ mol 1 at 63C) is higher by ca. 7 kJ mol 1. While a barrier of 55 kJ mol 1 (at 8C) has been determined for 2-thia[3.2]metacyclophane (579) [319], the barriers in the analogous 2-thia[3.2]pyridinophanes (576)/(577) (mixture) and (578) are higher by 23 kJ mol 1 (at 0 and 3C, respectively). The authors attributed this to the geometrical differences between the benzene and pyridine rings. At room temperature in CDCl3 solution, 2-thia10,11-diaza[3.2]metacyclophan-10-ene (580) exists as a 2:1 mixture of the syn and anti conformers [326]. Coalescence measurements of the SCH2 proton signals of anti-(580) give a DG value for the interconversion of the anti conformer into its enantiomer anti 0 of 56:7 ^ 1:0 kJ mol1 and the coalescence of the intraannular aromatic proton signals of the syn and anti conformers yielded DG 56:3 ^ 1:0 kJ mol1 for the syn into anti conversion. The similar magnitudes of these barriers make it very likely that the transition of one conformer into its enantiomer proceeds via the other conformer. In acetone or acetonitrile as the solvent, only the anti conformer of (580)
149
N N S O O S O
S O
(571) N
(572)
(573) N
(574) N
S O N (575) (576)
N (577)
N (578)
N N
R (579) (580) (581) R (582a), R = H (582b), R = Me (582c), R = Et
is present. 1H NMR spectra taken in CDCl3/[D6]acetone or CDCl3/[D3]acetonitrile mixtures of various composition led to the conclusion that specic solvation of the syn conformer takes place by inclusion of one molecule of acetone or acetonitrile into the space between the NyN and CH2SCH2 bridges. The analogue (581) only exists as the anti conformer. The singlet CH2 signal indicates rapid anti-to-anti 0 interconversion. Broadening of the CH2 signal starts only below 73C; DG is less than 38 kJ mol 1. The benzylic protons and the protons ortho to the three-membered bridge in [3.2]paracyclophan-10-ene (582a) and its dimethyl (582b) and diethyl derivatives (582c) [327] become diastereotopic at low temperatures. Signal coalescences between 30 and 25C gave barriers to bridge wobbling of 48.7 50.7 kJ mol 1 which are equal within experimental error for the three compounds and also very similar
to the barriers for the same processes in [3.3]paracyclophane (447) [276] and in [3.3]metacyclophane (411) [254]. Fukazawa and coworkers [328] investigated a [4.4]paracyclophanedione derivative (583). Molecular mechanics computations predicted three conformers of approximately equal energy (I III) of which the most stable one (I) corresponds to the conformation found in the crystal. When the solid was dissolved in precooled solvent, a 1H NMR spectrum of the single conformer I was obtained. Dissolving the compound at room temperature and cooling the solution down gave two additional spectra of conformers II and III which are broadened at room temperature. Interconversion of II and III occurs by bridge ipping and requires little energy (ca. 50 kJ mol 1). I and II are interconverted by rotation of ring A (DG 76:6 kJ mol1 at 80C), I and III
150
O A O B
O O
O (583) O O
O O A O
G=76.6 kJ mol 1 rotation of ring A
O A O
O O
O I
rotation of ring B G50 kJ mol1
O II
G=95.0 kJ mol 1
bridge flip
O O A
O O
O O A O
O III
O IV
by rotation of ring B (DG 95:0 kJ mol1 at 160C). The conceivable conformer IV into which I could be transformed by a low-energy bridge ipping process is not populated. Hence the signals of I stay sharp at room temperature and below. The full paper treating this subject [329] also includes variable temperature 1H NMR and molecular mechanics studies of compounds (584) and (585). These preferred conformers are closely similar to I III of (583) and their rotational barriers are also similar to those in (583). In the series of 10-substituted 3,12-dithia[4.4]meta-
paracyclophanes (586a d) [330], those with X H and F show no evidence of restricted conformational motion down to 51C at 100 MHz 1H observation frequency. When X Cl, the free energy barrier to rotation of the para-bridged ring, DG para; is 75 kJ mol 1 and the barrier to ipping of the meta-bridged ring, DG meta; is 88 kJ mol 1. Replacing X Cl by X OMe lowers DG para to 67 kJ mol 1 but increases DG meta to 92 kJ mol 1. This was explained by the anisotropy of the steric size of the methoxy group. Increasing the bridge lengths by one methylene group each expectedly lowers the
151
O O
O O
S (CH2)n
S (CH2)n
X O (584) (585) O (586a) (586b) (586c) (586d) (586e) H F Cl OMe OMe
n 2 2 2 2 3
(587)
(587A)
(588)
20 10
(589)
activation barriers. DG para was found to be very small in (586e) Tc 51C and DG meta is only 59 kJ mol 1. A conformational analysis of 2,2,12,12-tetramethyl[4.4]metacyclophane (587) using the ring current method was performed by Fukazawa et al. [331]. Ring-current induced chemical shifts Dd of the aromatic protons (i.e. the effect of one benzene ring upon the shifts of the other) were dened as the shift difference between (587) and model compound (588). Trial conformations of (587) were then adjusted until the minimum discrepancy factor R was reached between the observed Dd values and those calculated according to Mallion [332]. The minimum R value of 5.8% was obtained for the anticlinal [333] conforma-
tion (587A) in which the planes of the benzene rings form an angle of ca. 100. This conformation is very close to the one observed in the crystalline state by Xray diffraction. At 100C, the 1H methyl signal resolved into two and the signals of the aromatic protons remained unchanged. No signals due to minor conformers could be detected. The spectra are consistent with the hypothesis that only one anticlinal conformer is present and that it interconverts to its mirror image by a ipping of the two benzene rings. This interpretation was supported by molecular mechanics computations. The ring current method was also applied to the conformational analysis of 2,2,13,13-tetramethyl[4.4]metacyclophane (589) [334]. Here it proved necessary to assume an
152
equilibrium between three conformers whose geometries were calculated by molecular mechanics (MM3). Their relative populations were adjusted at each measuring temperature to obtain the best t between the calculated and the experimental spectrum. Only conformationally averaged spectra were observed down to 100C. Very interestingly, one of the intraannular protons, H-10, has a chemical shift d 7:0; which remains rather constant from 27C to 100C, while the shift of the other one, H-20, varies from d 5:4 (27C) to d 4:1 (100C). The results indicate that, from 100C to 27C, the population of the main conformer changes from 56 to 18% and that of the next important conformer from 39 to 68%. The conformational mobility of [4.3]- (590a) and [4.4](1,4)naphthalenophane (590b) and of [4.3](591a) and [4.4](2,6)naphthalenophane (591b) was studied by Nishimura et al. [335]. The threemembered bridge in (590a) and in (591a) is too short to allow isomerization of anti-(590a) to its syn
isomer or of chiral (591a) to the achiral (meso) isomer. The 1H NMR spectra were unchanged when the samples were heated to 200C. Hence, the interconversion barriers are higher than 105 kJ mol 1. The longer bridge in [4.4]phane (590b) permits easy isomerization. Coalescence of the intraannular proton NMR signals for the syn and anti conformer occurs already at 10 ^ 5C; giving DG 54 kJ mol1 : In [4.4](2,6)naphthalenophane (591b) isomerization could also be observed, yet at a much higher temperature. The aromatic and the aliphatic proton signals of the meso and the chiral conformer coalesced at 175 ^ 5C; which indicates a barrier to rotation of the 2,6disubstituted naphthalene ring of 92 kJ mol 1. This was claimed to be the rst observation of naphthalene ring rotation in a (2,6)naphthalenophane. Hydrogenation of the cyclobutane rings of bis(cyclobutano)[2.2](3,6)phenanthrenophane (314) led to [4.4](3,6)phenantrenophane (592) [203]. This compound prefers the anti-conformation as was deduced from the high-eld shifts of H-4,5 and the
(CH2)n (590a), n = 3 (590b), n = 4 chiral (591a)
meso-(591b)
chiral (591b)
(592), anti
153
Hi S S S
Hi S S
Hi S S
Hi S
(593) (594) (595)
(596)
Hi S S S
Hi S Hi S S S Hi S
(597)
(598)
(599)
(600)
low-eld shifts of the other aromatic protons with respect to the starting material. In a study aimed at detecting edge-to-face arrangements of two aromatic rings in exible cyclophanes, Schladetzky et al. [336] compared the chemical shifts of the intraannular hydrogen Hi in compounds (593) (596) of the dithia[4.4]metaparacyclophane type and (597)(598) of the dithia[4.4]metacyclophane type with reference compounds (599) or (600). The shift differences Ddi di phane di ref : cpd: at 22C are 1.5 to 1.0 ppm for the metaparaphanes and 0.5 to 0.4 ppm for the metaphanes. They increase to 1.6 to 1.3 ppm and to 0.8 ppm, respectively, for three compounds whose spectra were also measured at 78C. The authors regarded the upeld shifts as indicators of the participation of edge-to-face arrangements in the conformational equilibria, but in the opinion of this reviewer the data do not provide a basis solid enough for such a conclusion. tzmacher [337] prepared a series of Funke and Gru diazadithia[n.2]cyclophan-enes, n 616; (601a) (601h). These are azobenzenes that have their p,p 0 positions joined by CH2S(CH2)mSCH2 bridges (m 2; 49, 12). The short bridged compounds
(601a)(601c) exist only in the cis-azo conguration, while (601d) and (601e) were obtained as cis/trans mixtures and (601f)(601h) were formed as pure trans isomers. The latter could be converted photochemically into the cis isomers, so cis and trans diastereomers were available for (601d)(601h). The 1H NMR spectra of the isomers differed characteristically in that the aromatic protons are shielded in the cis relative to those in the trans isomers as in azobenzene itself. In the trans series, decreasing the bridge length hardly affects the shifts of the aromatic protons but increasingly shields the CH2 protons as the centres of the bridges are forced over the azobenzene moiety. The highest eld shift was observed for four protons in (601e) at d 0:07: Decreasing the bridge length in the cis series causes high-eld shifts of the aromatic protons but only for the short-bridged compounds (601a) and (601b). These studies were extended to include the dithiadiaza[n.2]metacyclophan-enes (602a)(602f) [338]. The cis/trans isomerism of the azo group and syn/anti conformation of the benzene rings were determined from the 1H chemical shifts of the aromatic protons, in particular of Hi. From the thia[n.3]metacyclophane precursors (603)
154

(6.44) 6.82 (3.54) 3.65 (2.00) 2.32
CH2 S N
1.50.6 (0.20.0)
(7.88) (7.38) 7.88 7.46
(7.00) 7.19 (3.78) 3.74
CH2
1.61.2
N (CH2)m2
N N
S CH2
2.36 (1.87)
(CH2)m2 S CH2
trans-(601)
cis-(601)
H values for m = 12 (m = 2) H values for m = 12 (m = 6) a b c d e f g h m 2 4 5 6 7 8 9 12
N N Hi
S (CH2)m S
(602) a b c d e f m 2 3 4 6 8 12 [n] 6 7 8 10 12 16
with n 5; 6; 8; and carrying intraannular methyl groups, the [n.2]metacyclophanes (604) were synthesized by Yamato et al. [339]. The precursors all occur in the anti conformation as evidenced by their highly
tBu Me (CH2)n Me tBu
shielded methyl protons and by X-ray diffraction of compound (603b). Products (604b) and (604c), n 6 and 8, are also anti, but the [5.2]metacyclophane (604a) was formed as a syn and an anti conformer,
tBu Me (CH2)n Me tBu
n anti-(603a) b c 5 6 8
(CH3) 1.47 1.49 1.70 anti-(604a) b c

2.25
n 5 6 8
(CH3) 1.19 1.25 1.47
tBu tBu
Me
Me (CH2)5
syn-(604a)
155
tBu MeO (CH2)n
OMe tBu
tBu MeO (CH2)n
OMe
tBu tBu tBu
OMe OMe (CH2)n
anti-(605), n = 26
anti-(606), n = 26
syn-(606), n = 36 O
tBu HO (CH2)n
OH
tBu tBu tBu
OH OH (CH2)n
(CH2)n
anti-(607), n = 26
syn-(607), n = 34 O (608), n = 4, 5
which can be separated by chromatography. The syn isomer of (604a) has a normal chemical shift for the methyl group dH 2:25 as opposed to its anti counterpart, which shows dH 1:19: According to variable temperature 1H NMR measurements, (603a), anti-(604a), and (604b) are conformationally rigid and do not lose the nonequivalence of their methylene protons up to 150C. Compound (603c), on the other hand, is very exible and shows CH2 singlets down to 60C. Only for (603b) and (604c) could signal coalescence be observed within the accessible temperature range. The anti Y anti 0 interconversion barriers were determined to be 69.5 kJ mol 1 at 90C and, respectively, 85.8 kJ mol 1 at 140C. Compounds (605) and (606) carrying intraannular methoxy instead of methyl groups behave very similarly [340]. The thia[n.3]metacyclophanes (605) with n 26 are exclusively anti: d H of the OMe groups ranges from 3.05 for n 2 to 3.28 for n 5: The same is true for (606) with n 2 (d H for OMe 2.90). Of the [n.2]phanes with n 36 both the anti and the syn conformers could again be isolated. The longer the n-bridge, the higher the proportion of syn conformer in the product. The syn conformers have less shielded methoxy groups dH 3:513:59 but more highly shielded aromatic protons dH 6:296:72 than the anti conformers dH 6:777:12: All the dimethoxyphanes are
conformationally very stable. None of them show any CH2 signal coalescence below 150C, hence the barriers to ring inversion exceed 105 kJ mol 1. The methoxy compounds were hydrolysed and the anti conformers of the hydroxyphanes (607) with n 26 and their syn conformers with n 34 were obtained. These conformers can be differentiated by their OH chemical shifts (anti: d 2:14 for n 2 up to 3.32 for n 6; syn: d 5:42 for n 4) and by those of the aromatic protons (anti: d 6:927:10; syn: d 6:356:64). Anti-(607), n 5; shows no change of its 1H NMR spectrum up to 130C while for the [6.2]phane the benzylic signals coalesce at this temperature (solvent CDBr3), hence DG 130C 86:2 kJ mol1 : The latter compound exhibits a strong solvent dependence of its anti/syn ratio at 20C. It decreases with increasing dielectric constant of the solvent from 100:0 (CDCl3) to 65:35 (DMSO-d6). At room temperature, characteristic proton shifts of the conformers in DMSO-d6 are: dt-Bu 1:24 (anti), 1.05 (syn) and dOH 5:60 (anti), 7.75 (syn). The spectrum of the next lower homologue (607), n 5; shows no syn conformer at room temperature in CDCl3 or DMSO-d6 but does so at 60C, and the anti/syn ratio decreases with increasing temperature. Coalescence of anti and syn signals is not achieved up to 140C DG 105 kJ mol1 : The studies described above were
156
X OMe (CH2)n OMe (CH2)n
(CH2)n (610) X = OMe: (609), n = 2, 510 X = OH: n = 2, syn/anti n = 36, syn n = 46, syn
(CH2)n (611) X = OMe or OH: n = 24, anti n = 56, syn
later extended to compounds (605), (606), and (607) with longer (CH2)n bridges n 7; 8; 10 [341]. In a study of [n.2]metacyclophanediquinones (608) [342] it was found that it is much easier to effect ring inversion in these quinones n 4; 5 that have DG 82:8 kJ mol1 (130C) and 50.2 kJ mol 1 (30C) than in the dihydroxy[n.2]metacyclophanes (607) for which the barriers are higher than 115 kJ mol 1 at T 140C [340]. The higher barriers in the hydroxyphanes were attributed to the longer CO bond which makes it more difcult to rotate the oxygen through the annulus, but the role of the hydroxy proton should also be taken into account. The 1H NMR spectra of the dimethoxy[n.n]metacyclophanes (609) with n 2 and 510 were fully assigned and their 13C shifts reported [30]. For n 5; the benzylic protons are still nonequivalent at room temperature, indicating slow ring inversion. For n 6; equivalent benzylic protons show rapid movement on the NMR time scale at room temperature. Activation parameters for this conformational interconversion were not determined. Nishimuras group prepared a large number of different metacyclophanes and determined their structures by 1H NMR [343]. The compounds studied were the cyclobutano-annelated [n.2]metacyclophanes, n 26; (610), and the [n.4]metacyclophanes, n 26; (611). NOESY spectra served to determine the orientation of the cyclobutane rings in (610). The syn/ anti conformations of the metacyclophane systems were derived using the Dd technique by Krois and Lehner [260] (discussed earlier). The Dd values had, however, to be corrected in order to account for the effect of the OMe or OH groups. All compounds prefer the conformer indicated in the formulae except
dimethoxy[2.2]phane (610), which has a syn/anti mixture (4:3) that equilibrates slowly enough to see separate signals in the NMR spectrum, but too fast to allow isolation of the isomers. Intramolecular photocycloaddition of (612), n 4 or 5, gave syn-[4.2]phane (613), n 4; and anti[4.2]phane (614), n 4; while in the case of n 5 only the anti-conformer (614), n 5; could be isolated [344]. Syn-[4.2]phane (613), n 4; shows only one set of seven proton NMR signals in the aromatic region and only one cyclobutane CH absorption, whereas anti-[4.2]phane (614), n 4; has two sets of aromatic and cyclobutane CH signals because the cyclobutano ring destroys the C2 symmetry which otherwise would be present. Due to the eclipsed arrangement of the two carbazole subunits in syn[4.2]phane (613), n 4; there are general upeld shifts of all aromatic protons compared to reference compound (612). In anti-[4.2]phane (614), n 4; only H-1 (Dd 1:12 and 1.06), H-2 (Dd 1:45 and 1.07), and, to a lesser degree, H-4 (Dd 0:54 and 0.22) are substantially shifted with respect to (612), while the shifts of H-5 to H-8 are hardly affected. This proves the anti-structure for this conformer, in which there is only partial overlap of the carbazole subunits and the outer ophenylene rings are directed away from one another. The properties of anti-[5.2]phane (614), n 5; were similar to those of its four-membered homologue. [5.5]Dibenzocyclooctatetraenophane (615) should have been obtained as a mixture of meso and chiral diastereomers according to the NMR spectra of its precursors [345]. However, it shows only a single set of 1H NMR signals. This was ascribed to a dynamic process in which one dibenzo-COT subunit
157
N (CH2)n N N (H2C)n N
2 1
(CH2)n (612), n = 4 or 5 syn-(613), n = 4 anti-(614), n = 4 or 5
O (CH2)3 O
O OMe (CH2)3 O MeO (6162) (615)
O (CH2)3 O
O (CH2)3 O
O (CH2)3 O
O (CH2)3
meso-(6154)
chiral (6154)
attens and rotates about the phenolic CO bonds by 180, thereby interconverting the diastereomers. Reduction of (615) with potassium to its tetraanion (615 4) planarizes the COT rings and two sets of signals reappear because internal rotation in the tetraanion is slow due to the increased steric hindrance by the solvation shell of the ion pairs. In the tetralithium salt of (615 4), internal rotation is faster, so broad averaged signals are observed at ambient temperature. Hence, steric hindrance in the lithium salt is smaller than in the potassium salt because of the favourable formation of solvent separated ion pairs. Molecular models suggest that the reduction of and ring planarization in (615) decrease the distance between the central CyC bonds of one COT subunit from that of the other from 1200 to 500600 pm. Experimental
evidence for this was obtained from the increased 1 H shieldings in (615 4) of up to 0.4 ppm compared to the reference dianion (616 2). The reason lies in the mutual shielding of the attened parallel-oriented COT 2 subunits. Staab and coworkers, in a low-temperature 1H NMR study of various porphyrinquinone cyclophanes and analogues, observed three different dynamic processes that occur in these molecules, viz. NH/N-tautomerism, ring rotation in the cyclophane bridges, and a swinging bridge process [346]. Tautomerism causes doubling of the b-proton signals, has barriers DG of the order of 50 kJ mol 1 at 35 to 17C, and was conrmed by N-deuteration which increases the barriers by ca. 8 kJ mol 1 and the coalescence temperatures by ca. 40C. The barrier in
158
OMe MeO Ph N NH
HN N
Ph (617) X O Me Me Me Me (618) X OMe N NH HN N Me O
X Me Me Me
leading to DG 81C 39 kJ mol1 for (618, X OMe) and DG 4466C 70 kJ mol1 for (619, X CN). The third process was interpreted as a swinging back and forth of the cyclophane bridge between two equivalent unsymmetrical conformations, in which the planes of the porphyrin and the ring in the bridge are tilted against each other. This process has low activation barriers, e.g. DG 120C 31 kJ mol1 for (619, X OMe) and leads to doubling of the methine and NH proton signals. The activation barrier of the swinging bridge process is also barely dependent on the substitution pattern. Adams and Whitlock [347] studied the 1H NMR spectra of the tetraoxa[8.8](1,4)naphthalenophanes with two triple bonds in each bridge (620) and of their analogues with saturated bridges (621). A cyclization shift, Dcyc, of a proton was dened as the chemical shift difference between its signal in the cyclophane and the corresponding proton in an uncyclized model compound, Dcyc duncyc dphane ; positive values corresponding to upeld shifts on cyclization.
O OX OX )2 O OX OX O (621) X a b c C(=O)CH 3 C(=O)C 2H5 C(=O)CH 2Ph )2 )
2
MeO Me Me Me Me (619) N NH HN N
X Me Me Me Me
O (620)
)2
(617) is 49 kJ mol 1 at 23C. The rate of tautomerism is hardly inuenced by the incorporation of the porphyrin moiety into the cyclophane framework, as a similar barrier to NH/N-tautomerism is observed in the model compound tetraphenylporphyrin, DG 47 kJ mol1 at 35C. Expectedly, the barrier to ring rotation in the cyclophane bridge depends strongly on the size of the substituents present. While free rotation Tc 123C of the quinone ring is observed for (618, X H, Me, Cl or Br), methoxy and cyano groups efciently raise the coalescence temperatures of the porphyrin methyl signals
In the compounds (620) the rigid diyne bridges keep the aromatic rings apart so that they do not interact. This results in very small Dcyc values for the aromatic protons. Those of the acyloxymethyl groups, however, increase with distance from the aromatic ring to which they are bound, indicating that these groups are under the inuence of the opposing transannular ring. The exibly bridged phanes (621) have moderate Dcyc values (0.20.4 ppm) for the aromatic protons resulting from collapse of the rings upon each other as the rigid constraint of the diyne bridges is
159
removed. The strong shieldings of the functional group protons in (620) suggest that this compound prefers an anti conformation of the two naphthalene systems. Variable temperature spectra combined with full band-shape analyses of the CH2 and CH3 signals 0 in (620a) gave a barrier DG 298 for anti anti intercon1 version of 51:5 ^ 1:3 kJ mol : The spectra also indicate that a further conformer of low concentration participates in the conformational equilibrium, most probably the syn conformer, the percentage of which was calculated to be 6.5% at 13C DG0 298 6:6 kJ mol1 : As the same inversion barrier as for (620a) is also found for compounds (620b) and (620c), which possess larger acyloxymethyl substituents, one may reasonably assume that in the anti syn interconversion it is the fused benzo ring that rotates through the molecular interior, not the acyloxymethyl groups. The hydrogenated naphthalenophanes (621) show no sign of diastereotopic methylene protons down to 60C, but at 97C the H-6,7 peak splits into two, presumably because of a frozen anti/syn equilibrium. At 93 ^ 1C, the equilibrium constants K(anti/syn) for (621a), (621b), and (621c) are 1.3, 2.1, and 2.6, respectively, in line with the increase of the substituent size in this order. The upper limit of the conformational barrier was estimated to be 42 kJ mol 1. The more compact conformation and the lower barrier of the hydrogenated phanes compared to the acetylenic analogues imply that the former undergoes an accordion-like breathing in the syn/anti interconversion. Complexation studies with (620) and (621) are also described in Ref. [347] but are not discussed here. The combination of two 10b,10c-dimethyl-dihydropyrene units (317a) to form [10.10](2,7)dihydropyrenophane (622) was reported by Mitchell and Jin [348]. The compound has a highly symmetrical 1H NMR spectrum without unusual shifts dCH3 4:31: The fact that the trans-methyl groups of the dihydropyrene (dhp) system absorb as one common singlet in the 360 MHz spectrum, suggests that the dhp units can rotate on the axis along the 2,7-bonds. This process is not stopped on cooling to 100C. A NOESY spectrum showed an interaction between the 4,5,9,10-dhp and the methyl protons. Since such an interaction is not observed in the parent (317a), it must occur between protons of one dhp unit and of the other, suggesting that during rotation the methyl
protons pass close to the edge ring protons of the opposite ring.
CH3
O O (CH2)4 O O
2
O CH3 O (CH2)4 CH3 O O

7
CH3 (622)
6. Multiply bridged phanes 6.1. Phanes with multiple bridges between different aromatic rings As in the previous section, it is not possible to arrange the material in a strictly logical order, so the approach adopted is to proceed from phanes with few and short bridges to those with more and/or longer bridges. In an article on multibridged [2n]cyclophanes, the 1H and 13C NMR spectra of all cyclophanes with two to six two-membered bridges and the same substitution pattern in both benzene rings, (148), (149), (194), and (623)(630), and of the skew [2.2.2](1,2,4) (1,2,5)cyclophane (631) are assigned by NOE difference and 2D correlation spectroscopy [144]. The 1H NMR spectra of the bridge protons including the 13C satellites of the symmetrical compounds (194), (625) and (630) were analysed by iterative methods, cf. the earlier discussion of (194). Chemical shifts and coupling constants were discussed with regard to molecular geometries. A through-space isotope effect of deuterium upon 13C NMR chemical shifts in CHD2-[24](1,2,4,5)cyclophane (204) was discussed in Section 3.2. At room temperature, the 1H and 13C NMR spectra of the doubly positive bis[(hexamethylbenzene)ruthenium] complex of [2.2.2.2](1,2,4,5)paracyclophane, (632) [349] shows the molecule to be symmetrical
160
and to adopt a Ru Ru structure on the NMR time scale. At low temperature, however, two sets of NMR signals are present, showing the upper and lower halves of the molecule to be different and suggesting a localized Ru 2Ru 0 system with h 6- and h 4-coordination, respectively. This implies a net two-electron transfer between the ruthenium atoms in the equilibrium (632a) Y (632b). The line shapes of the 1H methyl signals were analysed at eight temperatures between 80 and 0C Tc 43C; and the kinetic parameters obtained are DH 53:1 ^ 3:4 kJ mol1 ; DS 33 ^ 13 J K1 mol1 ; and DG 43:1 ^ 5:0 kJ mol1 :
1 1 3 3 4 1
(148)
1 4 2 3
(149)
(194)
1 1 5 3
(623)
1 2 3 4 5
(624)
1 2 3
(625)
1 2
(626)
1 2 3
(627)
(628)
4 2
1 5 2 1
(629)
(630)
(631)
The 13C chemical shifts and the 1H shift ranges of the fully bridged [2.2.2.2](2,3,4,5)-thiophenophane (633) (superthiophenophane) and its precursor 2,10-dithia[3.2.2.3](2,3,4,5)thiophenophane (634) have been reported [350]. Unfortunately, no specic
shift assignments were made, nor were analyses of the AA 0 BB 0 spin systems in the 1H spectra carried out. Conformational analysis of hexadeuterio[3.3.3](1,3,5)cyclophane (635) was undertaken by Shinmyozu and collaborators [351]. There are two discernible conformers: (635A) and (635B), which interconvert slowly at 70C, their aromatic protons giving rise to three signals at d 6:71 (Hii), 6.52 (Hio), and 6.36 (Hoo) with relative intensities of ca. 1:2:1. This assignment is straightforward if one takes into account the deshielding effect by almost 0.2 ppm of a bridge upon its ortho-syn aromatic proton. Integration gave a 27:73 ratio of conformer populations at 70C which corresponds to (635B) being more stable than (635A) by 1.7 kJ mol 1. There are two possible bridge inversion processes: those between different conformers A O B and those between like conformers B O B: These processes have different activation energies but the nature of the spectra (four overlapping AB systems for the benzylic protons) allowed only the determination of one coalescence temperature (7C at 270 MHz) and a common barrier, DG 7C 51:9 kJ mol1 : It was concluded that the inversions of the three bridges are not correlated but that the bridges move independently. The trione (636) gave sharp spectral lines down to 90C. Hence it is much more exible than the hydrocarbon (635). The triply bridged trithiacyclophanes (637) and (638) [352], the cyclophane (639) and the cyclophanetriene (640) [353], each with one uoro substituent per aromatic ring, were investigated by Lai et al. Compounds (638)(640) are of interest because of through-space spinspin coupling between proton and uorine nuclei of opposite rings which are forced into close contact by the molecular geometry. The aromatic interdeck distances were estimated to be 319, 279, and 281 pm in (638), (639), and (640), respectively, from X-ray diffraction studies of the uorine-free parent compounds. In agreement with this, the interring J(F,H) is small, 2.4 Hz, in (638) and distinctly larger, 6.9 Hz, in (639). However, it is unexpectedly small in (640), viz. only 5.0 Hz. It is worth noting that the assignments of the 1H chemical shifts within the methylene groups ortho to uorine in (639) most certainly need to be reversed. The proper assignment is deshielded/shielded for the proton syn/anti to the uoro substituent as
161
2+
Ru
Ru2+
Ru0
Ru
Ru0
Ru2+
(632)
(632a)
(632b)
(633) D2 Hii D2 Hio (A ) (635) D2 D2 Hio (B) D2
(634) O Hoo O
D2 (636)
already discussed in Section 3.9. Similarly, the assignments within the SCH2 groups ortho to uorine in (637) and (638) need reversing, cf. the data for (405) in Ref. [165]. In the low-temperature 1H NMR spectrum (80C) of the triply bridged dioxadithia[3.4.3]phane (641) [354], the geminal protons in the three indicated kinds of methylene groups are anisochronous. At an observation frequency of 90 MHz their signals coalesce at ca. 50C (OCH2) and ca. 55C (SCH2), which give the same barrier of 45.3 kJ mol 1 for the different exchange processes. The conformational process taking place was believed
to be a concerted wobbling of the three bridges in the manner shown in (641) O (641 0 ). Cyclophanes (642) and (643) contain four threemembered bridges [355]. The sharp singlet d 6:90 of the aromatic protons of the 1,2,4,5-isomer (642) at room temperature suggests the mobile nature of this compound. NOE experiments show the most stable conformation to be boatboat. In the 1,2,3,5isomer (643), a sharp singlet of the aromatic protons d 6:62 as well as averaged benzylic proton signals (Heq, Hax) of the isolated trimethylene bridge indicate rapid inversion of the latter. The ruthenium(II), osmium(II), and iron(II)
162
F S R1 S S R2 (637), R1 = F, R 2 = H (638), R1 = H, R 2 = F Ha S He Hf (641) H O O Hb Hc S Hd (639)
F (640)
O O S
(641)
H (642)
H (643)
complexes of [3n]cyclophanes n 24; (644a) (644d), (645a)(645d), and (646a)(646d), respectively, were studied by 1H and 13C NMR [356]. The complexation shifts Dd d (complex) d(free
(644a), L = [32](1,4)cyclophane (644b), L = [33](1,3,5)cyclophane (644c), L = [34](1,2,3,5)cyclophane (644d), L = [34](1,2,4,5)cyclophane (645a), L = [32](1,4)cyclophane (645b), L = [33](1,3,5)cyclophane (645c), L = [34](1,2,3,5)cyclophane (645d), L = [34](1,2,4,5)cyclophane
Ru L
2+
2 BF4
Os L
2+
2 PF6
Fe + L Fe + 2 PF6
(646a), L = [32](1,4)cyclophane (646b), L = [3 3](1,3,5)cyclophane (646c), L = [34](1,2,3,5)cyclophane (646d), L = [3 4](1,2,4,5)cyclophane
ligand) of the protons at the metal-bound aromatic rings are ca. 0.5 to 0.7 and 0.1 to 0.4 ppm for the Fe(II) and Ru(II) complexes, respectively, whereas those of the Os(II) complexes are ca. 0.1 to 0.2 ppm. The Dd values of the tertiary carbon atoms in the metalbound aromatic rings are ca. 39 to 42 and 45 to 50 ppm in the Ru(II) and Os(II) complexes, respectively. The numbers for the quaternary carbon nuclei are 16 to 24 and 21 to 28 ppm, respectively. The observed complexation shifts are almost independent of the number of bridges in the cyclophane ligands. It was concluded that the 1H and 13C NMR chemical shifts of the metal-bound aromatic rings are strongly inuenced by the anisotropy effect of the metal. Cyclophane (647) with ve three-membered bridges [357] also shows conformationally averaged 1 H and 13C NMR spectra at room temperature, dHar 6:71 (CD2Cl2). The aromatic proton signal decoalesces at 70C and two singlets (d 6:58
163
and 6.82) were observed at 90C with respective intensities of 1.0:1.2. The activation barrier to interconversion was determined to be DG 40:2 kJ mol1 : MM3 molecular mechanics computations predict (647b) as the most stable conformation followed by (647a). This agrees with the relative chemical shifts of the aromatic protons because of the deshielding effect of the three-membered bridge in the syn-conformation, cf. (635). According to the MM3 results, the observed barrier probably corresponds to the ipping of the bridges at C-1/C-5. Flipping of the other bridges is estimated to have lower barriers by about 17 kJ mol 1. In line with the above, the correlated inversion of all six trimethylene bridges, which converts conformation (648a) of [3.3.3.3.3.3]cyclophane into (648b), is expected to be easy and does occur rapidly at room temperature [358]. This is obvious from the presence of only two averaged 1H NMR signals (benzylic CH2, d 3:19; and central CH2, d 2:46) and three 13C signals d 135:4; 28:2; 20:5: Variable temperature 1H NMR experiments on (648) [359] showed four different chemical shifts for the bridge protons below 40C. These were assigned by spin decoupling: d a, d b, d c, dd 3:21; 2.78, 2.55, and 1.70, respectively. Simultaneous decoupling of Hc and Hd at low temperatures allowed the observation of an AB spectrum for Ha and Hb, and its coalescence to a singlet. The inversion barrier DG (40C) is 45.6 kJ mol 1.
6.58
6.82
(647a)
(647b) Ha Hb Hc Hd
(648a)
(648b)
The 1H NMR data of the triply bridged [n.2.2](1,3,4)cyclophanes, n 45; (649), [n.4.4]
(1,3,4)cyclophanes, n 45; (650), and [n.2.2] (1,3,5)cyclophanes, n 24; (651) were reported [343]. For geometrical reasons, these compounds must assume syn conformations. This was also clear from the moderate upeld shifts of the aromatic protons relative to benzene model compounds and from the narrow ranges of these shifts in (649) and (650). The reaction of 1,2,4,5-tetrakis(bromomethyl)benzene with the analogous tetrathiol furnished the two possible isomers (652) and (653) [360]. Their structures were derived from the 1H chemical shifts (considering the distance of the aromatic rings and their relative orientation) and conrmed by an X-ray diffraction study of (652). This work disproved the earlier reverse structural assignment by Klieser and gtle [361]. A similar kind of isomerism arose Vo when the two tetrabridged biphenylophanes (654) and (655) were prepared from their two tetrafunctional precursors [362]. A comparison of the 1H chemical shifts of (654) and (655) with those of the model compounds 3,3 0 ,5,5 0 -tetramethylbiphenyl and 4,4 0 -dimethoxy-3,3 0 ,5,5 0 -tetramethylbiphenyl shows that the aromatic protons in the parallel phane (654) are shielded by 0.230.43 ppm relative to those in the model compounds. This is the normal value for eclipsed aromatic rings in syn-cyclophanes. In the crossed phane (655), the 2,2 0 ,6,6 0 -protons in both biphenyl subunits are shielded by ca 1.0 ppm with respect to the model compounds. The molecular formula shows that each of these protons is above (or below) one aromatic ring, though not exactly centred, of the opposite phane deck. When certain di-tert-butyl[n.2]metacyclophanediols are oxidized with K3[Fe(CN)6], their intramolecular OC coupling products (656) containing a spiro skeleton are formed [363]. When n 3; the 1H NMR spectrum in DMSO at room temperature shows two doublets J 1:5 Hz for the diene protons d 5:86 and 6.40) and a broad singlet d 6:93 for the aromatic protons. On raising the temperature, the diene and aromatic proton signals fuse and coalesce at 80C: the compound undergoes rapid [3.3] sigmatropic rearrangement between degenerate isomers. The barrier increases with increasing number n of methylene groups in the bridge. For n 8 signal coalescence cannot be achieved at 150C. The full paper on this subject [364] also reported [1.5]
164
MeO OMe
(CH2)n (649), n = 45
(CH2)n (650), n = 45
4.02/3.78
(CH2)n (651), n = 24
7.30 4.53/3.68
S S (652)
7.74
S S (653)
6.62
S S
6.96 6.54
6.17
6.16
MeO
6.84
OMe
MeO
OMe
(654)
(655)
(CH2)n tBu O O tBu (656) n G [kJ mol ] Tc [C]

1
(CH2)n tBu O O tBu
3 71.1 80
4 71.5 80
5 77.8 110
6 87.9 140
8 >105 >150
10 >105 >150
R1 O
O R2
R1 O
O R2
(657a), R1 = H, R 2 = Me (657b), R1 = H, R 2 = tBu (657c), R1 = Br, R 2 = tBu
165
(CH2)n2 (CH2)n S S
(658), n = 38, 12
(659), n = 310
sigmatropic rearrangements of the type (657) O (657 0 ), in which the spiro centre remains on the same ring when this is favoured by the nature of the substituents. For this process, coalescence temperatures of the aromatic and of the olenic proton signals are near room temperature and free energies of activation are of the order of 58 kJ mol 1. The triply bridged [n.2.1](1,2,3)cyclophanes (658), n 312; and (659), n 310; may also be considered dibenzocycloheptenes with an additional bridge. For small values of n, the protons of the ArCH2Ar methylene group are nonequivalent at room temperature because the short bridge restricts the conformational movement of the dibenzocycloheptene system [365]. This is the case for (658), n 5; and for (659), n 8: Large values of n lead to singlet absorptions for the ArCH2Ar methylene protons at room temperature, viz. in (658), n 7; and in (659), n 10: Barriers to conformational ipping of the aromatic rings ( inversion of the benzocycloheptene moiety), determined by the coalescence method, are given in Table 15. Formally, compounds of type (660) [366] are triply bridged phanes, viz. [n.2.2] (1,3,5)cyclophanes, but they are better visualized as tethered [2.2]metacyclophanes. Their conformational preference is deter-
mined by the length of the tether. A very long tether should have no inuence and thus allow the [2.2]metacyclophane to assume its preferred anti conformation (660a) with parallel rings. As the length of the tether decreases, the aromatic rings should be tilted with respect to one another as in (660b) and nally the anti conformation will be less stable than the syn (660c). At some intermediate tether length the two conformers may coexist. Indeed, the synthesis of phane (661a) with a 12-atom tether yields only the syn conformer which has a normal chemical shift, d 6:19; for the internal aromatic proton (para to the ether function) [366]. In contrast, phane (661c) with a 14-atom tether was isolated exclusively in the anti form. Signals of the internal protons are observed at d 4:83 and 3.30. These large shieldings prove the anti conformation and the large difference between them is due to the relative tilt of the rings as depicted in (660b). This tilt moves the internal proton of the inner ring further into the shielding region of the outer ring and the proton of the outer ring away from the shielding region of the inner ring. The chemical shifts of the two internal protons of (661c) were only assigned by this reasoning, not experimentally, yet it is difcult to devise a suitable experiment to achieve such assignment. Logically, the properties of
Table 15 Activation parameters of benzocycloheptene ring inversion in (658) and (659) as a function of the length of the third bridge Compound n Total bridge length Tc [C] DG [kJ mol 1] (658) 5 7 150 85.4 6 8 50 65.3 7 9 30 47.7 8 10 100 33.9 (659) 8 8 120 77 9 9 20 57.3 10 10 50 43.5
166

outer ring
H H
Hi Hi
inner ring
(660a)
(660b)
(660c)
H O (CH2)n O (CH2)n syn-(661a), n = 10 syn-(661b), n = 11 anti-(661b), n = 11 anti-(661c), n = 12 O H O
MeO H (662)
H OMe
compound (661b) with its 13-atom tether are inbetween those of the molecules with the longer and the shorter tether. It occurs as a mixture of syn and anti conformers that can be separated by chromatography. In solution at room temperature the conformers equilibrate slowly to a anti/syn ratio of 5.9:1, so their difference in free energy is ca. 4.4 kJ mol 1. The chemical shifts of anti-(661b) are more extreme than those of the compound with the longer tether (Table 16). anti-Metacyclophane (662) is a good model compound for a molecule with untilted rings and the differences Dd H between the shifts of the internal protons in the tilted compound and the internal proton in (662) reveal that the proton of the inner ring is essentially shielded by the same amount by which the proton of the outer ring is deshielded. The chemical shift difference between the internal proton of the inner and outer ring may serve as an indication of the extent of the tilt. A series of triply clamped triphenylmethane deri gtle [367]. vatives has been studied by Karbach and Vo
While, at a 1H measuring frequency of 90 MHz, the trithia[3.3.3]phanes (663) and (664) are conformationally exible (DG 54.9 and 56.0 kJ mol 1, respectively; temperature not given), the corresponding [2.2.2]phanes are rigid until at least 140C. The symmetrically substituted compounds (665) and (666) show one ABXY spectrum (wrongly described as two AA 0 BB 0 spectra) for their para-phenylene rings, which indicates that these are xed in a propellerTable 16 NMR chemical shifts of the hydrogens para to the ether functions in the tethered [2.2]metacyclophanes (661a)(661c) and in the model compound (662) Compound Conformation (661a) syn 6.19 (661b) syn 6.17 (661b) anti 5.07 3.03 0.99 1.05 (661c) anti 4.83 3.30 0.75 0.78 (662) 4.08
d H (outer ring) d H (inner ring) Dd H (outer ring) a Dd H (inner ring) a

a
Relative to the chemical shift of (662).
167
R1
S S S
H (663) (664) R H CH3
R2 R1 H OH OH R2 H OH CH3
(665) (666) (667) (668) (669)

CH3
HN
Me HN O N H
(670)
like arrangement. Unsymmetrically substituted compounds like (667) show two overlapping ABXY spectra (not four AA 0 BB 0 spectra). Upon dissolution in CDCl3/triuoroacetic acid-d (7:3), diol (666) is converted into dication (668) and mono-ol (667) into monocation (669). The ensuing chemical shift changes are discussed in terms of the propeller angles of the para-phenylene rings and the degree of nonplanarity of the trityl cation moieties. For the macrocylic phane (670) [368] a closed and two open conformations are potentially important. In the closed conformation, the capping benzene ring and the pentacyclic base are nearer to one another than in the open conformations because of a synclinal Ca Cb Cg Cd torsional angle. In the open conformations this angle is antiperiplanar, resulting in a larger distance between benzene ring and base. The analysis
of the 1H spin system of the tetramethylene bridges and the application of the HaasnootAltona variant of the Karplus equation [190] to the J(H,H) values obtained, led to the conclusion that the torsional angle in question is antiperiplanar. Consideration of the combined ring current effects of the aromatic rings of the base (estimated with the JohnsonBovey model [79]) upon the tetramethylene proton shifts and upon those of the capping benzene ring also favours an open conformation. gberg and Wennerstro m [369] studied the 1H Ho NMR spectra of the bicyclophanes (671), (672) and (673), which have unsaturated bridges, and their saturated counterparts (674), (675) and (676). Rather detailed chemical shift considerations and comparisons with the shifts of suitable model compounds led the authors to conclude that the unsaturated
168
Ar Ar Ar Ar
Ar
Ar
Ar
(671)
Ha
(674)
(672) (673)
S
(675) (676)
compounds prefer a compressed chiral conformation, in which the distance of the trisubstituted benzene rings from one another and the volume of the central cavity are minimal and the twist angles (i.e. the projected angles between the start and end of a bridge as seen from a point on the threefold axis of symme7.35
try) are at a maximum. The other extreme conformation, not taken up by the molecules, is that of C3h symmetry which has the bridges eclipsed and a maximum distance between the 1,3,5-trisubstituted rings. The saturated compounds also prefer the compressed conformations. Remarkable chemical shifts occur for Ha in (671), dH 8:86; and in the saturated analogue (674), dH 6:05: In the latter compound, Ha is sandwiched between the two trisubstituted benzene rings and exposed to the shielding effects of both of them. The linear constitution of the belt-shaped phane (677) was determined by X-ray diffraction and conrmed by an NOE observed between the protons at positions a and b [370]. This excluded the crossed arrangement (677 0 ) which, in principle, could also have been formed in the preparation. At room temperature the compound adopts an unsymmetrical conformation as indicated by four AB systems for the CH2N and two methyl signals for the tosyl groups. The CH2N absorptions and the methyl signals are averaged to one singlet each above 138C. In the same paper, the geminal protons of the CH2N groups of the fourfold bridged diaza[3.3.3.3](1,2,4,5)cycloNTs
NTs
a
TsN
NT
NT s
b
s
7.04
TsN
NT
NT
b
7.39
(677)
(677) S
H TsN
7.05
2 J = 22.4 Hz (?) 5.03 3.53
S
a
NTs
S S Ts N
b b
6.48
(678) N Ts (679)
169
O
O O X O O
O
O O X O O
O X (CH2)3 (CH2)6 (CH2)7 (CH2)8 (CH2)9 (CH2)10 (CH2)11 (CH2)5CMe2(CH2)5
O X (CH2)3 (CH2)6 (CH2)7 (CH2)8 (CH2)9 (CH2)10 (CH2)11 (CH2)5CMe2(CH2)5 CH2CHCH 2 OSiMe2tBu
(680a) (680b) (680c) (680d) (680e) (680f) (680g) (680h)
(681a) (681b) (681c) (681d) (681e) (681f) (681g) (681h) (681i)
O
c
O O
H 3C O O O
(682)
phane (678) were reported as having a very large shift difference (d 5:03 and 3.53), most likely due to the adjacent tosyl group. The geminal coupling constant was reported as 22.4 Hz. This is an improbable value as such large magnitudes are found only rarely, viz. for CH2 groups situated between two p-systems in the proper conformation. The most stable conformation of the propylene bridges in (678) were shown to be boatboat by NOE experiments at 20C. The tubeshaped biphenylophane (679) has two biphenyl units parallel to the axis of the tube and one biphenyl at right angles to it. This was shown both by X-ray diffraction and by the NOE between the 2,2 0 -protons
(b) of the parallel biphenyls and the 4-proton (a) of the perpendicular biphenyl unit. Compounds (680a)(680h) and (681a)(681i) are tetraoxa[8.8]paracyclophanes and -phanetetraynes, respectively, in which a third bridge, the diester bridge, connects the C-2 positions of the p-phenylene rings [371]. Two ring-inversion topologies are possible for these molecules: the diester bridge can pass either through the paracyclophane cavity (donut-hole pathway) or around the outside (jump-rope pathway). Variable temperature 1H NMR experiments were carried out and the rate constants of ring inversion were determined by magnetization transfer for
170
(680a) and (681a) and by lineshape analysis of the remaining molecules apart from (681i). The latter molecule exists as two diastereomers that are transformed into one another by ring inversion, so the kinetics could be followed directly by evaluating the time dependence of the integrals. Earlier studies had shown [347] that the framework of diyne bridges is rigid and has a larger hole than the framework of exible saturated bridges that favours a more collapsed conformation. Hence, if for a given length of the diester bridge the ring-inversion barrier is smaller in the (681) than in the (680) series, the donut-hole pathway is preferred, while for a smaller barrier in the (680) series, the jump-rope mechanism prevails. At high n values of the (CH2)n chain, jump-rope inversion is expected to be favoured. Suppression of donut-hole inversion by gem-dimethylation in the middle of an ester chain is another topological probe; gemdimethylation should have little effect on jump-rope inversion. Applying these criteria, Brown and Whitlock [371] concluded that for n 7 the donut-hole pathway is followed, while the jump-rope pathway is followed for n 9: The (CH2)8 pair of compounds present borderline cases. The ranges of barriers observed are DG 25C 100 kJ mol1 (681i) and 90 (681a) to 44 kJ mol 1 (681g) in the phanetetraynes and 109 (680a) to 10 kJ mol 1 (680g) in the saturated-bridge phanes. The bowl-shaped cyclophane (682) shows equivalence of the geminal protons of the three different kinds of methylene groups at room temperature [372] At low temperatures, however, the methylene protons a d 3:87 and b d 4:90 turn into AB systems with coalescence temperatures of 10 and 11C, respectively. Methylene group c, on the other hand, absorbs as a sharp singlet down to 53C. These results indicate that the side bridges have some conformational constraints, while the C CH2 OC bonds of the central bridge make a cranklike rotation with a low barrier. Two isomeric cappedophanes (685) and (686) were isolated from the reaction of (683) with (684) [373]. When the cap (683) reacts from the bottom side of terphenyl (684), the product is (685); when it reacts from the top side, (686) is formed. The isomers could be distinguished from the chemical shifts of the m-terphenyl H-2 0 signals [d 6:24 in (685) and 5.70 in (686)] and H-5 0 signals [d 4:31 in (685) and 7.35
in (686)]. The strong upeld shift of H-5 0 in (685) is due to this proton being sandwiched between the two 1,3,5-trisubstituted benzene rings. Furthermore, when the signal of the same proton was saturated, a 10.4% NOE was observed at the proton signal d 7:62 of the para-phenylene ring. The two reaction products were the rst examples of two noninterconvertible conformers of a single host molecule, one (686) with a substantial cavity, the other, (685), with a self-lled cavity. Compound (685) was therefore called an autophagous (self-devouring) molecule. For other papers on cappedophanes and cuppedophanes the reader is referred to Ref. [374] and to the review of Vinod and Hart [375]. 6.2. in-Phanes A class of compounds that is very interesting both from the structural and an NMR point of view are the so-called in-cyclophanes. In these, a central atom is connected by several (usually three) bridges to the same aromatic unit. The geometric situation is such that the most stable isomer has the proton or other connected atom or group on the central atom pointing towards the aromatic unit, i.e. into the inside of the molecule. Apparently, the rst in-cyclophanes were prepared, but not recognized as such, by Ricci et al. [376]. One of their compounds, 2,8,17-trithia[4 5,12][9]metacyclophane (687) was later resynthesized by Pascal and Grossman [377]. They showed that the characteristic in-proton, whose 1H NMR resonance had previously been missed, has a septet absorption J 6 Hz at d 1:68: This is a higher-eld shift than the most shielded methylene proton of [5]- to [9]paracyclophane and clearly proved the in-stereochemistry. According to the results of MM2 molecular mechanics computations, the in-isomer is more stable, by ca. 29 kJ mol 1, than the out-isomer and the distance of the in-methine hydrogen from the mean aromatic plane is 221 pm. Subsequently, the authors succeeded in shortening all three bridges of (687) by oxidation and sulfone pyrolysis and obtained hydrocarbon (688) [378]. The distance between the mean aromatic plane and the in-hydrogen was estimated to be 178 pm with MM2, consistent with the extreme upeld shift of d 4:03 for this proton. The conformational ground state of the molecule is C3 as evident from the chemical nonequivalence of the benzylic hydrogens and the broadening of the other CH2 signals
171
O +
Br
Br
HS
SH HS (683)
SH
Br
5
Br (684)
S S H
2
S O S O O S H S O
5 2
H (685) (686)
at room temperature. The signals of the benzylic protons coalesce at 47C and DG for the bridge ip from one side of the symmetrical arrangement to the other is 61.9 kJ mol 1. The shorter-bridge analogues of (687), compounds (689)(691) with n CH2SCH2 and 3-n CH2SCH2CH2 bridges n 13 between the benzene ring and the central methine unit, show increased shielding of the in-proton with increasing number of the shorter bridges: d 1:94; 2.43, and 2.84 [379]. However, the chemical shift of the in-proton of (691) with its three CH2SCH2 linkages does not reach the extreme value of its counterpart in (688), d 4:03; in agreement with the longer CS relative to the CC bonds. The shift of the in-proton of (691) is 4.90 ppm upeld from the methine resonance in the acyclic model compound (CH3SCH2)3CH d 2:06: Compound (691) shows the same dynamic phenomenon as its tricarba analogue (688). At room temperature, the 1H NMR spectrum contains several broadened methylene
resonances which indicates slow enantiomerization of the C3 conformers, (691 0 ) and (691 00 ), on the NMR time scale. At 68C the broadened lines are resolved into two pairs of diastereotopic methylene resonances. The protons of the CH2 group adjacent to the apical methine have a chemical shift difference of 1.70 ppm in toluened8. Coalescence at 47C (250 MHz) gives a DG value of 60.3 kJ mol 1, just slightly lower than the barrier for (688). Schneider et al. [77] were very successful in semiempirically calculating the ring current effects upon the in-protons in (688) and (691). The next in-cyclophane (692) from Pascals group [380] has a central phosphorus atom linked to the 1,3,5-positions of a benzene ring by three fourmembered bridges. The 13C NMR spectrum shows spinspin coupling between the phosphorus and all of the aromatic carbon atoms. Of particular interest are the couplings to the quarternary and the tertiary carbon atoms of the basal ring; they amount to 7.5 and
172

1.07 0.72 2.36
H S
1.68
S
3.66 7.19
4.03
S
1.45
H
2.23/2.91 6.86
1.94
S (689)
(687)
(688)
(2.90 & 1.20 at 68 C) 3.1&1.7
S S H 2.43 S
S S H
2.84
X S
S
3.77
7.18
S (692), X = P (693), X = SiH S
(690)
(691)
S S (691) CH2Ph S S Si PhCH2 S H
S S (691") Z P
P Y S
CH2Ph
S X (695), X = NH 2, Y = H (696), X = NO 2, Y = H (697), X = Y = NO 2 (698a), Z = lone pair (698b), Z = O (698c), Z = CH 3+ I
(694)
3.5 Hz, respectively. These are obviously throughspace couplings as the nature and arrangement of the intervening bonds is not favourable for ve- and six-bond interactions. The 31P chemical shift of (692) is d 5; a substantial shift to high frequencies from the starting tris(2-mercaptophenyl)phosphine which has d 26:7: Hence, a shielding effect by the ring current of the basal benzene ring upon the phosphorus was not observed, in spite of the short distance (290 pm by X-ray diffraction) of the phosphorus atom from the centre of the base plane. The authors suggested a more phosphonium-like character for the
phosphorus as an explanation for the high-frequency shift. Typical methyltriarylphosphonium 31P shifts fall into the range of d 1826: Compound (693), the sila-analogue [381], has a chemical shift of the SiH hydrogen of d 1:04: This represents a shielding effect of 5.09 ppm relative to model compound (694) and agrees with the high-eld shift observed for the in-methine compound (691). Both the silaand the phosphaphane have diastereotopic benzyl protons due to the propeller-like conformations found also for (688) and (691). In contrast to these, heating to 180C does not result in signal
173
coalescence at 500 MHz observation frequency. The lower limit of the free energy of activation for the enantiomerization of cyclophanes (692) and (693) is thus 92 kJ mol 1. Derivatives of (692) substituted at the basal ring with one amino group (695), one nitro group (696) and two nitro groups (697), respectively [382], have irregular chemical shifts of the phosphorus dP 9:3; 6:9; 5:8 that could not be correlated with the electron donating and withdrawing power of the substituents, bearing in mind that (692) itself has dP 5:0: The magnitudes of the through-space P,Ccoupling constants are only slightly affected by the substituents. In this context it is of interest to note the existence of the out-phosphaphane (698a) with three ve-membered bridges [383]. Its chemical shift dP 14:2 is much closer to the normal range of triarylphosphine shifts than that of (692). The phosphine oxide (698b), dP 33:1; and the methylphosphonium salt (698c), dP 21:3; were also reported.
CH3 Si
shifts at room temperature. This indicates that the bridges are rigid under these conditions.
1.65
H
2.36
H H
(701)
(702)
The 1H NMR spectrum of trans-hexahydro[2.2]paracyclophane (701) [387] displays a high-eld resonance at d 2:36: This is due to the proton in the interior of the molecule. The rigidity of the molecule forces the in-proton to face the benzene ring. Its chemical shift is 4.0 ppm upeld from the methine resonance d 1:65 in the cis-isomer (702) [388]. 7. Multilayered phanes An extensive review of the NMR aspects of multilayered phanes has been written by Misumi [10], the protagonist in this eld of chemistry. Following his retirement the number of papers in this area has strongly declined. We mention only two papers, the rst one on the triple-layered [2.2][2.2]naphthalenophane (703) [389]. The subunit comprising the upper and the central naphthalene deck of this compound represents the chiral [2.2]naphthalenophane (285) as does the subunit consisting of the central and the lower deck. The protons of the outer decks are shielded by 0.180.26 ppm relative to those of (285) while the protons on the central (sandwiched) deck experience an upeld shift which equals almost twice that of the naphthalene a-protons of (285) with respect to 2,6-dimethylnaphthalene. The structure of (703), at rst derived only from the 1H chemical shifts and from MS data, was later conrmed by X-ray diffraction [390]. Other possible stereoisomers of (703) were not formed in the synthesis. The other paper concerns the two isomeric triplelayered phanes (704) and (705) with outer (3,6)phenanthrene decks and an inner naphthalene deck [391]. The difference between the isomers consists in the mode of connection of the phenanthrene rings to the naphthalene ring. It is parallel
Si S S (699) F S S
S S
(700)
The in-uorosilaphane (699) [384] with vemembered bridges between the silicon and the basal ring has the largest in-functional group in this class of compounds so far. Originally, its 19F nucleus was reported [384] to be shielded by 155 ppm relative to the model compound tris(o-tolyl)uorosilane, which has dF 160:6: This would have been an extraordinary nding, but the spectra were incorrectly referenced and the chemical shift of (699) was soon corrected to dF 155:3 [385], so the uorine nucleus is actually deshielded by 5.3 ppm. An attempt to prepare an inphane with an internal methyl group connected to silicon and six-membered bridges led to out-isomer (700) [386], which displays a normal SiCH3 shift of dH 0:73: It shows more than three methylene 1H chemical
174
5.55
6.69
6.17 6.91
(703)
7.57 7.76 7.44 7.93 7.35 7.20 6.56 5.86 7.39 8.45 7.75 7.58 7.45
7.62
(706)
7.44
(704)
(705)
(707)
(2,7)(3,6) in the rst case and crossed (2,6)(3,7) in the second. The mode of connection imposes an oblique structure upon (705) with the concave side of the phenanthrene and the naphthalene over one another. This leads to strong shielding of the phenanthrene H-4 Dd 1:89 and the naphthalene H-1 Dd 1:58 protons compared to the phenanthrene and naphthalene reference compounds (706) and (707), respectively. In (704) only phenanthrene H-4 is slightly shielded Dd 0:52 with respect to (706).
8. [mn]Phanes gtle [4], by [mn]phanes, written with an Following Vo italicized subscript n, we understand a cyclic arrangement of alternating aromatic rings and aliphatic bridges, for example [Ar(CH2)m ]n. The most common representatives of this class are the calixarenes. These and their close analogues are, however, not treated in this review. Instead, arrangements less regular than strict
[mn] are considered, i.e. cyclic sequences with more than two aromatic rings and intermittent aliphatic parts. Two conformers of trimethoxy[2.2.1]metacyclophane (708) were isolated by Tsuge et al. [392]. In the rst of these (later called folded inwards [393]), there is a parallel arrangement of the two benzene rings (A, B) connected by the single methylene group such that the molecule possesses a plane of symmetry, cf. (708A). The plane of the third benzene ring (C) is perpendicular to the plane of symmetry and the methoxy group bound to it points into the cavity between rings A and B, so it is shielded by the ring currents of both and attains the extraordinary 1H chemical shift of d 1:21 while the other two methoxy groups have almost normal shifts at d 3:44: In the second conformer (708B) rings A and C are held parallel to one another (proved by X-ray) so that an asymmetric structure results. The t of the B-methoxy group into the cavity between rings A and C is not as perfect as that of the C-methoxy group between rings A and B in (708A). Thus, the shift of the B-methoxy

3.44 ring A OMe ring C 3.24, 3.17 OMe
175
OMe B tBu
tBu MeO 1.21 C
OMe A tBu
tBu MeO B 2.64
(708A)
(708B)
R1 R2 R2
S R2
R1 R2
(CH2)n
(CH2)n (710), n = 1 or 2
1
(709), n = 1 or 2
2
R = Me, OMe; R = n-alkyl, O(n-alkyl)
R2
R1 2 R
(711)
group in (708B) is only d 2:64: Conformer (708B) is chiral and shows doubling of signals in the 1H NMR spectrum when Pirkles reagent (optically active 1-(9anthryl)-2,2,2-triuoroethanol) was added to the solution [394]. The internal methoxy groups of the two conformers show different reactivities towards BBr3. While that of (708B) is hydrolysed, that of (708A), well shielded by the A and B rings, is not attacked. A series of other [2.2.1]- and [2.2.2]metacyclophanes (709) and of dithia[3.3.1]- and [3.3.2]metacyclophanes (710) was later studied by the same group of authors [393]. It was found that some of the molecules prefer a folded inwards conformation like (708) and others an alternate conformation (711). The
preference strongly depends on the nature of the substituent R 1. Thus, while (710), n 2; R 2 Me, R 1 Et, assumes the folded inwards conformation (shift of terminal ethyl protons: d 0:06 as opposed to ethylbenzene, d 1:20), the analogous compound with R 1 n-propyl has a chemical shift of the terminal propyl protons of d 0:91; which is practically identical to propylbenzene, d 0:92: In the latter molecule the propyl group is too large to t inbetween the two other aromatic rings, so the molecule adopts the alternate conformation. The trimethoxy[3.2.2]metacyclophanes (712) and (713) proved to be much more exible than the [2.2.2]- and [2.2.1]phanes [395]. Both exist in an
176
equilibrium between a 2,3-alternate and a cone conformation, the former being preferred at room temperature. The former was recognized by a highly shielded and the latter by a deshielded methoxy group in the 1H NMR spectrum. Variable temperature studies gave the following equilibrium parameters for (712): DH 0 0:82 kJ mol1 ; DS0 7:98 J 1 K1 ; DG0 3:20 kJ mol1 at 25C; for (713): DH 0 6:73 kJ mol1 ; DS0 1:37 J mol1 K1 ; DG0 6:32 kJ mol1 at 25C. Lineshape analysis of the spectra of (713) gave an activation barrier DG of 79 ^ 4 kJ mol1 for conversion of the 2,3-alternate into the cone conformation.
3.28, 3.31
OMe OMe
3.56
OMe
4.22
OMe OMe
R R
OMe
2.72
5.72
R R (712), R = tBu (713), R = H

[ values for ( 712)]
R cone
2,3-alternate
The coordination shifts in the 1H NMR spectrum of (190) bis(h 6-[2.2.2]paracyclophane)chromium(0) have already been referred to in Section 3.1 [141]. The conguration of (714) with cis oriented hydrogens at the annelated cyclohexadiene ring could be determined from low-temperature 1H NMR spectra [396]. Upon cooling the sample, the signals due to protons of type He and Hf broaden rst, indicating slowed rotation of the phenylene rings next to the cyclohexadiene moiety. Further cooling resharpens the peaks and results in an ABCD-type signal pattern. The Ha, Hb, Hc, Hd proton signals (a sharp singlet at elevated temperatures) broaden more slowly as the temperature is lowered and resharpen to appear as two slightly broadened apparent singlets at 110C. This behaviour is consistent only with the cis isomer, in which Ha and Hb are chemically equivalent (as are Hc and Hd), the slight residual broadening of the signals being caused mainly by meta H,H coupling. If the trans isomer of C2 symmetry had been present, Ha and Hd would have been equivalent (as would have been Hb and Hc) and an ortho-like coupling would have been observed between the two signals. The barrier to rotation of the unique phenylene ring was
H He,Hf Hc Hd
Ha
Hb (715) H3C CH3 (716)
(714)
6.39 6.39
6.91 7.23
TsN
NTs
(717)
(718)
(719)
(R = H, Me, OMe, Br, CN, NO 2)
177
estimated to be ca. 50 kJ mol . It is not possible to determine this barrier in the parent compound (715) because its solution-phase symmetry is too high. When [2.2.2]paracyclophene (715) is converted into its dianion (716), neither diatropic nor paratropic ring current effects on 1H or 13C chemical shifts are observed [397]. The small upeld shifts that do occur could be interpreted as charge effects. The simple NMR spectra, two lines in the 1H and three lines in the 13C spectrum, were explained by assuming rapid interconversion between less symmetrical conformers in which two aromatic rings lie in the plane of the olenic double bonds and the third one is perpendicular to this plane. By comparing the 1H chemical shifts of (717) with those of the model compound (718), Kasahara et al. [398] demonstrated the mutual shielding effects in (717) of the para-phenylene rings, Dd d717 d718 0:84 and 0.52 ppm. This is forced upon the molecule by clamping the para positions with the vinylene group, which prevents the splaying out of the two phenylethynyl groups that takes place in the opened compound. When [2.2.2]phane (719), containing a triple bond in one of its bridges, has no internal substituent (R Hi), its benzylic protons absorb as one AB spectrum d 5:06 and 4.23, J 15:0 Hz: The intraannular proton Hi is deshielded to d 8:18 by the magnetic anisotropy of the neighbouring alkynediyl group. Internally substituted derivatives of (719) give two AB spectra for the CH2 groups. To explain this, the authors suggested a helically twisted conformation of the molecules [399]. tzmacher et al. [400] extended their studies of Gru azocyclophanes by investigating the trinuclear dithiadiazacyclophan-19-enes (720)(723) and -17-enes (724). The 1H NMR chemical shifts were discussed with respect to the structures of the molecules. The azo groups in (720) and (721) are exclusively cis, whereas for (722)(724) both cis- and trans-isomers are observed. Rapid conformational interconversions take place in trimethoxy[5.5.5]metacyclophane (725), as can be inferred from the equivalence of the benzylic protons that was observed in the 1H NMR spectrum at room temperature [30]. Compound (726), [14]paracyclo-bis(1,2)pyrazolium-phane, in solution (D2O or DMSO) at room
temperature exists as a mixture of chair and boat conformers, (726c) and (726b), in the ratio of 54:46 [401]. The conformers have rather similar 1H and 13C NMR spectra which were fully assigned and analysed, also with respect to 13C, 1H coupling constants. The conformers were distinguished by the different symmetries of the 1H spin systems of their p-phenylene rings. Both are of the AA 0 BB 0 type, but J(A,B) is an ortho-H,H coupling constant in the chair and a meta-H,H coupling in the boat conformer. The different 1H signals of the conformers coalesce at different temperatures from which the free energy of activation for the chair-to-boat interconversion was determined as DG 25C 72 kJ mol1 : The DH and DS values (the latter negative) were also derived but deemed not very accurate. In pyridinophane (727) the proton signals of the pyridinium rings are broad at room temperature [402]. This indicates relatively slow rotations of these rings about their NC4 axes. At lower temperatures decoalescence was observed for the a- and the b-proton signals of both rings A and B. Interestingly, determination of the rotational barriers DG from the different coalescence temperatures shows that rings A and B require different activation energies for internal rotation. The values determined for ring A are DG 41:3 ^ 0:6 kJ mol1 (63C) and 42:0 ^ 1:0 kJ mol1 (60C) from the a- and b-proton signals, respectively. The corresponding values for ring B are 46:1 ^ 0:4 kJ mol1 (30C) and 45:8 ^ 1:0 kJ mol1 (40C). The conformational properties of some tetrameric metacyclophanes incorporating mesitylene units were studied by Pappalardo et al. [403]. They compared the 1 H NMR chemical shifts of the methyl groups in compounds (728)(730) with those in analogous open-chain bridged di- and tetramesityls and with other cyclophanes of known conformation. They concluded that the 16-membered [1.1.1.1]metacyclophane (728) prefers a saddle conformation while the 18-membered [2.1.2.1]metacyclophanes (729) and (730) adopt a xed crown conformation, resulting from the peculiar geometry of the disulde bridges. The same authors also investigated the 13- to 17membered metacyclophanes (731)(733) containing sulde and/or disulde bridges [404]. Correlations of their 1H chemical shifts with those of model compounds led to the assumption that (731) and
178
N N
C
S
B
N N
S
substitution patterns ring B rings A & C
S
configuration N=N
configuration N=N
(720) (721) (722) (723)
cis cis cis & trans cis & trans (CH2)5
1,4 1,3 1,4 1,3
1,4 1,4 1,3 1,3
(724)
cis & trans
OMe MeO (H2C)5 OMe
(CH2)5
N N
N N
(725)
(726)
N N
N N
N N N
(726c)
N N
N (727)
N N
(726b)
(732) prefer conformations with a propeller-like arrangement of the aromatic rings while (733) prefers a saddle-type conformation. Low-temperature 1H NMR spectra of (734) [405], a methoxy analogue of (730) with a differing substitution pattern, show that a saddle structure with C2 symmetry is present. At room temperature, (734) undergoes fast dynamic interconversion between two symmetry related structures resulting in overall four-fold symmetry. The activation parameters, obtained by lineshape analysis between 101 and 60C, are DH 41:4 kJ mol1 and DS 29:7 J K1 mol1 : The
high exibility of (734) seems to contradict the presumed xed conformation of (730). But as the latter compound could only be studied at 150C in nitrobenzene solution because of limited solubility, no experimental evidence of its low-temperature behaviour is available. Pappalardo et al. [406] also reported the 1H NMR spectra of the mono- to tetrahydroxy derivatives of mesitylene-based [1.1.1.1]metacyclophane (735). All ve compounds occur as 1,3-alternate conformers, i.e. having their benzene rings up-downup-down. This is apparent from the ca. 1 ppm upeld shift of the
179
MeO S S
OMe
X MeO X Y MeO X Y (728) CH2 CH2 (729) CH2 SS (730) S SS OMe X OMe
(731), X = S (732), X = S S
MeO S S
OMe MeO MeO
MeO S S
OMe
OMe OMe
MeO S MeO S MeO (733) OMe S
OMe S OMe MeO S MeO MeO (734) S OMe OMe S OMe
intraannular methyl groups d 1:1 relative to an open chain model compound. The 1H NMR spectra do not change between 25 and 80C. The 1,3alternate conformers of the mono- to tetraols have characteristic CH2 absorptions, viz. tetraol: 1 s, triol and mono-ol: 1 AB and 1 s (1:1), distal diol: 1 AB; proximal diol: 1 AB 2 s. The extraannular hydroxy groups appear as sharp singlets at d 4:5; indicating weak (if any) intermolecular hydrogen bonding. The 1H NMR spectra of dithia[3.1.3.1]metacyclophane (736) and of tetrathia[4.1.4.1]metacyclophane (737) do not show any signal doubling down to temperatures of 100 and 80C, respectively, indicating that these systems are conformationally very mobile [407]. In contrast, the tetramethylated dithia[3.1.3.1]metacyclophanes (738) and their [2.1.2.1]metacyclophane (739) and [2.1.2.1]metacyclophanediene (740) analogues do show temperature dependent 1H NMR spectra, from which Mitchell and Lai derived their conformational behaviour [408]. They concluded that all of these compounds undergo
a conformational process of type (741). Depending on the nature of the bridges X, Y, and Z, the barriers for this process were estimated to be in the range 39 to over 85 kJ mol 1, the low value applying to the dithia compounds (738). Both of the other series have barriers centred around 70 kJ mol 1, but the dienes (740) are quite sensitive to the nature of the onemembered bridges X and Y (range 57 to 85 kJ mol 1), whereas this plays a minor role (range 6672 kJ mol 1) for compounds (739) which have saturated bridges. Minor isomers, (742), of (740) were also found and shown to possess two trans double bonds. The aryl-CH3 groups of (742) have d H values between 1.30 and 1.14, the spectra being temperature independent between 100 and 150C. The room temperature 1H NMR spectrum of octamethyl[2.2.2.2]paracyclophanetetraene (743) [409] shows only three singlets for aromatic, olenic and methyl protons. Around 70C, a dynamic process with DG 42 kJ mol1 was observed (doubling of the aromatic and the methyl proton signals,
180
R1
X R4 R2
(736), X = S (737), X = SS R3 R1 OH OH OH OH OH R2 OH OH H OH H R3 OH OH OH H H R4 OH H H H H X S Y S
(735a) (735b) (735c) (735d) (735e)
(738)
X Y
X Y
(739) X a b c
(740) Y CH2 CH2 C=O CH2 C=O C=O
appearance of an AB-pattern for the olenic protons) which was interpreted as a correlated ipping of the four benzene rings within the favoured conformer shown in the formula as opposed to rotation of the benzene rings. Here, ipping means that the aromatic ring passes a plane perpendicular to that of the four olenic bridges whereas rotation means that it passes the plane of the bridges themselves. Support for the ipping mechanism came from the tetraethyltetramethyl derivative (744), for which ring ipping and ring rotation could be observed separately. Ring rotations ultimately interconvert one conformer into its enantiomer and this process exchanges the methylene protons that are nonequivalent when ring rotation is slow. The coalescence of their AB signals (CH3 decoupled) gave an approximate DG of 63 kJ mol 1
at 32C. Ring ips interchange the inner and outer sites of the aromatic rings and the signals involved with the aromatic rings and the methyl groups are doubled when this process is slow. This was observed between 20 and 80C. The free energy of activation for this process is ca. 42 kJ mol 1, in agreement with the value for (743). The latter barrier was believed to be essentially due to loss of p-electron delocalization rather than due to steric crowding in the transition state. In its NMR spectra, tetraester (745) of [2.2.2.2]cyclophanetetraene shows only one set of peaks although, in principle, two rotational isomers are possible [410]. As fast rotation of the ester-bearing arene rings is improbable for steric reasons, the presence of only one rotamer seems likely. Preparation of the diester (746) resulted in two constitutional
181
X Z Z Y Z X Y
(741) X, Y = CH 2 or C=O Z = CH 2SCH2 or CH2CH2 or CH=CH
X (742a) CH2 (742b) C=O (742c) C=O
Y CH2 CH2 C=O
R R R
R R
R R
(743), R = H (744), R = CH 3
isomers, one with C2 and the other with Cs symmetry. Fast rotation of the unsubstituted p-phenylene rings occurs because different chemical shifts for inside and outside protons are not observed. Given this, the isomers differ in that the p-phenylene hydrogens of the C2 isomer should form a common AA 0 BB 0 spin system, whereas they must give rise to an A4 singlet for one ring and a B4 singlet for the other in the Cs isomer. In fact, one isomer shows two singlets of four protons each d 7:12 and 7.07) at room temperature and thus has to be Cs isomer (746b). The other isomer shows one singlet of eight protons which, on
improving the resolution by warming to 47C, resolves into a pattern caused by two different chemical shifts with mutual coupling, termed AB by the authors. Hence, this is the C2 isomer (746a). Further support for this assignment was obtained by the observation that on cooling to 53C only one of the singlets in the spectrum of (746b) starts to broaden. This can only happen in the Cs isomer, in which the two pphenylene rings are nonequivalent. llen and collaborators [411] examined the 1H Mu NMR spectra of the dianions of nine macrocyclic cyclophanes and of two tetraanions. Unexpectedly,
182

6.77 6.54 7.00
MeO2C
MeO2C CO2Me
7.88 3.80
CO2Me
7.11 7.11 6.52 6.52 6.49 6.93
(745)
3.85 7.36
CO2Me
7.85
7.12 6.50 6.57 NOE 7.44 7.83 3.84
MeO2C
7.41
MeO2C (746a), C2
7.39 NOE 6.92 6.50 7.07
CO2Me
(746b), Cs
strong diatropic ring currents were observed in all of the dianions resulting in deshielding dH 814 and strong shielding dH 3 to 12) of the protons on the outside and inside, respectively, of the macrocycle. The 1H chemical shifts of (747), (749), and (750) are shown as examples. Obviously, the dianions behave as annulene-like true diatropic [4n 2]pperimeter systems while the neutral cyclophanes behave normally and display unspectacular chemical shifts. The presence of the local aromatic units in the unsaturated cyclophanes does not quench peripheral ring current effects in the dianions. Also, in contrast to the neutral hydrocarbons, internal rotation of the para-phenylene units is slow in the dianions so that inner and outer hydrogens can be distinguished. Extensive consideration of chemical shifts and model calculations of ring current effects led to the conclusion that the global ring current of the dianions may follow an outer, an inner, or where possible (naphthalene units) a middle route through a local aromatic unit. According to the authors the observed ring current effects can be understood in terms of a macro-
cyclic diamagnetic ring current modied by the local diamagnetic ring currents. The tetraanions investigated, for example (748), show paratropic shift effects that shield/deshield the outer/inner protons.
9. Conclusion This review has tried to point out the importance of NMR spectroscopy to the eld of phane chemistry as evidenced by the literature of the past 18 years. The progress of NMR spectroscopy that has occurred since the end of the previous review period (1981; cf. Mitchells work, Ref. [9]) has allowed much more detailed investigations of the structure and dynamics of this class of fascinating molecules than were possible before. In particular, the increasing availability of high-eld NMR spectrometers has facilitated the analysis of often rather intricate 1H NMR spectra, allowing the extraction of chemical shifts and spin spin coupling constants and their application in deriving ne details of the molecular structures. It is hoped

2 4
183
-7.07
9.26
12.76
4.48
9.56
2.09
(747)
11.4 b 13.6 12.8 -8.1a -12.0 -9.1a 11.8 12.1 b 2
(748)
9.44 b 8.74 b 10.48 -7.23 -5.79 a -4.35 a 9.99 0.09 9.55 0.20
-6.31 0.11
9.38 0.08
(749)
a, b
(750) : interchangeable assignments
that phane chemists will nd the present article benecial to their work. References
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Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190 www.elsevier.

NMR studies of cyclophanes

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

6.2. in-Phanes . . . . 7. Multilayered phanes 8. [mn]Phanes . . . . . . . 9. Conclusion . . . . . . . References . . . . . . . . . .

170 173 174 182 183

Keywords: Cyclophanes; High-resolution NMR; Review

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

X (1) (2) (3) (4) (5) H Cl Br Br D

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

(CH2)n Ph N (12), n = 9 (13), n = 8 (14), n = 7 (15), n = 6

(CH2)n N (16), n = 9 (17), n = 8 (18), n = 7 (19), n = 6

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

(21a), X = H (21b), X =OMe

(22), R = Me (23), R = OMe

(24), R = H (25), R = OC(=O)Ph

G = 42.7 kJ mol 1 (48 C) bridge flipping

G = 36.4 kJ mol 1 (73 C)

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

R S (26a), R = H (26b), R = F (26c), R = Cl (26d), R = Br O2 S R S O2 (E,Z)-(29a), R = H (E,Z)-(29b), R = Br

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

OMe (CH2)n (30), n = 815

(31) (32) (33)

N 41.0 N+Me 40.6 O+ 37.2

FSO3 +N CH3 (CH2)n (34), n = 610

.. N + CH3 (CH2)n (34)

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

Hb R=H R = CN (37a) (37b)

MeO2C (38) (39A)

3.22 0.44 3.72

2.87 1.59 0.06 3.73

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

1.18 H 1.72 H 1.31

H 1.72 H 3.45 H 2.12

(42a), R = CO 2Et (42b), R = CO 2Me

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

(46), R = H (47), R = CH 3 (48), R = CH 2OH

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

R (CH2)6 R (52a), R = Ph (52b), R = Me (53) (CH2)6

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

H (59a) H (59b) CO2Me H (59c) CO2Me CO2Me

139.0 7.13 136.0 7.07 137.6 7.19 134.7 7.93

132.1 or 132.0 7.20

134.6 7.34 133.7 7.34

CO2Me anti (59b) R E syn

S CH3 O H 3C (63) H 3C (63) O H3 C S (64) CH3 CH3

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

N Ts (72), R = H, n = 510 (73), R = Me, n = 510,12

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

1.54 2.62 7.09

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

O R N E (CH2)n E O O (85a), n = 8 (85b), n = 10 O O R N E R N E (CH2)n O O (87), n = 8 R = CH 2Ph, E = CO 2Me E E R N E

(CH2)n O O (84a), n = 8 (84b), n = 10 O O

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

(CH2)n (CH2)n (99a), n = 9 (99c), n = 7 (100a), n = 9 (100b), n = 8 (100c), n = 7 HB HD (CH2)n2

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190

O (CH2)m O O D2 (105) m 14 15 16 [n ] 16 17 18 D2 (106) D2 D2

N N NH (CH2)n n 4 5 6 7 8 10 O NH Zn (108) HN O O O NH Zn (107a-f) (CH2)n

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47190