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Gábor Krajsovszky

Heterocyclic compounds
ISBN: 978-615-5722-01-1

© Gábor Krajsovszky

Responsible editor: Gábor Krajsovszky


Publisher’s reader: István Mándity
Translated by Péter Tétényi

Department of Organic Chemistry


Pharmaceutical Faculty
Semmelweis University
Budapest, 2018
Acknowledgements

The editor wants to express many thanks


to Dr. István Mándity, who is Associate Professor and Director of Department of Organic Chemistry,
for the careful proofreading service of the current manuscript,
as well as to Dr. Péter Tétényi, who is Assistant Professor,
for the translation to English language.

Moreover, the editor renders many thanks to Mrs. Ferenc Juhász and Ms. Nikoletta Zlatzky
laboratory assistants for drawing material of the figures.

Dr. Gábor Krajsovszky


Associate Professor
Department of Organic Chemistry
Literature used
Alan R. Katritzky, Charles W. Rees:
Comprehensive Heterocyclic Chemistry
Parts 2-3, 4-6, 7
Pergamon Press 1984
Oxford • New York • Toronto • Sydney • Paris • Frankfurt

T. Eicher, S. Hauptmann, A. Speicher:


The Chemistry of Heterocycles
Structure, Reactions, Syntheses, and Applications
Wiley-VCH GmbH 2003
Weinheim

E. Breitmaier, G. Jung:
Organische Chemie
Grundlagen, Stoffklassen, Reaktionen, Konzepte,
Molekülstruktur
Georg Thieme Verlag 1978, 2005
Stuttgart • New York
Clauder Ottó:
Szerves kémia II/2. Egyetemi jegyzet
Semmelweis OTE Budapest, 1980

Bruckner Győző:
Szerves kémia III−1.
Tankönyvkiadó, Budapest, 1964

Természettudományi Lexikon − Harmadik kötet


Clauder Ottó: 'Heterociklusos vegyületek' címszó, 155-161.
Főszerkesztő: Erdey-Grúz Tibor
Akadémiai Kiadó, Budapest, 1966

Szabó László:
Szerves kémia előadások - heterociklusos vegyületek
Semmelweis OTE Budapest, 1978-1996
Three-, four- and five-membered
heterocycles with one heteroatom
and their derivatives
Three-membered heterocycles with
one heteroatom and their
derivatives
Nomenclature
1 1
H
O S N 1

3 2 3 2 3 2

Hantzsch-Widman name oxirane thiirane aziridine

Radicofunctional name ethylene oxide ethylene sulfide ethylene imine

Replacement name oxacyclopropane thiacyclopropane azacyclopropane

1 1 H
O O N 1
diazomethane
2 2
2
3 O 3 NH 3 NH H2C N N
dioxirane oxaziridine diaziridine
structural
isomers

H 1
1 1 N
O S N N
3 2
2 N
3 2 3
H
H
oxirene thiirene 1H-azirine 2H-azirine 3H-diazirine
2-azirine 1-azirine
Preparation [2+1] intermolecular ring closure
With contribution of atoms from olefin [2] and peracid [1]
O
R CO3H
R CH CH2

R
Br2 / CCl4
R: oxirane derivatives

Cl2 / H2O Cl perbenzoic acid


m-chloroperbenzoic acid KOH
HCl

Br OH

R CH CH2 R CH CH2

Br Cl +HCl
halohydrin
Ethylene oxide is used for gas sterilisation. It must be diluted
with carbon dioxide, otherwise explosive mixture would be
formed with air. Peracids are explosive, toxic compounds!
Br OH

R CH CH2 R CH CH2

Br Cl
halohydrin
OH Cl
H2S NH3 SOCl2
R CH CH2 R CH CH2
aminoalcohol NH2 haloamine NH2
SH
KOH
S
R CH CH2 HBr KOH +HCl
HCl
Br
+HBr R
halothiol H
thiirane derivative N

2
R
CH2 3 1 aziridine derivative
N
C N
carbene Aziridines are carcinogen compounds.
benzonitrile
2H-azirine derivative

e.g., CH2N2 Only singlet carbene (not triplet)


is suitable for the reaction.
Epoxidation with peracid without catalyst

O
O C C
H H
CH3(CH2)7 (CH2)7COOH
H H CH3COOH
C C enantiomers
CH3(CH2)7 (CH2)7COOH 20 °C, 3 h H H 1:1
one-step C C
syn-addition CH3(CH2)7 (CH2)7COOH
oleic acid O

O C C
CH3(CH2)7 H
H (CH2)7COOH
CH3(CH2)7 H CH3COOH
C C enantiomers
H (CH2)7COOH 20 °C, 3 h CH3(CH2)7 H 1:1
one-step C C
elaidinic acid syn-addition H (CH2)7COOH
O
Asymmetric oxidation of alkenes
Sharpless epoxidation

Knowles, Noyori, Sharpless 2001 Nobel-prize, Chemistry, chiral catalysis

A)
diaster eo(enantio-)selective

EtOOC OH O
Ti[OCH(CH3)2]4 H
H O
+ O
HO (CH3)3C O OH
H COOEt CH2OH
O H CH2Cl2
H
O
CH2OH diethyl tartrate enantiomers

H
EtOOC H O
Ti[OCH(CH3)2]4 H
allyl alcohol OH
+ O
derivative H (CH3)3C O OH
HO COOEt CH2OH
CH2Cl2 O
H

B)
O

HO
H OEt

OEt
H
HO S
O
OH
(2S,3S)-(-)-Diethyltartrate
R2
R
R
O
2
R R1
R (CH3)3C-O-O-H / Ti(OiPr)4
molecular sieve R
Z R 1
OH R2
O
HO S
O
R
R1
H
HO OEt
OEt 1 2
HO R<R <R
H
O
(2R,3R)-(+)-Diethyltartrate
O

HO
H OEt

OEt
H
HO S
O
OH
(2S,3S)-(-)-Diethyltartrate
R2
R1
S
O
R2 R
R1 (CH3)3C-O-O-H / Ti(OiPr)4
molecular sieve R
E R OH R2
O
HO R
O R1
R
H
HO OEt
OEt 1 2
HO R<R <R
H
O
(2R,3R)-(+)-Diethyltartrate
Chemical properties 2,2'-iminodiethanol 2,2'-[(hydroxymethyl)imino]diethanol
2-[(2-hydroxyethyl)amino]ethan-1-ol 2-[bis(2-hydroxyethyl)amino]ethan-1-ol

O O
CH2CH2OH CH2CH2OH
HN N CH2CH2OH
CH2CH2OH CH2CH2OH
O δ
NH3 OH NH2
diethanolamine triethanolamine
CH2 CH2
δ In ointment,
lacquer
KOH
H
N
SOCl2 Cl NH2 KOH

CH2 CH2
aziridine
Baeyer strain is greater for 3-membered rings than for 4-membered ones. As
a consequence of this ring opening, reactions are easier for the former ones.
Ring opening – it may occur with acid or with base
Different regiochemistry:
with acid: SN1-like mechanism (alkyl cation of higher order is more stable)
with base: SN2 mechanism (for sterical reasons, the nucleophile attacks the
carbon of lower order)

H H H

O O O O
H Y Y OH

R CH CH2
R R R R

Nu
O Nu OH Nu
H
R CH CH2 R CH CH2
OH

CH2 CH3
LiAlH4
OH OR
RO
CH2 CH2

O OH
HO
CH2 CH2

OH
RMgBr

MgBr

O R NH4Cl OH R

CH2 CH2 CH2 CH2


O
HO / H2O 1 2
H2S
HO CH2CH2 SH
2-sulfanylethanol
RO / ROH 2 1
O S RO CH2CH2 SH
SCN 2-alkoxyethanethiol
HCl
Cl CH2CH2 SH
thiirane R1
2-chloroethanethiol
NH
R1
R2
N CH2CH2 SH
R2
2-dialkylaminoethanethiol
Some important derivatives

O CH3 O
(CH3CO)2O
+ N CH3 HOCH2CH2N(CH3)3 H3C COCH2CH2N(CH3)3
CH3 Cl Cl
HCl choline chloride acetylcholine chloride

Acetylcholine: neurotransmitter of parasympathic nervous system


(it can be found in the parasympathic part of the vegetative nervous system
and in the central nervous system)
b) pathway

Ar OH competing reaction
O O
OH Cl
b) pathway HO
Ar OH + Ar O CH2 CH CH2
CH2 Cl a) pathway HCl Ar O CH2
a) pathway (main pathway)
epichlorohydrin RNH2
steric reason

RNH2 OH NHR
prototypes:
Ar O CH2 CH CH2

Ar R name β-adr enoceptor blocker

CH3
CH propranolol
CH3

CH3
CH pindolol
N
H CH3
Four-membered heterocycles with
one heteroatom and their
derivatives
Nomenclature
1 2
O S HN

4 3
Hantzsch-Widman name oxetane thietane azetidine
Radicofunctional name trimethylene oxide trimethylene sulfide trimethylene imine
Replacement name oxacyclobutane thiacyclobutane azacyclobutane

1 2 1 2 1 2 1 2
O S N HN N

4 3 4 3 4 3 4 3

oxet(ene) thiet(ene) 1-azetine 2-azetine azet

1 2 1 2
S S HN NH

4 3 4 3

1,2-dithiet 1,2-dihydro-1,2-diazet
Preparation
By intramolecular ring closure

OCCH3 Cl HS
Cl O Cl H2S Cl KOH S
HO
AlCl3 HCl

H3C SO2NH2

Br Ts
Br Ts NH2 N LiAlH4 HN

ether
Chemical properties

RMgX
R CH2CH2CH2OH

LiAlH4
CH3CH2CH2OH

O HBr
Br CH2CH2CH2 Br

RNH2
RNHCH2CH2CH2OH
HO O O
OH O pr opano-3-lactone
1
β-propiolactone
H2O cyclic ester
β β α
α 3 2

EtO O O
pr opano-3-lactam
NH2 NH
ether β-propiolactam
EtOH cyclic amide
β α β α (antibiotics)

O
O S pr opano-3-thiolactone
[2+2]
S C β-propiothiolactone
cycloaddition
C C H3C Ph cyclic thioester
H3C Ph Ph Ph Ph Ph

HY O O Nu O
Nu Y Nu H YH
Nu H
Some important derivatives
β-Lactam antibiotics
• Penicillins
• Cephalosporins
Antibiotics: natural compounds produced either by microorganisms (e.g., fungi), or by
a higher organism against other microorganisms (e.g., bacteria) to block the life and
reproduction of the bacteria. Antibiotics are efficient in low concentration.
β-lactame ring of penicillins is sensitive to acids, bases, or penicillinase enzyme.
Nowadays penicillins with broad therapeutic range also exist (see microbiology).
Cephalosporins (1948) makes the other main group of the β-lactame antibiotics.
These are resistent to penicillinase enzyme.
The bacterium produces penicillinase/cephalosporinase enzyme in order to be resistent
against the given penicillin/cephalosporin derivative. Thus, newer and newer penicil-
lin/cephalosporin derivatives must be synthesized. Their total synthesis is possible, but
it would be too expensive, thus new derivatives are produced by semisynthetic me-
thods. The fermentation processes are combined by chemical methods (beginning of
biotechnology).
Clavulanic acid: inhibitor of the β-lactamase with low antibiotic effect. Clavulanic acid
is produced by Streptomyces clavurigeus (the same fungus also produces penicillin as
well as cephamycin).
Augmentin® contains amoxycillin and potassium clavulanate.
β -Lactam antibiotics

Basic skeletons

azetidine + thiazolidine azetidine + [1,3]thiazidine


1 1
6 5 S 2
7 6 S 2

7 8
N 3 N 3
4 5
O O 4

penam cepham
lactam lactam
Penicillium notatum Cefalosporium acremonium

1 6-aminopenicillinic acid 7-aminocephalosporinic acid 1


H2N H H
2 H2N H H
5 S CH3 6-APS 7-ACS 6 S
6 6-APA 7-ACA 7
2
CH3
7 8
N OH penicillinase enzyme cephalosporinase enzyme N O CH3
4 3 5 3
O cleaves cleaves O 4

O O
penicillins "-cillin" cephalosporins "ceph(a)-" O OH

O NH2 O
H H
CH2 C NH CH C NH
3
6 7 CH3

benzylpenicillin cephalexin
G-penicillin

O O
H
H S NH
NH O CH3
3
7
N 6
O CH3 O
oxacillin cephalotin
O

N OH
H O
RNH COOH RNH X
S Y
CH3 Clavulanic acid

N CH3 N Z
O O
COOH
Penicillins COOH

Cephalosporins (X=H, Y=S)


NH Cephamycins (X=OCH3, Y=S)
OH O
β -Lactam skeleton
H3C Y
Z RNH
N O
OH
O
COOH N P O K
H3C Y O
Penems (Y=S) OCH3
NHR
Carbapenems (Y=CH2) N S 2-Azetidinon-1-phosphonate
O
COOH
Thienamycin (R=H) RNH X

N SO2O K
O
Monobactams
Five-membered heterocycles with one
heteroatom and their derivatives with
condensed ring systems
I/ Furan and its derivatives
Nomenclature

CH
O O O O O C

furan α-furyl- β-furyl- α-furfurylidene- α-furoyl-

Preparation

1/ By Paal-Knorr synthesis from dioxo compounds

NH3 P2S5
R R ((NH4)2CO3) R OO R R S R
N
H
R NH2 P2O5
160 oC

R N R R O R
R
Its mechanism: E P2O5, H

H
+E

R R R R R R
OO O O O O
E E
E

H
H H 2O

R R E R R
O O
O
H E
2/ From polyhydroxy oxocompound

HO OH 4 3
H H O
O
Found in wheat germ, 5
H OH HO C H 3H2O
O
2 C
corn germ 1 H

pentosane furfural (furfurol)


furan-2-carboxaldehyde

3/ From mucoic acid

HO OH
H H HCl
HO OH HO OH
OHHO O
O O O O

4/ By decarboxylation from dehydromucoic acid

OH
O - CO2 O
O
5/ By ring synthesis from β-oxoester and from α-chloroketone

ROOC H Cl
NaOEt
- EtOH
- NaCl
O O

ROOC ROOC

O O O
Feist-Benary

aldol

EtOOC H R1 EtOOC R1
+ O

R2 O SN i Cl R2 O

O-alkylation
This can be the side reaction of Hantzsch reaction

EtOOC H Cl EtOOC
+
R2 O O R1 R2 O R1
C-alkylation
EtOOC EtOOC H EtOOC
3
R -NH2

R2 O R2 N R2 NH
R3 R3
Hantzsch

EtOOC Cl EtOOC

+
R2 NH O R1 R2 N R1
C-alkylation
R3 R3

EtOOC R1 EtOOC R1
O
+
R2 NH Cl R2 N
R3 N-alkylation R3
Physical properties

The parent compounds (furan, pyrrole, thiophene) are poorly soluble in water,
but imidazole and pyrazole are water-soluble due to hydrogene bridges

Their UV spectra are rather different from benzene


IR spectra: there are group vibrations
pyrrole has ν NH band at 3400-3300 cm-1 (sharp and strong band)

1H NMR spectra: the signal of α H appears at lower δ value (more shielded), compared to the
signal of β H (each within the usual aromatic range)
There are usual couplings typical for aromatic compounds.
Chemical properties
O O O O O O

1/ SEAr reactions E attacks the α position ground state

E H H H
α
O O E O E O E

E
β E E
H H

O O

α > β σ−complex is more stable, since more mesomeric structures can be written for it.

Friedel-Crafts alkylation

R Cl previous explanation: furan is a superaromatic


AlCl3 or ZnCl2 compound, since the aromatic reactions take
O O R
place much easier, than of benzene

current explanation: furan is much less aromatic,


than benzene, since its reaction is energetically
much easier, than of benzene

R Cl
AlCl3
O R O
Nitration

cc. HNO3 is destroying the ring

O
O
acetic anhydride
CH3C O NO2 anhydride
HNO3 anhydrous
acetyl nitrate

O NO2 O2N O NO2


2/ Addition reactions

1,4-addition

Br Br 2 CH3OH CH3O OCH3


Br2 CH3OH H H H H
O O O

CH3O > Br 1,4-addition -HBr


C atoms with acetal characters

1. H2 Ni
2. H3O
H Br
O

O O
Diels-Alder reaction

O H H O

O O O O
maleic anhydride
H O
O H
3/ Other reactions

Cannizzaro reaction

1. cc. KOH
2 + OH
H 2. H 3O
O O CH2OH O
O O
furfural furfurylalcohol furan-2-carboxylic acid
(furfurol)

Acyloin condensation

KCN
H KOH
O CH C
O O
O OH O
furoin
(similar to benzoin)

C C
O O
O O
furyl (similar to benzyl)
Polymerisation

n H

O O O O
n

1,4-addition
addition polymerisation
O O

Reduction

H2 Ni
o butan-1,4-diol
150 C 100 atm (for preparation of diolefins by Reppe synthesis)
O
O
THF
tetrahydrofuran
More important derivatives
H
H2O, 400 oC
H2/Ni
cat.
80 atm H - H2, - CO2
O CH2OH O O
O
Al2O3 350 oC furfurol, the cheapest
-H O aromatic aldehyde H2 /cat.
2

4
3 5 ROH/H

2 6 O
H3O
O O OR
1 - ROH
butadiene polymer,
BUNA or copolymer

O OH OH OH O OO OR
H H

- H2O

cc. HCl

O Cl Cl O OR
cc. HCl 2 KCN
HCN
O O Cl Cl N C C N
O
N 1,4-dichlorobutane

red.
NaCN
1. H3O H2/cat.
c
2.. c. H
Na Cl
O CN

O
N C C N NH2
pimelic acid dinitrile HO HN
OH
H2/cat O H
H3O
adipic acid butan-1,6-diamine
6C 6C
HO OH hexamethylene diamine
C C
O O
NH2 NH2 O
HO NH2
pimelic acid butan-1,7-diamine N
7C 7C H
O 6C 6C
polymerisation
HO OH Nylon 66
HN NH2

O O H
- H2O

H
HO N NH2
polimerisation
O O
7C 7C
Nylon77
2 2CO Na ε-caprolactam + ε-aminocaproic acid
2 2NaCN H2
2 O
O
O O O -H2O O
N
ε γ ε-amino- NH
H2O α OH caproic acid H2N OH
2 H2N
O δ β
N 6C 6C
H O O
Nylon 6
ε-caprolactam
Nylon 6
OH

H +CH2O
CH3 CH2 N(CH3)3 H
OH O polymer plastics
O
H H O

OH OH HO OH OH
H2
(+)-2S,3R,5S HO
Muscarin
(H H ) C CH CH2OH

alkaloid of O
-H2O O
Amanita muscaria C
H H

−δ O OH polymerisation chances
H
R C H OH
+δ R CH
OH
II/ Furan derivatives with condensed rings

Nomenclature

4 4
5 3
5 3

6 2 O
6 2
O O
7 1
1

benzo[b]furan benzo[c]furan dibenzofuran


coumarone isocoumarone diphenylene oxide
(derivatives of it
are known only)
Preparations

H H OH
C O O Perkin
H2C C synthesis CH Br2
+ CH H
O
H3C C NaOAc C O O
OH OH OH O O
O O HO
coumarin
C O
H3C
Br

Br +KOH Br
H
-KBr OH
O O -H2O OO O O O
HH O
3,4-dibromocoumarin coumarilic acid coumarone

HO ZnCl 2
Cl - HCl -H2O
OH O OO O

coumarone HH
dibenzofuran
R
CH2 R CH2 R'
C
+ O C
R' N
O NH2 O
O-phenylhydroxylamine O-phenyloxime

R R
CH R'
C C R'
C
NH
O OH NH2

R
according to Fischer’s indol synthesis
O R'

CH2 R R
+ O C
NH2 R' R'
N N
H H
III/ Thiophene and its derivatives

Nomenclature

β' β
O
α' α
S S S S CH2 S CH S C

thiophene α−thienyl- β−thienyl- thenyl- 2-thenal 2-thenoil-


2-thienyl 3-thienyl α-thenal α-thenoil-

Preparations
1/ By Paal-Knorr synthesis from dioxo compounds

NH3 P2S5
R R ((NH4)2CO3) R OO R R S R
N
H
R NH2 P2O5
160 °C

R N R R O R
R
2/ From acetylene

CH CH

HC CH
S S

3/ By dehydrogenation, then by ring closure


4S
+ 3 H2S
650 oC
S

-2 H2S 2S 2S -H2S

4/ According to Hinsberg

R R R
R
C CH3ONa
C
O O 20 oC
ROOC S COOR

ROOC CH2 S CH2 COOR


5/ From dialkyl acetylenedicarboxylate

COOR COOR ROOC COOR


C C S
C C 150 oC
ROOC S COOR
ROOC COOR

Chemical properties

1/ By halogenation

SO2Cl 2 SO2Cl 2
sulfuryl
chloride Cl Cl Cl
S S S

2/ By chloromethylation

CH2OH, HCl

S S CH2Cl ClCH2 CH2Cl


S
3/ By Mannich reaction

CH2O CH2O
NH4Cl
CH2 NH2 HCl CH2
S S S
HN
Cl CH2

4/ By Vilsmeier formylation

N CH3
C H
O
H
POCl3
S S
O

5/ By Friedel-Crafts acylation
O
Wolff-Kishner
CH3C Cl red.
AlCl3
CH3
S S C S CH2CH3
O
6/ Transformation to mercury derivatives

HgCl2
ClHg S HgCl
HgCl2
CO2
S S HgCl
NaSCN
O OH
R C S
Cl O
NaI Br2

S SCN R
S
O
Mg

S I S Br S MgBr
7/ By Diels-Alder (addition) reaction
F F
S
F F

F S F
F F

8/ By polymerisation

S S S
n

9/ By hydrogenation

Raney Ni H2
R CH2 C OH EtOH R CH2 C OH CH2 C OH
S S
O O R O + H 2S
10/ By indophenin reaction

O O

S S
N O O N
H H
isatin
HCl

S S compound with
blue colour
N O O N
H H
indophenin
IV/ Thiophene derivatives with condensed ring system

Nomenclature
4 4
5 3 5 3

6 2 6 S2
S S
7 1 7 1
thionaphthene iso-benzothiophene dibenzothiophene
benzo[b]thiophene benzo[c]thiophene
isonaphthene

Preparations

O O
K3 FeIII(CN)6
OH H2O / OH OH O H -H
C
-H O - CO2
SH S S S
oxid.
mercaptocinnamic acid

white-hot
iron
S S
O O
S K3 FeIII(CN)6 S

S oxidation S
O O
thioindoxil
trans thioindigo

red precipitation

O O

S S

cis thioindigo
Chemical properties

NO2 NO2 NO2 NO2

HNO3 KNO3 / H2SO4


+
S S 25oC S S
O 2N
main product side product

the aromatic system H H


is saved Y Y
preferred
C 3
S S

Y
S
C 2 H H

S Y S Y
the aromatic system is
decomposed
disadvantageous

H H H

S Y S Y S Y
V/ Pyrrole and its derivatives

Nomenclature

N N N N
H H H H O
pyrrole α-pyrryl- β-pyrryl- α-pyrroyl-

Preparations

1/ By Paal-Knorr synthesis from dioxo compounds

NH3 P2S5
R R ((NH4)2CO3) R OO R R S R
N
H
R NH2 P2O5
160 °C

R N R R O R
R
2/ By Hantzsch synthesis
CH2 Cl
ROOC ROOC ROOC C
CH2 R NH2 CH2 CH2 O R
C R = alkyl, C C
H3C O aralkyl H 3C N H3C NH
R R

ROOC ROOC
CH CH2
C C R
Cl H3C NH O H 3C N R

R R
3/ By Knorr synthesis
H3C C5H11ONO H3C
C O (isopentyl nitrite) C O Zn / CH3COOH
CH2 or C
ROOC NaNO2 CH3COOH ROOC N OH
R = Et

- H2O H3C COOR H3C COOR


H3C COOR
C O H2C
CH C ROOC CH3 ROOC CH3
ROOC NH2 O CH3 N N
H
- H2O
EtOOC EtOOC H EtOOC
3
R -NH2

R 2
O R2 N R2 NH
R3 R3
Hantzsch

EtOOC Cl EtOOC
+
R2 NH O R1 R2 N R1
C-alkylation
R3 R3

EtOOC R1 EtOOC R1
O
+
R2 NH Cl R2 N
R3 N-alkylation R3
4/ By pyrolysis of ammonium mucoate

HO OH

NH3
HO OH HO OH
OO N - 2 CO2 N
O HH O O H O H
main product

NH2
N
H O side product

5/ From dehydromucoic acid through furan

NH3 450 °C
OH
O - CO2 O Al2O3 N
O H
6/ According to Reppe, from butyn-1,4-diol

NH3,
HO CH2 C C CH2 OH
Al2O3 - ThO N
H
H2CO CH2O

H C C H

according to Reppe NH3


O Al2O3 N
H
THF
Chemical properties

1/ Acid-base properties

a/ pyrrole, as base Absorption of a proton is an addition process (not SEAr)


Protonation takes place at the C-2, not at the N
Protonation ceases the aromatic system, resulting in
H
a conjugated diene with much higher reactivity.
For this reason, pyrrole is sensitive to acids
H
N N
H
H
pKa = - 0.3

b/ pyrrole, as acid Pyrrole is a weak acid – and an amphotheric compound


Furan, pyrrole, thiophene are stable against bases

H
N N
H
pKa ~ 15
(pKa water = 15.6)
2/ Tautomerism
Tautomerism of hydroxy- and amino-derivatives
The hydroxy compounds exist mostly in oxo forms, the amino compounds in amino forms (→ can be diazotised)

tautomers tautomers

N α OH N OH N α NH2 N NH
N O H H H
H H
lactam amino form imino form
cyclic amide (stable)
mesomers
NH
NH2
β

N O N N
H H H

OH tautomers O tautomers
OH
β
N N N
H H vinylogous
lactam
mesomers
O

N
H
3/ SEAr reactions
Take place in two steps, with much greater reaction rate, compared to of benzene

E H H H
α
N N E N E E
N
H H H H
E
β E E
H H

N N
H H

α > β σ−complex is more stable, since more mesomeric structures can be written for it.

If attack happen to β position E = H protonation reaction takes place.


Otherwise the electrophilic reagent attacks the β position, if the α position is occupied.

Protonation
H
protomers
H
addition N
N N
H H
H H
By bromination

Br - Br H H - HBr
1,4-addition Br elimination Br
N Br N N
H H

By chlorination

Cl Cl
Cl2 SO2Cl2
sulfonyl
Cl N Cl N chloride N Cl
H H H

By nitration, sulfonation
O
equimolar HNO3
O S O
N
S N (CH3CO)2O NO2
N OH O N
H H explosive mixture H
O o
the reaction runs at low (20 C) temperature
O

HO O
N SO3 N O
CH3 C O
HO C CH3 N
O O
O
acetyl nitrate
By Friedel-Crafts acylation
pyrrole > benzene (SnCl4 < AlCl3 both are
(CH3CO)2O electrophilic catalyst, but the latter is much
SnCl4 CH3
more powerful, therefore the latter is not
N N
H H used for the acylation of pyrrole, since the
O reaction would be too vigorous

By Reimer-Thiemann reaction

CHCl3 Cl hydrolysis (
OH
cc. base CH CH
N N N
H H Cl H (OH
Cl
Cl CH
δ δ Cl

H
-H2O pyrrole > benzene (reacts more easily)
N
H
O

KOH
At first, N-potassium salt is formed due to cc. KOH
N N
H
K
Formation of dipyrrylmethane

H
C O H N
H
H
N N CH2 OH -H2O
H H

analogous process to the formation of phenol resins

O' from the air


'
-H
N CH N N CH N
H H H H
H
dipyrrylmethane
mesomers

conjugate acid
(many mesomeric N C of dipyrrylmethene
N
structures can be written) H H

there are 4 pyrrole rings in


the synthetic intermediates -H
of compounds with porphin N C N
H H
ring system
dipyrrylmethene
By Fischer-Orth reaction

O CH3
C N CH3
H CH3 HCI CH N
N N
H H
CH3
Ehrlich reagent
(dimethylaminobenzaldehyde)
mesomers

CH3
N CH N
CH3
red colour

By Fischer-Bartholomäus reaction

N N Cl N N Cl

N N N N
H H

4 3
5
N N N1 2 N N
H
2,5-bis(phenylazo)pyrrole
4/ Transformation to heteroalkene-, or heteroalkane derivatives

By reduction reactions

4 3
Zn / H Pt / H2
5 2
N1 HCl N N
H H H
3 tetrahydropyrrole
- pyrroline
3 - pyrroline Ph-Al2O3 (pyrrolidine)
H2
Zn: electrondonor
water: protondonor
4 3 4 3
5 2 5 2
N1 N1
H H
2 1
- pyrroline - pyrroline
2 - pyrroline 1 - pyrroline

LiAlH4 or
O N O Na metallic / pentan-1-ol N
H H
By oxidation reaction

CrO3

N glacial O N O
H acetic acid H
maleic acid imide

By Diels-Alder reaction
F F
F
F F F
+ NH
N
H F F F F
F
F

there is no reaction with pyrrole, but there is formation of adduct with hexafluoro-Dewar-benzene

By polymerisation

H
N N N N
H H H H
5/ Amphotheric properties of pyrrole

Metal derivatives and their transformations


thermodynamic
kinetic control
KOH control
RI R
N N N rearrangement N
H H
K R
CO2
Kolbe
synthesis O
HCl R C Cl
OH OK R
N N N rearrangement N
H O H O H O
C
O R

CH3MgI R I
N - CH4 N - MgI2 N N R
H H
O MgI R

H5C2O C Cl
ethyl chloroformate

O
O R C Cl
C OC2H5 R
N N N
H H O
C
O R
Pyrrole does not react by nucleophilic substitution reactions
H The H at α-metil group is not active (the C-H bond is stable due to π electron excess)
N C H
H H

electron rich C-atom


CH2 CH2
N N
H H H
More important derivatives

a/ monocyclic pyrrole derivatives

X O X = H proline
C = OH hydroxyproline
OH N N O
N CH3 H H
H pyrrolidine pyrrolidone

HO OH 200 °C

OH cc. NH3 HC CH
HO
O O N O
O H
butyric acid butyrolactone

N O N O

HC CH2 CH CH2 N H + H C C H N CH CH2


n
vinylpyrrolidone polyvinyl-pyrrolidone
MW 5 - 10 thousand
X-H addition to acetylene
b/ compounds with porphin skeletone
Porphin

N N N N
H tautomers H H
H 4 tautomers
N N are possible N N

- bonds in aromatic system 4n+2 n=4


- alkene bonds (double bonds) 18 π electrons
The Fe, Mg, Co salts of porphin can be found in nature.
Very stable, what is necessary for it purposes. Mp: 300 °C, red crystals

N N N N
H mesomers H
H there are 12 H
N N mesomers N N
totally

The tautomer forms can be also described by mesomers.


Each tautomer may have many mesomers.
Vitamin B12 (cyanocobalamin)
Preparation of it was carried out from liver, from mud of canals, or by
fermentation (Streptomyces griseus)
Structure determination was executed by X-ray analysis (Dorothy-Crowfort
Hodgkin)
Synthesis of it was carried out by Robert Burns Woodward (Harvard
University) and Albert Eschenmoser (ETH Zürich)
Vitamin B12 has been isolated from mud of canals by Richter Pharmaceutical
Works (Budapest, Hungary) since Years 1950s. Woodward synthesized
chlorophyll by total synthesis in 1965, while Woodward and Eschenmoser in
cooperation prepared Vitamin B12 in 1972-73.
Vitamin B12 has important role in biological methylation. It is the antidote of
Anemia perniciosa (pernicious anemia). Its appearence is in deep red needles.
Liver extracts were useful in this disease.
It was the first macromolecule, which structure was elucidated by X-ray
analysis. There is delocalisation in Vitamin B12, but it is neither a cyclic
delocalised system, nor aromatic system. The current Vitamin B12 extract is of
not synthetic origin.
The question is the following: how did these compounds appear in nature
and why not other compounds were prepared by biosynthesis. There are
building blocks for living organisms – hem, or chlorophyll were prepared at
rather low stage of evolution. Usually the most symmetric structure is set –
the rest is prepared, but disorderness has always greater probability →
enthropy is increasing by having the least symmetry elements. It is selected
by molecular evolution and does the job perfectly. The role of cobalt in
Vitamin B12: it depends on ring size. Woodward’s report on it is a complete
chemical thriller.
VI/ Pyrrole derivatives with condensed ring systems

Nomenclature
H

N
N N CH3
H
3H-indole N-methylisoindole
1H-indole
benzo[b]pyrrole benzo[b]pyrrole (isoindole does not exist)
(indolenine) benzo[c]pyrrole

O O

N N O N N O
H H H H
indoline oxindole indoxil isatin

HO OH

NH2 NH2 O
N N N
H H H
tryptamine serotonine 3-indolylacetic acid
5-hydroxytryptamine heteroauxin
takes place in the
important for brain work plant growing
biosynthesis of indolealkaloids
hormone
Preparations

1/ Preparation of indole

H3C COOH
H3C COOH COOH
O ZnCl2 250oC
+
N -CO2
NH NH2 N N N
H H
H

CH3 KOC(CH3)3
O
-H2O
NH CH N
H

2/ Preparation of indole derivatives a/ Fischer’s indole synthesis

R2 R2 R2
+ CH2 ZnCl2 or
CH2
NH2 C polyphosphoric acid
C 1
N O 1 N N R -H2O, -NH3 N R1
R H H
H

CH3 CH3 CH3


ZnCl2
+
- H2O 180 oC
NH NH2 O NH N NH
- NH3
3-methylindole
Mechanism of the Fischer’s indole synthesis
O
HC
CCl3 CH N OH CH N OH
C Cl C OH
NH2 H2N OH N N
H Cl H OH

N O
N OH cc. H2SO4 C H 2O
O
-NH3
N O N O N
H H isatin H
Zn/HCl

OH red. oxidation
Na/Hg
O O O H
red.
N N N
H H
oxindole
N
H O
indigo
b/ Heumann’s indigo synthesis
H
HO O
HO C NaNH2
+ Cl CH2 COOH
-HCl CH2 -H2O
NH2 N
H

O H
ONa
O2 N

Fe3+ N cis
N
H H O
Na2S2O4/NaOH
reduction O2 deep blue, insoluble in water
trans indigo
oxidation
it is reduced at first,
Na
then is oxidised O H
Indigofera tinctoria
N
colourless, water soluble
N leucoindigo
it is adsorbed and H O
keeps its colour Na
O O O

ONa NaOBr OH
NaOH
NH HCl CO2
NH2
NH2
O O
anthranilic acid

O O
O
OH ClCH2COOH OH KOH
CH2 melting
NH2 NH COOH N COOH
H

-CO2
O
H
N O
oxidation
N
H
O N
H
indigo
O O

OH HO OH O
+ Cl CH2 COOH
-HCl CH2 C OH
NH2 N
H

O O
KOH O2
melting OH -CO2 Fe3+
N N
H H
O
indoxil
indoxil-2-carboxylic acid

O H
O
N oxidation

N N O
H H
O
isatin
indigo
Chemical properties

1/ SEAr reactions

halogenation
goes to nitration
β position mainly sulfonation
N
H alkylation
acylation

2/ Other reactions
O

CHCl3 H
KOH
N N
H H

N N Cl N N

N
H
CH3
CH2N(CH 3)3
(CH3)2NH CH2N CH3I I
CH3
N HCH
H N gramine N
O H H

COOR KCN
H C NHCOCH3 CH2CH2NH2 CH2CN
COOR red.
KOH
- NH(CH3)2 N tryptamine N
H H
indole alkaloids
COOR
CH2 C NHCOCH3 hydrolysis,
COOR decarboxylation

N
H

H2/cat. H2/CuCrO 4

N N N
H H H
octahydroindole indoline
O

OR
CH3MgI ClCH2COOR
-CH4 N
N N
H H
Na MgI
K N NH2
-1/2 H2
-1/2 H2 H
N
N H
CO2
Na O
OH
N
K R X

N
H
N
R R

R: alkyl, acyl
N
H
Benzocondensed systems with five-membered heterocycle

SEAr
4 X: NH 1H-indole β (α)
5 3 (β)
O coumarone α
6 2 (α)
X S thiocoumarone β (α)
7 1

β
E alkylation (β)
E
acylation (β)
NH alkylation N rearrangement NH α sulfonation (α)
acylation
E
sulfonation
E : R
O
R C
SO2OH
H

O E coumarone
advantageous

E E
H H

E O O

disadvantageous

E
N N N
H H H
aromatic
1H-indole and nonaromatic
advantageous
thiocoumarone disadvantageous
E

E
S S S
Five-membered heterocycles with two
or more heteroatoms and their deri-
vatives with condensed ring systems
Compounds with two heteroatoms
Nomenclature

4 3 4 N3 4 3 4 N3 4 3 4 N3
5 N2 5 2 5 N2 5 2 5 N2 5 2
O1 O1 S1 S1 N N
H1 H1
isoxazole oxazole isothiazole thiazole pyrazole imidazole
1,2-oxazole 1,3-oxazole 1,2-thiazole 1,3-thiazole 1,2-diazole 1,3-diazole

Introduction of another nitrogen → the pyrrole-like properties are shifted to the pyridine-like properties,
e.g., at basicity, water solubility.
I/ Isoxazole and its derivatives

Preparations

1/ By 1,3-dipolar cycloaddition (Huisgen)

H 5C 6 C 6H 5 H5C6 C6H5 It takes place by 4n+2 electrons, n=1


C C
suprafacial reaction, 1,3-dipolar
C N N cycloaddition, in one step through a
H5C6 O H 5C 6 O cyclic transition state

nitrile oxide

1,3 - dipolar
one of the components (nitrile oxide)
is dipolar

C6H5 C 6H 5
C mesomers C1
the charged atoms (C, O)
N N are in 1,3 positions
O O
3
By 1,3-dipolar cycloaddition
1 1
R 1 R
a R a
a a
2 b
b+ + + b+ 2 b
R c 2 c R
c - R - c
E-olefin
dipól dipól
(dipolarofíl)

1 1
R 1 R
a R a
a a
2 b b+ + + b+ 2 b
R c 2 c R
c - R - c

dipól Z-olefin dipól


(dipolarofíl)

1 1 1
R R R
a a
a a
2 b b+ + + b+ 2 b
R c c R
c - 2 - c
R

a a+ a b c a b c
a a+
C N N N N C
b b C N N N N N b b
+ +
c c C N O N N O c c
- - - -

R. Huisgen, Angew. Chem. 75 (1963) 604-637. 742-754.


A. Padwa, 1,3-Dipolar Cycloaddition Chemistry. Vol. 1-2. John Wiley and Sons 1984.
2/ By other ring syntheses

H CH3 R R R
H2N OH
H3C N N N O
O - H2O O Cl - H2O Cl
OH HO
R=H

CH3
H2C C
H3C C N R = CH3
O HO
Chemical properties

1/ It is sensitive to bases, resulting in ring opening It is relatively stable against acids


H
R = CH3
H2N NH2 OH
N N N
R N base R O base R
OH OH
H
R=H E - H2O

E
2/ SEAr reactions
N N
R O R
O
R=H

E: Br+, NO2+, HSO3+


3/ Basic strength in aqueous solution

pKa values for the conjugated acids of the bases

N N
N NH
N S N O
H H

pKa values 7.0 2.5 2.5 1.3

basicity Imidazole >> Thiazole > Pyrazole > Isoxazole


More important derivatives
H2N O
H
Oxamycin antibiotic NH
N O Oxacillin semisynthetic O
O N penicillin O
benzisoxazole anthranil H5C6 C NH
benzo[d]isoxazole benzo[c]isoxazole
6-amino-
O CH3 penicillanic
- H2O - H2O acid fragment

N O
OH OH
OH NH

H2N OH Sn / glacial acetic


acid, red. Penicillin: was prepared from Penicillium
notatum fungus (Fleming, 1929) at first by
O O fermentation method. It was the first antibiotic
compound: 6-amino-penicillanic acid. Some
OH NO 2 microorganisms are preparing it by cleavage of
the acyl group. This is useful for preparation of
salicylaldehyde
other semisynthetic derivatives
II/ Oxazole and its derivatives
Preparations
1/ From 1,2-bifunctional compounds
H5C6 H5C6
2.
2. C O H 2N C N
3.
H2C 1. C 3. H 1.C H C
Br O CH3 - H2O Br O CH3

C atoms with 1., 2., 3. oxidation levels


H5C6
3.
N
3.
O CH3

H 3C H3C
1. 1.
HC NH2 Cl HC NH 1. PCl5
2. C C 3. 2. C C 3.
O - HCl H5C6 R 2. NaOH
H5C6 O R O O

H3C H 3C
N N
3.
3.
H 5C 6 R - H 2O H5C6 R
OO O
HH
1.
H2C NH2 Cl HC NH 4
1.
1. N3
HC C 3. CH C 1. 3.
- HCl
H3C OH O R H3C OH O R H 3C 5
O1 2 R

H 2-oxazoline derivative
.
C2
O R
1.
CH2 NH 1. NH
1.
HC 1. 2.
CH
H3C OH H3C O R
HO R
oxazolidine
derivative

More generally:

1 H
1 R 1
R NH2 Cl N R= CH3
C6H5
C 3 2
2 O R 3
O R O R
R

2
R = -H,-CH3,-C6H5
3
R = -CH3,-C6H5
a. a.
Cl H2N it is difficult to alkylate the amide nitrogen
N b. Cl HN C
O
O a. O
OH HO

reactions run similarly at both pairs


b. NH2 Cl
b. NH2
Cl C
O O
OH O

it is easy to acylate the primary amine nitrogen

Differences in saturation of the products can be


reached by selection of the proper oxidation level of NH2 Cl N
the starting materials.
R R
OH O O

N 6 π-electrons NH2 O NH
the nonbonding electron pair of O
takes part in the formation of an aromatic sextet R
O OH H R O

1 due to C-N bond 1,5


due to the 1/2
alkene N N 3. N
1/2
C=N
O C-O O O
1,5 3. 3.
1 due to C-O bond
R R
NH2 Cl N
-HCl
Ph O S R' -H2O Ph S R'

R': Alkyl, NH2

R R R
NH2 Cl N NH3 N
-HCl Ph
Ph O O Ph -H2O Ph O Ph N Ph
H

NH4OCOCH3
CH3COOH

Ph Ph
O H2N N

-HCl
Ph Cl X Ph Ph X Ph
-H2O
X: O, S, NH
Chemical properties

1/ SEAr reactions

4
N E

One of the most stable derivatives of 2-oxazoline is 2-methyloxazoline. This


5 O 2
compound has an interesting feature, since mechanism of acyl migration
(Bruckner, at ephedrine or alkaloids with tropane skeletone), as well as the
ring opening due to bases or acids can be easily demonstrated.

2/ Sensitivity against bases and acids

N N HOH NH CH2 NH
HO CH3 CH3
HO CH2 C CH3
O CH3 O OH O OH
OH O

NH NH2 CH2 NH3


N H HOH CH3
H CH2
OH COCH3
CH3 O CH3 O O
O
More important derivatives
O O
OR H2N EtONa NH
C + NH3 + ROH
H2N O
OH O O

2,4-oxazolidindione

NH2 Cl EtONa NH
C + HCl + H2O
O Cl O O O
OH O

2,5-oxazolidindione

O
H3C C N H3C C
H3C HCN H3O C OH ROH/H
C C
H3C OH H3C OH
H3C O
aceton-cyanhidrine

O O CH3
O H2N NH N
C OR ( CH3O )2SO2 H3C
H3C H3C
C H2N O )
H3C O O H 3C O O
H3C OH Ptimal

Drug of the ‚petit mal’ form of epilepsy


NH2 NH H N
formylation C hv
O O
OH OH

NH CH3 N
C
(CH3CO)2O CH3
O
OH O

blocks maturation of rye mould


III/ Isothiazole and its derivatives

O
O
O2N
cc. H2SO4 H Na2S2
H 2
2 cc. HNO3 160 oC EtOH
Cl
Cl

O O O
O2N O2N
HH Br2/CCl4 H
100 oC
S S S
Br

O2N H2N
cc. NH4OH N FeSO4 N ox.
benzene S alcohol S
red.

O O
1. CH3N2 H 2N
HO HO 2. H2NNH2 N
N N
HO -CO2 3. Curtius
S S degrad. S

1. NaNO2 /HCl N
2. H3PO2
S
3. base
isothiazole
SH SnCl2
S
cc. HCl N
NO2
thioanthranil

O rotation NH CONH2
NH3 C C
CO NH
O =
NH3
S NH2
SH SH

CONH2 COOH

H2O2
N 1. OH N 175 oC N
ox. 2. H3O -CO2
S S S
benzisothiazole
IV/ Thiazole and its derivatives

1/ Hantzsch synthesis N 6 π electrons


(similar to oxazole)
S
R1 R1
HN
OH N
3.
2
2/ Gabriel’s preparation
HS R
Br S 3. R2

R1 2. H2N
O 3.
NH 3. N
1. S R 2 P2S5 3.
2
Br R1 OO R R1 S R2

( oxazole is formed without P2S5)


R
R 2. N
H2N 3. 4.
O 4.
1. 1.
S NH2 NH2 (Preparation of partially or fully
S NH2 saturated compounds: see at the
Br 2. Cl 3. more important derivatives)
R1 O
1 O R2
R 1
2. R
O NH2 P 2S 5 3. N
3.
1. 3.
2
Cl
O R S R2

( oxazole is formed without P2S5)


R R
NH2 Cl N
-HCl
Ph O S R' -H2O Ph S R'

R': Alkyl, NH2

R R R
NH2 Cl N NH3 N
-HCl Ph
Ph O O Ph -H2O Ph O Ph N Ph
H

NH4OCOCH3
CH3COOH

Ph Ph
O H2N N

-HCl
Ph Cl X Ph Ph X Ph
-H2O
X: O, S, NH
Chemical properties N N
E
E
1/ SEAr reactions S S

N N
E
E
S XH S XH

X=O, NH
2/ SNAr reactions

H3C H3C
N N
NaNH2 pyridine-like property

S S NH2

N N N N
melting
S NH NH S H2N S NH2
S

N N
NaNO2/HCl
0-5 oC
S S N N Cl
reduction Y = halogene, hydroxy, etc.
(see reactions of (aromatic) diazonium compounds)
N

S Y
3/ By oxidation

N N
ox.

H 3C HO
S S
O
thiazole ring is resistant to oxidation

More important derivatives


R1 1. R1 1. 3
NH2 4 N
HN 3. -NH3
1.
C -ROH 5 3.
RO R 3 1. 2
R2 SH R2 S R3
1

2-thiazoline derivative

4 3
1. 1.
NH2 NH
O 2. 2.
1. 5 2
C 1.
SH H H S
1
thiazolidine
NH2 N
O 3.
3.
C
HO H S
Cl
benzo[d]thiazole
benzo[d][1,3]thiazole

CH3
NH O C CH3
NH C CH2 N
SH Cl
O S O
SO2 NH S

1.
Ultraseptyl
2. NaOH
NH C CH3 chemotherapeutic agent
O NH2 with antibacterial effect
H O R = H 6-aminopenicillanic acid (6-APA)
HOOC N
β O
H3C α
H3C S NH R R = C6H5 CH2 C
H H
benzylpenicillin
penam skeletone Penicillin G
(condensed ring system of thiazolidine and
R=
azetidine monocycles)
O
C C6H5

N
H3C O
Oxacillin (see at isothiazoles)

Β lactam ring is unstable group, sensitive to acids, to bases, as well as to penicillinase enzyme.
They are inhibitors of synthesis of cell walls. If a microorganism produces penicillinase, then it
will be resistant to the given penicillin derivative other derivative must be prepared.
Previously, penicillin derivatives were prepared from ferment solution, adding phenylacetic acid
to it, generating benzylpenicillin. Benzylpenicillin + enzyme 6-APA +R-COCl many
thousands penicillin derivatives.
Source: Penicillium notatum, P. crysogenum bacteria. Antibiotics are more uniform compounds,
than vitamins.
Antibiotics are natural compounds, produced by some microorganisms against other
microorganisms, blocking the latter. Fleming observed extinction spots, thus he had hard earned
the Nobel Prize.
Currently penicillin derivatives are prepared by semisynthesis methods: 6-APA is made to be
produced by bacteria. This was one of the first trials of biotechnology.
V/ Pyrazole and its derivatives

Preparations

1/ By 1,3-dipolar cycloaddition (Huisgen)

R R
2. 2. 2.
R 2. O N
O NH2 R N
H R = H, alkyl
H2N
R H R
2.
R C C 2.
CH2 2.
2. C C N N
N R R
C N N
N H
R

2/ By isosteric replacement from isoxazole

NH3
N N
O pressure N
H
Chemical properties

1/ Acid-base properties

Introduction of a nitrogene shifts the


pyrrole-like properties to the N HO R
pyridine-like properties. N
H

makes a H-bridge
weak base pKa = 2.5
(pyrrole< pyrazole< imidazole< pyridine)
very weak acid pKa = 14
(it is amphotheric compound)

2/ Tautomerism virtual tautomerism


N NH (equivalent tautomerism)
N N the two tautomers can not be
distinguished from each other
H
H
real tautomerism - if a R group (alkyl group) is attached
N N to the ring, the tautomer is fixed. The indicated H is migrating
R N R N - it can be marked by isotope or substituent

H
3/ SEAr reactions E E

N N N N
N E N E N N
H H H H
E
advantageous not advantageous not advantageous
4 3

5
substitution on the C-4:
N2
N 1
bromination, nitration, sulfonation
H

O2N H2N
HO-NO2 H2 OH
N N N
N N N
H H H OH
NaNO2 / HCl
0-5 oC
Cl N N

coupling N
N
reaction N
N
H

N N
H
More important derivatives

O NH N
2
acrolein N
H2N H
2-pyrazoline

Br NH
NH2
Br N
H2N H
pyrazolidine

CH3 benzene
O
N
N 20 oC -benzoic acid
N N N
- H2O H
C C
O C 6H 5 O C6H5 indazole

N-benzoyl-N-nitrozotoluidine
CH3
CH3
NH
O N N
H HO N N
O N CH3
pyrazol-3-one

(CH3O)2SO2
tautomerism
antipyrin
CH3 CH3
H CH3 fever- and pain-killer compound
NaOEt CH C
O - H2O NH
O OEt C N tautomerism O
O N
NH2 N
- EtOH NH

norantipyrin
O O OH
tautomerism
NaOEt
OEt NH N
O OEt O N HO N
NH2
H H
H2N

O O O
tautomerism
NaOEt
OEt N N
O O N HO N
OEt

NH
NH
H9C4 O
H9C4 O
NaOEt
NH N
OEt
NH O N
O OEt

Phenylbutazone
inflammatory drug

E (NO, Br )

CH3 O N CH3 H2N CH3


HO-N=O H2
N N N
O N CH3 O N CH3 O N CH3

H C O
H O
H C
Br2
OH
H3C
N CH3
(CH3)2NH H3C Leukart-Wallach's
reductive methylation
N
O N CH3

Amidazophene
CH3
H2N CH3 CH N CH3 CH N CH3

CHO
N N CH3X N
O N CH3 O N CH3 O N CH3

CH3 CH3
HN CH3 O3S CH2 N CH3

HCHO
N HSO3 N
O N CH3 O N CH3
H3O SO2OH
CH2OH

Methamisole
VI/ Imidazole and its derivatives
Preparations

1/ From 1,2-bifunctional compounds


C6H5 H 5C 6
- H2O N
C6H5 2. C N
3. 3.
C O H2N H CH C
1. CH2 C 3. N C6H5 N C6H5
Br HN C6H5
- HBr

C6H5 1. C6H5
CH NH2 Cl CH NH
2. 3.
C C C C
C6H5 O O R C6H5 O O R

O C 6H 5
CH3C O NH4 N
3.
3.
C 6H 5 N R
H
R R
NH2 Cl N
-HCl
Ph O S R' -H2O Ph S R'

R': Alkyl, NH2

R R R
NH2 Cl N NH3 N
-HCl Ph
Ph O O Ph -H2O Ph O Ph N Ph
H

NH4OCOCH3
CH3COOH

Ph Ph
O H2N N

-HCl
Ph Cl X Ph Ph X Ph
-H2O
X: O, S, NH
R1 O R2
pyridine, water, NaOH
HOOC CH NH C CH NH2 + N C S
pH=9, 40 o C

R1, R2: alkyl groups

R1 O R2 R1 R2
CH3NO2 NH
HOOC CH NH C CH NH HOOC CH NH3 Cl +
HCl
C O N S
HN S

thiohydantoin

Edman sequencing of peptides


Chemical properties

1/ Acid-base properties 2/ Tautomerism


H
N N virtual
N pKa 7.2 tautomerism
amphotheric compound N N

N H

H pKa 14.5 N NH
real
tautomerism
R N R N
H

as base as acid
H
N tautomers N N N

N N N N
H H

-H +H -H +H mesomers

NH NH
N
mesomers
N N
H H
N
3/ By SEAr reactions

E (sulfonation, nitration, coupling with diazonium salt)

N (methylation, formylation by N-methyl


E formamide derivative)
H

4/ By SNAr reactions More important derivatives

N N 1. 1.
Y NH2 O 3. N
-X C 3.
N X N Y 1. 1.
H H HO R N R
NH2
H
X =Cl, Br
R = H, alkyl 2-imidazoline derivative

1. Ar 1. Ar
N N
H O
1. CH2 1. 2.
NH N
2.
Ar Ar
imidazolidine derivative
H5C6 H 5C 6
1. 1.
H2N H 5C 6 NH diphenylhydantoin
H5C6 C OH
3. 4. 3. 4.
C phenytoin
N O O N O
O OH H Diphedan
H2
diphenylglycolic acid

O O H
C NH 4. 1. N 4.
3. C OH H2N 4. 3.
C O red.
C O O
3. C OH 3. 3.
H 2N C NH
O N hydantoin
O O H
parabanic acid

H 1. H
1. NH3 Cl N N N 4.
4. HgO
S S O
C
3. S K N 3.
N N N
O OR O O H2 O H O H
R

O CH2 COOH O
CH C C CH2 CH COOH
N H HN N H2 N
C O N O NH2
hydrolysis
C
N N N
H H H histidine
azlactone essential amino acid

CH2 CH2
N histamine
NH2 biogenic amine
-CO2 generated in allergic reactions
N
H
2
R
2 2 NH2 2 NH COOH R
KCN, (NH4)2CO3 R R 3
R NH
C O C C
3 CO2, pressure 3 3
R R C R C HN O
O
N N

2 2
R R
H2O R
3
NH R1 X R
3
NH

O OH O
O N O N
H
1
R

R1 R2 R3

Phenytoin H

Diphedan antiepilepticum

Mephenytoin CH3 C2H5

Sacerno antiepilepticum
NH H 2N X NH2 X NH2
R NH C + R NH C R NH C
S CH3 H 2N S CH3 S CH3

- CH3SH R1
- CH3SH
- NH3 NH
- HX
R2
N
R NH C NH
N R NH C
H N R1
R2

C2H5OH NH
CH2 CN CH2 C
HCl OC2H5
CH2 CH2
200oC H2N
NH2 NH2.HCl

N H2N
CH2
N
H
tolazoline sympatholytic
CH3 CH2 Br CH2CN

CH3Cl Br2 KCN


AlCl3 hν DMF

N
CH2CN CH2
N
H2N CH2 CH2 NH2 / HCl H

melting

Naphazoline
X' H H
O N N
S
Cl2 / H2O, H2SO4
R: Cl

N N N
X" H
Ph

N N
R NH2 + R NH
Cl N X N
H H

NH2 POCl3 X
1) PhSCN R N X
2) CH3SO2Cl NH NH2
C
Cl NH2 X
R'
NH POCl3
R' NH2
R N C N Ph R NH C N Ph

H2N CH2CH2 NH2 - PhNH2


R NH C N Ph
NH2
HN
CH2
CH2
NH2
O 3. N H 3C N
C H 3.
HO N
NH2 H H 3C N
o-phenylene diamine benzimidazole ribose
(structural element of B12 vitamine)

1
NH2
OH NH
+
2
NH2 O H N
3

Br C N benzimidazole
- HBr

NH
C N NH NH

NH NH NH N NH2
H benzimidazol-2-amine
Monocyclic compounds with more
than two heteroatoms
I/ Triazoles and its derivatives
4 3 4 3 4 3
N N NH2
HO 5 N
2 2 2
5 5 N N
N N 6
N1 N 1
NH2 O N1
H H H
1,2,3-triazole 1,2,4-triazole 1,2,3-benzotriazole

R R R
NH
NH N
N
N N N
R R N R N
H H
acetylene azoimide
derivative
H
ROOC ROOC N stereospecific reaction
H N geometry of the starting material and
H
N N of the final product are identical
ROOC
N Huisgen
ROOC H N for 1,2,3-triazoles
R alkylazide R
dialkyl maleate

R R
H3N O N
O
NH N
R N R N
H H
1,2,4-triazoles
II/ Tetrazole and its derivatives

4 3 4 3
N N N N N N N N
5 N 2 NH C N N
2
N1 N1 H N N
H H
H
1H-tetrazole 2H-tetrazole

H N N N
O
hydrogen azide
O
(azoimide)
- N2 NH
H N N N
mesomers

N
Pentetrazol N
analeptic agent N N

1,5-pentamethylenetetrazole
III/ Thiadiazole and its derivatives

4 3 4 3
4 3 4 3
N N N N
5 N 5 N 5 N N 5 2
2 2 2
S S S S
1 1 1 1

1,2,3-thiadiazole 1,2,4-thiadiazole 1,2,5-thiadiazole 1,3,4-thiadiazole

NH NH2 N N (CH3CO)2O N N
C C
S S H2N S SH HN S SH
H2N S
C
thiosemicarbazide O CH3

N N N N
O NH3 O
HN S S Cl HN S S NH2
C O C O
O CH3 O CH3
Fonurit
Diamox
diuretic compound
with carboanhydrase blocking effect
IV/ Oxadiazole and its derivatives

4 3 4 3 4 3
3 4
N N N N
5 N2 5 N2 5 N N2 5
2
O O O O
1 1 1 1
1,2,3-oxadiazole 1,2,4-oxadiazole 1,2,5-oxadiazole 1,3,4-oxadiazole
(azoxime) (furazane)

H3C CH3
H3C CH3 H 3C CH3
C C C C
N N - H2O N N
O O
O
OH HO
+ 2 H2N OH
dimethyl glyoxime

N N
HN NH

CH3 H3C O CH3


H3C O O

symmetric diacyl
hydrazine
Prenoxdiazine

H2NOH.HCl
H2N
N C Na2CO3
HO N

N Cl

N N O

O N

Libexin
O HN
2
N
O N
Less frequent heterocyclic rings and
ring systems
I/ Dioxolanes and dithiolanes

3 4 3 4 3 4 3
4
O S
5 2
5 O2 5 2 5 S 2

O O S S
1 1 1 1

1,2-dioxolane 1,3-dioxolane 1,2-dithiolane 1,3-dithiolane

OH O
tosylic acid
O CaCl2
CH2
OH O

Br Na2S S
Br S
II/ Crown ethers and cryptands

O O O
O O O O
Na
Li O O K
O O O O
O O

4 crown 12 5 crown 15 6 crown 18

number of Crown ether with O atoms: cyclic polyether


heteroatoms number of
elements of Crown ether with S, P, N atoms: cryptands
the skeletone

C.J. Pedersen, J.M. Lehn and D.J. Cram


1987 Chemical Nobel Prize
Crown ethers
C. J. Pedersen discovered these cyclic polyethers with many oxygen atoms in
1967. Their curiosity is that they are able to form insoluble complex with
various metal cations, e.g., Li, Na, K, depending on the inner diameter of the
ring, resulting in removal of these cations by filtration. This discovery had
great importance from organic chemical point of views. Large-scale pre-
paration of crown ethers was carried out by industry. There are crown ethers
with 4, 5 and 6 oxygen atoms.
Application of crown ethers may take place in organic chemistry by dissolu-
tion of a crown ether in aprotic solvent, then adding potassium, or sodium
salts to it, the crown ether makes complex with the cation, and precipitated.
There is a highly reactive anion in the solution after filtration. E.g., potas-
sium permanganate becomes soluble in benzene after treating it with crown
ether, then this apolar solution of permanganate anion is used as strong oxi-
dating agent. Similarly potassium cyanide, potassium fluoride, potassium
nitrite, potassium iodide can be dissolved apolar solvents. Reduction by so-
dium borohydride can be carried out in aromatic solvents, if crown ether was
added. E.g., dehydration of an O-tosylate runs for 42 hours at usual condi-
tions, while the yield is only 9 %. The same compound has dehydration in
the presence of crown ether within 1 hour with yield of 70 %. Many such
kind of applications can be found in the literature.
Pedersen, then Jean Mary Lehn were working with such crown ethers in
1965. They prepared ethers with greater ring size → crown ethers. The oxy-
gen atoms are arranged in the structure in order to make noble gas confi-
guration with the proper cations. The counter anion is attached from outside.
KMnO4 is insoluble in benzene. However, adding some crown ether to the
suspension, − e.g., [18] crown [6] − colour of benzene turns to be of violet,
showing dissolution of KMnO4. The crown ether can solvate K⊕, while per-
manganate ion is attached to this complex in form of ion pair, from in front
of the ring or from behind the ring. Permanganate ion is naked, there is only
electrostatic attachment of ions. Therefore, the oxidating behaviour of per-
manganate ion is remained. KOH can be dissolved in apolar solvents by a
crown ether. Hydroxide anion is naked, its nucleophilic power is remained in
SN reactions. The only condition of dissolution of the reagent is that the ca-
tion must make stable complex, while the anion is naked. The similar disso-
lution happens in dipolar aprotic solvents. The naked anions are of much
more nucleophilic, than any solvated anions. Such kind of dissolutions are
called as solid-liquid transfer. Liquid-liquid transfer: see PTC reactions
(phase transfer catalysis).
III/ Pyrrolizidine

H 2C C CH2
NH3/ H2
O CH2 O CH2 70 atm,70 oC
C HO C NH2 -2 H2O N
OH HO
OH
O O O O O

8 1
7
LiAlH4
6 N 2
4
5 3

pyrrolizidine
(in alkaloids)
Six-membered heterocyclic compounds
with one heteroatom and their
derivatives with condensed ring system
I/ Pyrane and its derivatives

Nomenclature
H
4 4 4
5 3 5 3 5 3

6 6 6 X
O 2 H O 2 O 2
1 1 1
2H-pyrane 4H-pyrane pyrilium salt
α-pyrane γ-pyrane the benzopyrilium salts
these are not stable compounds are stable compounds

Preparations
C6H5 C6H5

C6H5
C
O H H5C6 OH O C6H5
H5C6 OO C6H5 H
H3C H3C

H5C6 O O C6H5

C6H5 C6H5

H3O oxidation

H5C6 O C6H5 H5C6 O C 6H 5

pyrilium salt
O acetone O O
H3O
C
CH2 CH2 R-ONa H aqueous acid
H H - 2ROH anhydrous
ROOC OO COOR acid ROOC O COOR
OR OR

ROOC O O COOR

dialkyl oxalate

O O O OH
tautom.
NH3
-2CO2
HOOC O COOH HOOC N COOH N N
H H
Cu
γ-pyrone derivative γ-pyridone derivative γ-pyridone 4-hydroxypyridine
( chelidonic acid)

O O O
-2CO2 O
O NH

O N acid amide
O H ester

vinylogous
ester
O acid amide
γ-pyrone
O
C
H 2C CH2
NaOEt/EtOH O
H H anhydrous anhydrous
hydrochloric acid
OEt OEt heating

EtOOC COOEt
EtOOC O O COOEt O O

O O
aqueous
hydrochloric acid NH3

EtOOC O COOEt pressure


HOOC O COOH

O O OH

heating

HOOC N COOH N N
H H
OH
HOOC H O H
NaOH HOOC H
C
H aqueous medium
H O heating H O
HO O O HO

OH
H
HOOC H HOOC
heating heating

-2H2O -CO2
H O O O
OH OH

CH3NH2 / H2O

pressure, boiling
O O N O
CH3
More important derivatives
O
4
5 3

6 2
O O O O O
1
3,4-dihydro- tetrahydro 2H-pyran--2-one 4H-pyran--4-one
-2H-pyran -pyran α-pyrone γ-pyrone

O O O
α-chromen chroman γ-chromen
2H-chromen (stable) 4H-chromen (unstable)

O O

O O O O O O
2H-chromen-2-one α-chromanone γ-chromanone 4H-chromen-4-one
α-chromone γ-chromone
coumarin
O
O
4
chroman isochroman
5 5 4 5 4

6 3 6 3 6 3

7 2 7 2 7 O 2
O O
8 1 8 1 8 1
2H-chromen 4H-chromen isochromen
O

O O O O
coumarin chromone isocoumarin
O

O O O O
2-chromanone 4-chromanone isochromanone
(dihydrocoumarin) (dihydrochromone) (dihydroisocoumarin)

+
O -
+ X
O
chromilium salt isobenzopyrilium salt
(benzopyrilium salt)
H
Al2O3 H 3O
O CH2 OH 350 oC O
- H 2O O HO
Raney
Ni/H2
H3O ROH
protection of
alcoholic
O
OH
RO O
Br

KOH 1,7-heptandiamine

O O
Nylon 77
(see at tetrahydrofuran)
OH
H
HOOC H HOOC

O -2 H2O - CO2
H O O O O O
aldol
dimeri- α-pyrone
sation HOOC

H OH
enol
R = H α-pyridone
O R = CH3 N-methyl-
H
HOOC H α-pyridone N O
R
C
H O HO O

formylacetic acid

O O It is a double vinylogous lactone


Both mesomers contribute to the
real structure
mesomers

O O
4.08 D measured 22 D
1.75 D calculated
oxo reagents
H2N NH2
O or
H3C O H there is no reaction
HO NH2
1. CH3MgI
2. H2O H
O O stable
it is an ester, O
+HCl it can be Br2
hydrolysed base Br Br
-H2O
by base substitution
(vinylogous (it is not addition)
ester) O O
CH3

O
HO OH
O Cl shifted to the
oxo form
pyrilium salt
O O
aromatic
it can be isolated from
wheat germ oil
Vitamin E it participates in
α-Tocopherol keeping pregnancy
CH3
(tokos: birth, ferein: carry)
HO
* * CH3
*
H3C O
CH3 CH3 CH3 CH3
CH3

Coumarin - its hydroxy derivatives occur in glycoside form in nature

OH OH

dicoumarol
an anticoagulant these differ from each
(its antidote is Vitamin K) other in the position of a
O OO O
tautomers H (H anion) and of
a double bond
H

H
(difference lays at oxo-enol taumerism
in differences in mobile H as well as
O O H position of a double bond)
4H-pyran 2H-pyran
-H
oxidation
C6H5
stable aromatic
not existing compound

O H5C6 O C6H5
ClO4
Anthocyanines

These derivatives are compounds with conjugated double bonds (conjugated: 2H-pyran,
or isolated: 4H-pyran) (heterocyclic alkenes). The compounds are reactive ones with high
energy content.
hydrolysis
Anthocyanines are glycosides anthocyanidine (aglycon) + sugar component
Flavinium salts: coloured materials of plants with glycoside type (flower petals, fruits, strawberry,
pelargonium, red poppy, black grape, bluebonnet, chrysanthemum): these might be red, purple,
violet, blue
α-Chromene derivatives are polyhydroxy compounds with 5 hydroxy groups. Its derivatives occur
in the nature only, e.g., methyl ether, acetyl derivative, or with free hydroxy groups.
The glycoside structure is the remnant of molecular phylogenesis, representing its carbohydrate
origine.
Cyanin (greek) – blue
The actual colour depends on pH of cells as well as on depth of layers, since coloured components
do not move freely within the cells, these form layers. Blue colour of bluebonnet and red colour of
red poppy comes from the same molecule.
Colour depends on: 1. pH value
2. number of hydroxy groups
3. the actual form of hydroxy group (free, methyl ether, glycoside)
4. position of glycoside group
OH OH
OH OH
-H

+H
HO O HO O

sp2 OH O
OH O H
cyanidine chloride salt anhydro base
pH = 3 red (red poppy) pH = 8 violet (bluebonnet)

+H2O
+H
- H 2O +H -H

OH OH
OH OH
sp3

HO O HO O
HO
OH O
OH O

pseudobase pH = 11
colourless blue (flower petals)
These differ in the number and positions of hydroxy groups, in quality and
position of the sugar components.
Source of red colour can be carotenoids (red pepper), while other carotenoids
are yellow.
White colour of flower petals come from the colourless air, but from not a
coloured material.
There is sp2 conjugated system in cyanidine chloride, where the pyrilium salt is
the auxochrome component.
Appearence of a sp3 carbon separates the two chromophores, resulting in no
absorbance in the coloured range.
Flavonoids Colour of tulips and other plants by springtime.
There can be 4 types of hydroxy derivatives (free,
Yellow colour of yellow plants (flavus – yellow) methyl ether, acetoxy derivative or glycoside),
γ-chromene derivatives similarly to the anthocyanines.

Ο Ο
5 4
6 3
ΟΗ

7 ∗
Ο 2 Ο Ο
8 1

2−phenylchromane flavanone flavanonol


flavane
Ο Ο
ΟΗ

Ο Ο Ο

2- phenyl-4H-chromene flavone flavonol


flavene

Ο Ο
x
Ο
2-phenyl-2H-chromene flavinium salt isoflavone
O O O

CH3 Cl CH3
pyridine
O
OH O C
O
O
KOH glacial acetic acid
pyridine H2SO4 ,
OH O
50 oC -H2O
O

OH OH
H OH
HO HO
O O
O O
O OH Prof. Géza Zemplén
O Technical University at Budapest :
he was a flavonoid
HO O researcher
rutin OH flavanol type
D - glucose L- ramnose
coloured dye of OH
Ruta graveolens rutinose
Vitamine P: discovered by Szent-Györgyi, Rusznyák, Bruchner
It decreases permeability of capillaries, increasing their resistance.
OH O
erythrodicthiol + hesperidin
R=H R = CH3

sugar O O

OR
OH

O O O

Na
Et O
OH O O O OH
C H
H O

- H2O

isoflavone
O
O
O CH3 C
+ O / NaOAc
CH3 C - H2O - CH3COOH
OH O O
O O
H
salicylic aldehyde O CH3

Perkin-synthesis

O O
coumarin
O O H O
1) KOH /EtOH
CH3 H / MeOH
+ or
2) H NaOAc/MeOH
OH O H

hydroxychalcone

OH O

O O
H
flavanone
Anthocyanines: α-chromene derivatives
Flavonoids: γ-chromene derivatives
Anhydrobases: compounds forming salts with acids without generating water (see the
examples on the previous slides)
Pseudobases: some secondary carbons with OH can dissociate to hydroxy, similarly to the
effect of bases pseudobases

- OH

H OH

+ OH
O OH O N OH
R
OH OH

+ OH N
+ OH
O O N R

R
anhydrobase
H
H H
H
O O
OH O H + H2O
OH H O
I II OH
compound II is an anhydrobase, since it contains one water molecule less, than compound I

OH OH O

+ OH
X OH II
- H2O
O does not run O H O
I anhydrobase

Dibenzopyrans and their derivatives HO H

xanthydrol
red.
O
O O
8 1
Cl
7 2

6 3
O O O
5 4
xanthene xanthone
CH3

OH
COONa
CH3
O CH3
HO O O tetrahydrocannabinol
fluorescein indicator psychotomimetic agent
Cannabis indica
II/ Thiapyran and its derivatives
O
Structure

S S S
α-thiapyran γ-thiapyran tetrahydrothiapyrone

Preparation Na2S
EtOH
Br Br S
tetrahydrothiapyran

S S O S
α-thiachromene thiacoumarin thiaxanthone

S S S
thiachroman γ-thiachromone thiaxanthene
III/ Pyridine and its derivatives

Structure

X X
N O N
H

aromatic compounds with π - electron deficiency


Preparations
Homologues of pyridine are isolated from coal tar
Homologues of pyridine with 1 methyl groups are called as picolines
1/ Isolation from coal tar Homologues of pyridine with 2 methyl groups are called as lutidines
Homologues of pyridine with 3 methyl groups are called as collidines
Homologues of pyridine with 4 methyl groups are called as parvolines

picolines: CH3
CH3

N CH3 N N
α β γ

lutidines: CH3 CH3


CH3 H3C CH3 H3C CH3

N CH3 N CH3 N CH3 H3C N CH3 N N

collidines: CH3 CH3 CH3


CH3 H3C CH3 CH3 H3C

N CH3 N CH3 H3C N CH3 N CH3 H3C N CH3

parvolines: CH3 CH3


H3C CH3 H3C CH3 CH3

N CH3 H3C N CH3 H3C N CH3


2/ Hantzsch synthesis
O O O R O
H H
H R H
EtO OEt EtO OEt
CH - H 2O
O O O OO

aldehyde

ethyl acetoacetate

O R O O R O

EtO OEt - 2 H 2O EtO OEt O

H H atmospheric
OO N N
HH H H

enol form 1,4-dihydropyridine


derivative
O R O
pyridine derivative stabilised, therefore its dihydro
EtO OEt derivative is easily oxidised to aromatic compound

N
3/ From 1,5-dioxo compounds

H 3O

R OO R R OO R R O R
HH

NH3 ox.

R N R R N R
4/ By isosteric exchange

see at pyran and its derivatives

5/ By Chichibabin synthesis
CH3
CH3
C - 3H2O
O H -2H
H 3C CH3 H 3C N CH3
(oxidation)
C C collidine
H3C O O CH3
NH3
Physical properties

The parent compounds have high solubility in water


Their UV spectra are similar to of benzene.
There are group vibrations in their IR spectra: pyridine counts to monosubstituted benzene,
in respect to the fingerprint region of 700-900 cm-1
Their NMR spectra:
7.50
6.20
.
7 12
compare to: 6.68
.
6 61 N
N H 8.00

Chemical properties

1/ Acid-base properties
The compounds are stable against acids (salt formation), while are somewhat labile to bases
(hydrolysis), except for pyridine. Base sensitivity increases by the number of heteroatoms.
Pyridine is of basic property – introduction a second N decreases basicity.


Ν pKa = 5.2 Ν
Η
2/ Tautomerism This is function of solvent, of pH, of structure, and of functional group(s)
NH2 NH

tautomerism tautomerism

N NH2 N NH N N
H H
amino amidine amino vinylogous amidine

tautomerism mesomerism

N OH N O N O
H H
lactim lactam

OH O O
tautomerism mesomerism

N N N
H H
vinylogous lactim vinylogous lactam

OH O
protomerism
there is no tauto-
merism
N N
H
N α XH N X N X
H
H

XH X X

N N N
H
gas phase H
in polar solvents

XH X

N N
H

X = O, S, NH in water only;
50% ratio of it

Diazotization if the amino group is possible,


NH2 N N proving that the equilibrium is shifted to the
NaNO2/ HCl amino form in highly acidic conditions.
0 - 5 oC Cl The 2- or 4-diazonium derivatives can be
N N decomposed easily, while the 3-diazonium
derivative is stable.
3/ SEAr reactions It takes place with difficulties, and into β position only
Ο
O
Br Br ΗgO C CH3
Br2 Hg(O-C-CH3)2
300 oC 150 oC
N Ν N
KNO3
*
+ H2SO4/SO3
300 oC Hg Friedel-Crafts reaction
SO3/ cc.H2SO4
300 oC does not run
oleum
NO2 Ο
S O
Ν with low yield Ο twin ionic structure
N
H

* Sulfur trioxide absorbs the water generated in the reaction. KNO3 is less volatile, than HNO3. HNO3 is generated in the reaction
mixture.
Pyridinium ion withdraw electrons from ring carbons even more.
Pyridine reacts in SEAr reactions with difficulties due to two reasons:
a) electron density is decreased in α- or in γ-positions especially, the least in β-position
b) Protonation of the N atom (NH+) increases electronegativity of N, thus withdrawing electrons from the ring carbons even more.
4/ SNAr reactions It takes place in α- and γ-positions mainly due to the lower electron density in these
positions
NaH is deprotonating the amidine NH2, resulting in H2.
The reaction becomes irreversible, since H− is the leaving group, and it reacts with
α-substitution: the proton source NaH.

acid amidine
system
Na-NH2, liq. NH3
H
N -33 oC N NH2 N NH2
Na
+NaH

H2O

N NH2 N NH

α-pyridinamine Na +H2

RMgX RMgX
150 oC
N N R R N R
Regioselective α- and γ-substitution
N X
CH3
alkyl pyridinium salt
HO M KCN

C N
N C H
K3 FeIII(CN)6
H I2
N O N OH oxidation
N N
CH3 CH3
MX CH3 CH3
+KX

NH2

Cl NH2
KNH2/NH3 liq. + NH3 γ-substitution
- 33 °C +
N - HCl N N N

3,4-dehydropyridine 25% 45%


("hetaryne")

KCN H α-substitution
- KI - CH3OH
N N CN N CN
I
OCH3 OCH3
Pyridine in nucleophilic reactions

H H H
N NH2 N NH2 N NH2

NH2 NH2 NH2


Z
H H H
N Z =NH2 N N N

H2N H H2N H H2N H

N N N

Pyridine in electrophilic reactions

H H H
N Br N Br N Br

Br Br Br
Y H H H
N N N N
Y = Br

Br H Br H Br H

N N N
In ground state
There are lower electron densities in α- and γ-positions

In nucleophilic reactions
The ring N causes –Iα>-Iγ, the β carbon does not react. The negative charge in
the intermediate can appear on the N, as well.

In electrophilic reactions
The relatively highest electron density is found on the β ring carbon, since there
is no positive charge on the N, and moreover, there is no positive charge in any
mesomers if β-substitution takes place.

Pyridine in ground state

N N N N N
5/ Reactions at a lone pair of electrons
oxidation
H2O2
HX CH3COOH
pyridin-N-oxide
PCl3
N X N N
H X = Cl
O O O
R-I I-I O C
SO3 R C X R

Thus pyridine
X is catalysing
acylation
N
N N N I
I C
R O S O I R
O
O R' OH

Fixing the salt structure results O


in difficult cleavage of the R group R' O C R acyl pyridínium salt
acyl cleavage
+ it is less stable, than the
alkyl pyridínium salt

+HX
N

Reactions of pyridin-N-oxide
One of the nonbonding orbitals of oxygen can be coplanar (in the same
plane) to the combining p AO-s of the ring atom. Thus, the +M effect of the
oxygen is overcompensating the -I effect of the nitrogen, resulting in
O N electron richness in α- és γ- positions of the ring. One electron is excited to
the LUMO orbital. Size of delocalisation is increased.
NO2 NO2 NH2

HNO3/H2SO4 PCl3 red.


o
100 C -POCl3
N N N N
O electrophilic reaction O
in γ-position

Not at 300 oC-on, like for pyridine t = 200 oC the difference in reactivities is 108 times

NO2
H NO2 O
Hg(OCCH3)2
-H the electrophile
N N N N Hg
goes into
O O O α-position O O
σ-complex C
O CH3
control of orbitals are the reasons of α-, or γ-selectivity
control of charges
X NO2

H2SO4

N N N N
O O O OH
X = NH2, Br, Cl, CN

SO2OH SO2OH
MgBr H2SO4

N N N
nucleophilic reaction
OH
SO3

SO2O

N N N
H
O S O
O
6/ Addition reactions
The Diels-Alder reaction has a very complex mechanism with pyridine, the reaction is not concerted
(asynchronous) and the final product is formed by aromatic stabilization of the previous, coloured
intermediate.

CH3
CH3
O CH3
O O O CH3
O O
+ O
O CH3 N
O
2 O O
O
O CH N
3
O
O CH3 O
O O CH3
dimethyl acetylene- O O
dicarboxylate CH3
CH3
oxidation by red intermediate
Hg(OCOCH3)2
ring closure
O O CH
3
O CH3 O O CH
3
H O CH3
O
N O O
N O
O CH3
O O CH3
O CH3
O O CH3
colourless product
yellow product
7/ Reduction Ni or Pd
piperidine
H2
N N
H
Reduction is the easiest, if the compound has strong electron absence.

NaBH4
+NaCl
N K3 FeIII(CN)6 N
Cl
CH3 CH3

O O
reduction H H
NH2 +H NH2

N -H N
R oxidation R R = H nicotinic acid amide

This system can be reduced even It is a biochemical H-transfer agent,


more easily, since it has stronger electron main ingredient of coenzymes
absence reduction takes place NAD, NADH
in α- or in γ-positions

8/ Oxidation 9/ Polymerisation
The stronger the electron absence, the more difficult is the It does not run, in the contrary of five-membered
oxidation. heterocycles.
There is no ring opening for pyridine by oxidation.
Formation of N-oxide is possible from pyridine.
There is active H at α- and γ-methyl groups
for heterocycles with π-electron deficiency

-H

N CH2 H N CH2 N CH2 H N CH2


H

R R
N CH2 N CH2
C C
O CH2 H HO CH2

CH2 H CH2

-H
CH2 H CH2
N N

N N CH2 CH2
H

N N N N N
N CH2 N CH2 N CH2

CH2 CH2
N N
N CH2 N CH2 H H H
X=CH3, O X X
10/ Reactions of the active C-H group
O
CH3 C H
O
N CH2 H HO N CH2 CH CH3
H

HO H D (deuterium)
-H2O exchange is possible OH
N CH CH CH3
H

mesomers -H2O
N CH2 N CH2
N CH CH CH3

Na/EtOH
N CH2 CH2 CH3
H
racemic coniin
More important derivatives nicotine: the very poisonous alkaloid of tobacco (Nicotiana tabacum)

O O
H
OH )N cc. HNO3 OH
OH
N N CH3
N N coenzyme complex belonging
O O to the vitamin B group
2-picolinic acid nicotinic acid it is oxidised
at this carbon NH2
O OH
N

isonicotinic acid

O OH O OCH2CH3 O NH NH2
CH3

oxidation CH3CH2OH H2N-NH2


cc. H2SO4
N N N N

isonicotinic acid hydrazide, INH


Cl first drug of tuberculosis, 1952
CH3
N N CH2 CH2 N R
CH3
HOCH2 CH2OH

N CH3
chloropyramine (Synopen) R
an antihistaminic drug pyridoxine -CH2OH
(pyridoxol vitamin B6 ) their phosphate ester is used
in coenzymes of transaminating
pyridoxal C O and of redoxy reactions
H
pyridoxamine CH2 NH2
H2 /cat.
- NH4Cl Cl
N N
H NH2 NH3
piperidine

coal tar CH3I, then AgOH

NaNH2
CN
C CN C O
H H Na Na CN
-2NaCl CH3CH2OH OCH2CH3
compound with
actíve methylene group H2SO4
HH Cl Cl Dolargan, meperidine
OH OO N N (pethidine)
2 SOCl2 CH2 CH2
CH3NH2 CH3 CH3 morphine substitute
CH2 CH2
H
N N
O
O CH3 N
CH3
CH3
nitrogen mustard
O MgBr
C O
H H -H2O then H2O OH
CH2 C CH2 CH2 N
C + C
H CH2 CH2 N
O N
HCl
H Parkan
Mannich reaction an antiparkinson drug
Indolizine, indolizidine
8
7 1

6 N 2 N
4
5 3

indolizine indolizidine
(in alkaloids)

Quinolizine, quinolizidine

COOR 9a
Diels- COOR
COOR Alder 9 H 1
COOR 2
reaction 8

7
+ 4 CO2
N N N 3
COOR 5
COOR 6 4

COOR COOR 9aH-quinolizine

dialkyl acetylenedicarboxylate
H2

N N

quinolizinium salt quinolizidine


(in alkaloids)
The benzocondensed derivatives of pyridine

2
1 3
5 4 5 4 8 9 10
1
4
6 3 6 3 7 2 9

7 b c b c
7 2 6 8 5
2 N 3 N
8
N 1 5 N 4 7 6
1 8
10
quinoline isoquinoline acridine phenanthridine
benzo[b]pyridine benzo[c]pyridine benzo[b]quinoline benzo[c]quinoline

9a
9 1 9 1 9 H 1
8 H 2 2
2 8 8

7 3 3 3
N 7 N 7 N N
6 5 6
5 4 5 X
4 6 4
H
2H-quinolizine 4H-quinolizine 9aH-quinolizine dehydroquinolizinium salt
Quinoline
Preparations

1/ By Skraup synthesis
H CH O H glycerol
Michael-type addition
HC OH
H
CH2 OH

NH2 O
cc.H2SO4
aniline O - 2H2O
CH
CH H
CH2
CH
cc.H2SO4 CH2
(it is not formation CH2 N
of Schiff-base) H
acrolein

OH
H NO2

- H2O nitrobenzene isolation by steam


N N oxidating agent N distillation
H H
-2H quinoline
dihydroquinoline

isolation of quinoline may take place from coal tar


2/ By Döbner-Müller process
O
O
CH
CH CH2
cc. HCl oxidation
+ CH
CH
NH2 CH N CH3 - H2O N CH3
H H
CH3

N CH3

Chemical properties

SE SN
These are similar to of pyridine:
5 4
SE reaction takes place at the carbocycle, in
position 5, or 8 bromination
SN reaction takes place at the heterocycle, in nitration SE Ar
position 2, or 4 2 sulfonation
8 N
SN

SE
oxidation: the carbocycle is oxidized in basic medium,
1/ Oxidation while the heterocycle is oxidized in acidic medium

O O

OH KMnO4 KMnO4 HO
OH H HO HO
N N
O O
2/ Reduction Ni/130 oC Pt/acetic acid
the carbons of heterocycle have low
electron density, therefore oxidation of
H H the carbocycle takes place in neutral/
basic medium. Protonation of the N helps
improving acidity of the heterocycle,
trans therefore phthalic acid is prepared in
N cis N
H H acidic medium.
H H

reduction: depends on
catalyst and solvent
3/ Electrophilic reactions

E
5
6
E
+
N N N
8
E

E = SO2OH E

N
kinetic control
H SO 2OH
+
H2SO 4/H

+
N -H N
SO 2OH
H2SO 4
kinetic
+
+H control +
-H thermodynamic N
control +
-H
+
+H
SO 2OH
SO 2OH
thermodynamic
control
 
N N
H H (see below) H H

N SO 2OH
H H

X X X
X H
H
H
 H
N N H N N
A A N N
H H

H H
X X X X
 H H

N N H N N A
N N A
H H

A: advantageous
N: not preferred
4/ Nucleophilic reactions KCN
O Cl
Cl
N N CN
C C
Chichibabin reaction O O C6H5
main product
NaNH2 Li H3O
H
N NH2 N N
+ Li
NH2 N COOH
HO CH3I oxidation by
-LiH C
nitrobenzene O C6H5

N UV light
N OH N I
N
PCl5 CH3
+ OH
HO N
OH KCN
O
CN CN
N Cl
N I2
Cl PCl5
N oxidation N
NH3 HO I
CH3 CH3
N
UV light
NH3
O OH
NH2 CN

HO

N NH2 N N N
More important derivatives

O OH
CH3

CrO3 oxidation
cinchonine
oxidation
N CH3 N N
quinaldine lepidine

O OH
Atophen (aciphenoquinoline)
drug against gout and joint diseases

SN (NaNH2)

O SE mainly
9
H (nitration)
dehydration 2

N N
H 4

SE
drugs and dyes with acridine skeletone
Plasmochin (Chloroquin): against malaria. There were many patients infected with malaria during the II.
World War in Japan, due to the tropical climate. There was international cooperation for drugs against malaria:
100 thousand compounds were tested during 3 years, and 11 compounds became drugs.

CH2CH3
H3C CH CH2 CH2 CH2 N
NH CH2CH3

8 1 8 1

7
N 2 N N 2
7
Cl N 6 3 6 3
Plasmochin N5 4 5 4

1,5-naphthiridine 1,8-naphthiridine
8-Hydroxyquinoline (Chinosan) pyrido[3,2-b]pyridine pyrido[2,3-b]pyridine

H Al, Fe
makes insoluble complexes with heavy metals
(see analytical chemistry)
N
O H alkaloids with quinoline skeletone (see alkaloids)
OH OH OH
NH2 CH2 N N
Skraup Cl2 I2 /KI
O CH synthesis SEAr
CH

OH Cl

I N

Cl
Enteroseptol

CH3O O CH3O CH3O


CH
NH2 CH N redukció N
NO2 O NO2 NH2

CH3O CH3O
H2N NH2
N N
O
NH NH

CH3CH(CH2)3 NH2 CH3CH(CH2)3 N

Primaquin
O
O O

CH3CH(CH2)3 Br K N CH3CH(CH2)3 N
Br Br
O O
Phenanthridine

H N N

O NH2 benzalaniline
1. CH3I
2. NaOH

oxidation
N N N
CH3 CH3 CH3
O OH HO

drugs with trypanocidal activity


Isoquinoline
Origin of it is from coal tar.

Preparations

1/ Bischler-Napieralski synthesis

(R CO) 2O ZnCl2 or
or O H N polyphosph-
NH2 R C oric acid
O H
Cl
β-phenylethylamine R
may contain
also P2O5

Pd / 160 oC
- H2O N dehydrogenation N
- PdH2
R (palladium hydride) R
2/ By Pictet-Spengler synthesis

CH3O O CH3O CH3O


R C o
H Pd /160 C
NH2 NH N
CH3O H2O, pH=5 CH3O CH3O
R R

Position 6 is activated by the methoxy groups, similarly to the biosynthesis.

Chemical properties

SE (main) The chemical properties are similar to of pyridine


5 SE the carbocycle reacts mainly - bromination, nitration, sulfonation
SN the heterocycle reacts in position C-1

N
1
(8)

SE SN
(minor)
1/ By oxidation The carbons of heterocycle have low electron density, therefore oxidation
of the carbocycle takes place in neutral / basic medium. Protonation of the
N helps improving acidity of the heterocycle, therefore phthalic acid is
prepared in acidic medium.

O O

OH KMnO4 KMnO4 HO
OH H N HO HO N

O Pt/acetic acid/sulfuric acid O

H H

2/ By reduction
NH NH
H H
cis trans
4 : 1

3/ By electrophilic reactions
E
5

E
+
N N N
8
E
E = SO2OH
4/ By nucleophilic reactions

NaNH2 CH3MgI
N N N

NH2 CH3
CH3I

I KOH oxidation X
N N N CH
CH3 CH3 3

OH OH
More important derivatives
O O
CH3O CH3O

NH2 NR3 NH reduction


CH3O CH3O O
O Cl NaBH4
OCH3
OCH3
OCH3
OCH3

By Zoltán Földi CHINOIN industrial synthesis

OH
CH3O CH3O
P2O5 / toluene
NH boiling N
CH3O O CH3O
- 2H2O
OCH3 OCH3

papaverine OCH3
OCH3

muscle relaxant drug


Six-membered heterocyclic
compounds with two or more
heteroatoms and their derivatives
with condensed ring system
Compounds with two nitrogens
I/ Azines and its derivatives

N
N
N
N N N
pyridazine pyrimidine pyrazine
1,2-diazine 1,3-diazine 1,4-diazine

Similar heteroaromatic compounds with oxygens or sulfur atoms are not important, their partial or
fullly saturated derivatives only. Introduction of the second nitrogen makes the derivative with even
more π-electron deficient.

Pyridazine and its derivatives


Structure

N
N N N
N N
cinnoline phthalazine benzo[c ]cinnoline
Preparations

Schiff's base structural unit Hydrazone structural unit


O O
Cl Cl
HN HN
N N
Cl Cl

O O H + + OH + +
-H /+H +H /-H
R R C N R' R C N R' R C N R'
R' -H2O
H2N R'' R' H R' H R'

R: alkyl, aryl hemiaminal Schiff's base


R': alkyl, aryl, H (N-substituted imine)
R'': alkyl, aryl

O
R + R C N NHR'
H2N NHR'
R' R'
hydrazone
Amide structural unit Hydrazide structural unit
O O
Cl Cl
HN HN
N N
Cl Cl

O H R + - O
O -H /-X
R R' N C R
X X NHR'
H

amide
R' NH2

R: alkyl, aryl
R': alkyl, aryl,
O
X: halogen, OC R

O O
R + H2N NHR' R
X NHNHR'

hydrazide
Mechanism

O O O
O Cl
Cl AN Cl E δ+ Cl
HO HO HO
O Cl O -H /-H HO -H2O H2N N
Cl Cl Cl
δ+ H
HO H H N
H H NH2
N
NH2 SNi

OH O
HO O
Cl Cl H
N HN Cl
H N
N N
Cl Cl -H N
Cl
lactim lactam
3 3
R R
R1 R
1
NH2 O N
+
NH2 O 2 N
R 2
R
R4 R
4

O O
1 1
R R
NH2 HO HN
+
NH2 O 2 N
R 2
R
3
R R3

O O
1
R R1
NH2 HO HN
+
NH2 HO 2 N
R R2
O OH

O O
1
R R1
NH2 HN
+ O
NH2 2 N
R 2
R
O
OH
CH3 CH3 CH3
4
CH2 NaNO2 / HCl / H2O CH2 3

0-5oC - HCl N2
NH2 N N Cl N
1

4-methylcinnoline

Ar N N Ar N N
electrophile
O O
CH3 CH3 N
N N N Cl N N

O N O N
CH3 CH3

pyrimido[5,4-c]cinnoline
ring system
O O

NH2 hydrazinolysis NH
O +
NH2 NH

O O
phthalic anhydride phthalic acid hydrazide

There are many drugs


O with phthalazine ring
O system:
NH2 NH NH NH2
N R + + R NH2
NH2 NH
N
O O N

N-alkylphthalimide phthalic acid hydrazide


Aprezolin
renal dilatator
O Cl NH NH2

NH POCl3 N 2 H2N-NH2 N
NH 150 oC N N

O Cl NH NH2

Nepresor
decreasing blood pressure
Basic strength in aqueous solution

pKa values for the conjugated acids of the bases

strong repulsion medium repulsion weak repulsion

N
N
N
N N N

pKa values 2.3 1.3 0.7

basicity pyridazine > pyrimidine > pyrazine


N
N
N
N N N

strong repulsion medium repulsion weak repulsion

high medium little


energy energy energy
released released released

N
N
N
N N
N H
H H
Pyrimidine and its derivatives
R R
Preparations 1. NH if R = H
O N
+ pyrimidine
-2H2O
R O H2N R
R N R
CH3 CH3 CH3
4
2. O 5 NH N
NH2 -H2O 3
+ 6 2
O OR -EtOH O N1 O HO N OH
H2N O
H
O O Cl
NH2
3. OR NaOEt NH POCl3 N
+
H2N O - ROH
O OR O N O Cl N Cl
H
HI reduction
O O
R1 NH2
R1
R2 OR NaOEt NH N
+ H2N O R2
- ROH
O OR O N O N
H
barbituric acid pyrimidine
derivative
O O
NH2
4. OR NaOEt NH
+ HN O
N H HN N O
H
addition step
O O

OR H 2N NH
5. +
O OR H2N NH O N NH
H
O O

OR H2N NH
6. +
O OR H 2N S O N S
H
R R
H 2N
O NH
7. +
H 2N O
R O R N O
R' R

O H 2N N
8. +
O OR H 2N S HO N SH
R' = CH3
Basethyrin
hyperthyreotic
compound
R1 R2 R3 X
O
R1 R 3 Amobarbital C2H5 CH2 CH2 CH
CH3
H O

2 N CH3
R Dorlotyn (narcotic, with medium length)

O N X Butobarbital C2H5 CH2CH2CH2CH3 H O

H Etoval (narcotic, long)

Barbituric acid derivatives Cyclobarbital C2H5 H O

The barbiturate name is improper,


can be applied for salts only. Uses Hypnoval (narcotic, medium)
are against insomnia (usually not for
surgical uses).
Barbituric acid itself is without Hexobarbital CH3 CH3 O
effects.
Novopan (parapulmonar narcotic agent)

}
long
medium
The efficient
period depends
Phenobarbital C 2H 5 H O
short on the excretion
ultrashort Sevenal (narcotic, long, antiepileptic agent)

CH2 CH3
Inactin C2H5 CH H S
CH3
Venobarbital (parapulmonar narcotic agent)
O O O
C OEt C OEt C OEt
1. OEt 1. OEt R1
1 C
C H2 1 R CH 2 2
2. R X 2. R X R
C OEt C OEt C OEt
O O O

R O
H N 1
R
R
1 COOEt C2H5ONa R
C X N
2 C + 2
R COOEt EtOH R
H N
-2EtOH O N X
H H
R = H, CH3 H 3O
X = O, S, NH (X = NH)

R NH O
HN 2 2
1 CN C2H5ONa R R HO R R
R N 3 N
2 C + C X 1 1
R COOEt R (X = NH) R
H 2N
R = H, CH3 O N X O N O
H H
X = O, S, NH barbituric acid
derivative
O O
R CH CH (CH2)n CH2
OEt OEt
+ R CH CH (CH2)n CH2 X
O OEt O OEt

O O
(CH2)n-1
OEt OEt
+ X (CH2)n X H2C
O OEt O OEt

O O O O
EtO OEt EtO OEt
+ X (CH2)n X + (CH2)n
EtO OEt EtO OEt
O O O O

O O O O
EtO OEt EtO OEt
+ O C (CH2)n C O + CH (CH2)n CH
EtO H H OEt EtO OEt
O O O O
NH2 NH2
H2N
H2N X

X: O, S, NH

CH3 CH3
CH3
N N
O
O N O N X
O OEt H H

O O O

OEt NH NH

O OEt O N O N X
H H

NH NH
C N
NH NH
C
N HN N HN N X
H H
Chemical properties
O
4
H
NH 5 N3 NH
H2
6 2
O N O N1 N
H H
pyrimidine 1,3-diazacyclohexane
active H

1. Pyrimidine is a weak base, pKa =1.3


It is able to participate in nucleophilic reactions:
OHCl; Cl H
2. Electrophilic reactions do not run.
3. Centre No 5 is the most reactive, it is an active methylene group in barbituric
acid. But it is impossible to run alkylation or arylation in centre No 5 of barbituric
acid after ring closure, since the alkyl or aryl group attacks the heteroatoms only.

O R H O
O C
NH R C NH
H
O N O O N O
H H
4. Resists oxidation: the substituents are oxidised only

O OH
CH3

N oxidation N

N KMnO4
N
5. There is tautomerism at hydroxy- and at aminoderivatives, e.g.,

barbituric acid dilactam- mainly this trilactam


pKa = 3 -monolactim is present
OH OH OH at pH4-6 O
The tautomeric equilibrium
N N N tautomers NH depends on temperature
and solvent strongly.
HO N OH HO N O O N O O N O Rate of N-alkylation is
H H H H higher, than rate of O-
alkylation.
trilactim is dilactim- Usually more than one
the main tautomer -monolactam H H H H
tautomer are present in
at highly acidic pH crystalline form, the actual
(pH=1 or less) main tautomer depends on
O O
the isolation conditions.
N mesomers N

O N O O N O
H H

N N NH
X = O, S, NH
N X N XH N X
H

polar medium gas phase


Benzocondensed derivatives of pyrimidine

O H2N O OH
Cl
+
OH HN H NH PCl5
N
N
formamidine
NH2 N N
N

HI red.
O OH

HO N N KMnO4, H2O N
HO KOH ox.
N N N
O quinazoline
S
+ C H
NH2 N S N SH
S
NH2 NH NH
2-aminobenzyl-amine

+ C
Br
N
H
N NH2
NH3
N
(CH3)2SO4/NaOH

S CH3
} dihydro derivatives

N NH
NH2 NH NH NH NH2
NaOEt / EtOH
+ H2N NH2
OH NH N
NH
O O O

Cl S

NH2 NH2 NH S
LiAlH4/THF Cl CH3I
NH2 NH2 Et2O NH EtOH
(anhydrous)
- 2HCl
O
R1
R1
I HN
NH S CH3 N N
R2
R2
NH - CH3SH NH
- HI
More important derivatives
O NH2 O
H 3C
NH NH NH
pyrimidine bases
N O N O N O
H H H
uracil cytosine thymine
RNA RNA DNA
DNA

7H-purine derivatives
7
O R1 R2 R3
1 R
R xanthine H H H
N
N
theophylline CH3 CH3 H in Chinese tea

N theobromine H CH3 CH3 in cocoa beans


O N
3 CH3 CH3
R caffeine CH3 in coffee beans

Each compound can be found in all of these plants, but the main component is characteristic.
They have diuretic effect.
Synthesis of uric acid and of purine

These are compounds isolated in the XVIII. Century (Scheele, 1776). The following synthetic method for purine
was introduced by E. Fischer (1898):

O O O O
C NH C N OH
H2N RO CH2 (CH3CO)2O NaOH HN HO-N=O
) HN
+
C C C N SE
NH2 N O NH2 O N O O N NH
O H H
nitrosation of actíve
methylene group

O Cl
O
NH2 H N
Al, HCl HN H2N N POCl3 N
C O NH Cl
H2N O
O N NH2 N Cl N N
H O N H H
H
exists in tautomeric forms uric acid
I
H
HI/PH4I N Zn N N
N N N

N N N N N
I N H H
purine
Another synthesis of a purine derivative is Traube’s method (1900):

OH O
NH2 N
N H HN
C O
HO
H2N N NH2 H2N N N
H
guanine

O OH
H
NH N N
N

O N N HO N N
H
H
xanthine
Compounds with purine ring system

Synthesis of theofilline (Traube synthesis)

H3C O O O O
NH CH3 H3C H3C N O
RO C
C + CH2 NaOEt N CH2 N HO - NO N
O NH C
C
CH3 N O NH N O N NH2 O N NH2
CH3 CH3 CH3
O
O O
H3C NH2
red. N HO H3C H3C
+ N NH N NH
H
O N NH2 O
O N NH2 C H O N N
CH3 O
CH3 CH3
theofilline
Synthesis of theobromine (Traube synthesis)

O O
H 2N O
POCl3 / pyridine 1) NaNO2 / acetic acid NH2
C HN HN
O NH + HO
heating 2) (NH4)2 S (reduction)
CH3 C O N NH O N NH2
N CH3 CH3

O O CH3
H
H 2N N (CH3)2SO4 N
HN HN
C H H
O
O N N CH3OH / HO O N N
boiling H2O, 60 o C CH3
CH3
theobromine
2. Cl N N
Cl 3.
SN reactions N N
H
1. Cl
6 H
1 5 N7 N N More important derivatives:
N 8 - guanine
2
N 4 N9 N N9 - adenine
3 H - xanthine
(7H)-9H-imidazo[4,5-d]pirimidin - theofilline
(unusual, biogenetic numbering) - theobromine
Purine - caffeine
9H-purine derivatives purine bases

NH2 O OH

N N N
N N N

N N N N
N H2N N H2N H
H H
H
adenine guanine
RNS RNS
DNS DNS

Vitamin B1 Thiamine, aneurine

Cl
CH2 CH3 Eykmann (1896); absence of it may
N N cause disease beri-beri.
It was isolated at first by Funk from rice
H 3C N NH2 S CH2CH2OH bran. Peeled rice may cause beri-beri.
HCl
It gives positive thiochrome reaction
Pteridine and its derivatives
O
folic acid COOH
OH C
4 5 NH C H
N N CH2
3
N 6 N CH2
N
2 7 H CH2
N N H2N N N
1 8 COOH
pteridine pterine part p-aminobenzoic acid L-glutaminic acid

pteroyl group

Folic acid is an important vitamin: its N-formyl derivative builts the C1 unit in biosyntheses

O O
e c
f N d N N
N NH NH
g b
N N a N N O N N O
H H
benzo[g]pteridine alloxazine isoalloxazine

HO CH CH2 OH CH2OH
3
CH2 HO C H
8 9 1
H3C N 2 O HO C H
7
HO C H
6 NH
H3C N 3
5 4 CH2OH
10
O
Vitamin B2 ribitol
take place by prosthetic groups of enzymes
(flavoproteide enzymes, e.g., FAD)
Compounds with pyrimido-pyrimidine ring system

COOCH3 H 2C
HN N anhydrous toluene
+ pyrimido-pyrimidine skeletone
S N CH3 N boiling
H
CH3

COOCH3 COOCH3
HN N HN N
stereoisomers
S N N S N N
H CH3 H CH3
CH3 CH3

regioisomers regioisomers

H3COOC CH3 H3COOC CH3


N N
HN HN
stereoisomers
N N
S N S N
H CH3 H CH3
Pyrazine and its derivatives
H H H
Cl Cl N N N
NH3 HCl
+
EtO OEt EtO OEt EtO OEt HO OH HO O OH
O O O O
chloroacetaldehyde diethylacetal Et Et H H

H
NH2 H 3N N
heating
-2 NH4Cl
NH3 H 2N N piperazine
H

N N
SN
Y
N N Y
SE
Y
R NH2 O R' R N R' R N R'
dehydrogenation

R NH2 O R' R N R' R N R'


Benzocondensed derivatives of pyrazine

O
NH2 O H N N
KMnO4 HO
+
HO
NH2 O H N N
o-phenylene diamine glyoxal quinoxaline O

NH2 O CH3 N CH3


+

NH2 O CH3 N CH3


o-phenylene diamine dimethylglyoxal 2,3-dimethylquinoxaline

O
O
N NH2 N
O
dyes
N NH2 N
o-benzoquinone phenanthrene quinone
phenazine

dibenzophenazine
Compounds with two different
heteroatoms
I/ Oxazine and its derivatives
4 4 4
5 3 5 3 5 3

6 NH 6 6
2
N2 N
2
O O O
1 1 1

2H-1,2-oxazine 4H-1,2-oxazine 6H-1,2-oxazine

4 4 4
5 5
N3 N3 5
N3
6 2 6 2 6 2
O O O
1 1 1

2H-1,3-oxazine 4H-1,3-oxazine 6H-1,3-oxazine

4 4
N N 3
5 3 5
Further derivatives: benzocondensed
6 2 6 2 derivatives
O O partially saturated derivatives
1 1
2H-1,4-oxazine 4H-1,4-oxazine
H
NH3Cl H 2N N

+
OH HO O
dibenzo-1,4-oxazine
phenoxazine
CH3O
O
CH3O C
+ Cl
N H CH3O CH3O O
N 3,4,5-trimethoxy-
HCl
benzoyl chloride CH3O C N O
O O O NR3 CH3O
H H morpholine
4-(3,4,5-trimethoxy-
NH3
ClCl benzoyl)-morpholine

NH N
1 2 1
R R R O R
RO OR O

acetals of β-acetyl-
aminoketones
II/ Thiazine and its derivatives

4
4 4 4 H
3 N N 3
5 5 N3 5 3 5

6 6 2 6 2 6 2
NH
S 2 S S S
1 1 1 1

2H-1,2-thiazine 2H-1,3-thiazine 2H-1,4-thiazine 4H-1,4-thiazine

O OH cepham skeletone -NH2


O C
O 7- amino-cephalosporanic acid
CH3-C-OCH2
N
O
O
S NH C CH2 CH2 CH2 CH C
OH
NH2

Cephalosporin C antibiotic drug


Cephalosporium fungi species

Antibiotics: microorganisms (fungi) are producing against other microorganisms (bacteria)


10
9 H 1
H
N N 2 many important drugs have
o 8
120 C phenothiazine ring system
7 3
+ S (neuroleptics,
6 S 4 anthelmintic agents)
5

phenothiazine

CH3
Na
H CH2 CH2 CH2 N
N Cl N Cl CH3
N Cl
NaNH2 Cl (CH2)3N(CH3)2
S 120o C
S
S
chloropromazin (Hibernal, Largactil,
Plegomazin)
neuroleptic drug

OCH3
O
O CH3
C CH2 N CH2 CH2 CH2 N N CH2 CH2 O C OCH3
CH3
N N
OCH3

S S

Ahistan (antihistaminic Frenolon (original Hungarian drug)


agent) neuroleptic drug
prepared at first by O. Clauder

There are phenothiazine dyes (methylen blue), and other benzocondensed derivatives.
Compounds with three heteroatoms
I/ Triazines
4
4 4
5
N 3 3
N3 5 5
N N
6 6 6
N2 N2 2
N N N
1 1 1

1,2,3-triazine 1,2,4-triazine 1,3,5-triazine / sym-triazine


(vicinal) (asymmetric) (symmetric)

NH2 N N 6 R NH2 NH2


3 HN C 3 HN C
H H
N
formamidine
6 NaNH2
OH
NH2 3 Na2N CN
+ N
sec. amines
HO N NH2 + 6 RX

N NH

N N
purine
OH O

N N HN NH
3 HO CN
cyanic acid HO N OH O N O
H
cyanuric acid
Cl

N N HO
3 Cl CN
cyanogen chloride Cl N Cl
NH R
3 RNH2
cyanuric chloride
N N

R NH N NH R

H2N C N NH2
addition
Ca N C N H2N C N H2N C NH C N H2N-CN N N
calcium cyanamide cyanamide NH
H2N N NH2
dicyandiamide
melamine
important raw material of plastic industry

HCHO

aminoplast
polymers
Cl

Cl Cl NH
NH O
H2N C NH CN H C OH N N

N
NH2 NH C NH C NH2 Neourofort
diuretic agent
NH NH
prepared by O. Clauder at first

Cl N

3 N
N N H N N triethylenemelamine
against leukaemia, leucosarcoma
Cl N Cl N N N [2,4,6-tris(aziridin-1-yl)]-1,3,5-triazine
II/ Thiadiazines
5 4
H
6
N 3
Cl N
hydrochlorothiazide
O diuretic agent
7 NH NH
S 2 H 2N S S
8 1 O O
O
2H-1,2,4-benzo[e]thiadiazine

Cl NH2 Cl NH2 Cl NH2


Cl SO3H NH3

ClO2S SO2Cl H2N O2S SO2 NH2

H
O
Cl NH2 Cl N O
H 2N C NH2 CH3I
N
H2N O2S SO2 NH2 H 2N O 2 S SO2 H

H
Cl N O Cl NH2

N OH
H2N O2S SO2 CH3 H 2N O 2S SO2 NH CH3

R CHO

H
Cl N R

N
H2N O2S SO2 CH3
Cl NH2 Cl NH CHO Cl N
HCOOH
N
H2N O2S SO2 NH2 H2N O2S SO2 NH2 H2N O2S SO2 H

Cl NH2
HCHO H
H2N O2S SO2 NH2 Cl N

N
H2N O2S SO2 H
Cl N NaBH4

N
H2N O2S SO2 H
Compounds with four heteroatoms
I/ Tetrazines

H2S red. CH
N N N NH N H2N
N N N NH N
H2O2 ox. CH H2N

-2CO2

O O OK O OH
EtOC
CH N
KOH N NH H N N
N N
N NH ox. N N
N CH
COEt
O OK O OH
O

N
N N

sym. tetrazine
Heterocyclic compounds with
seven- and eight-membered
rings and their derivatives
Heterocyclic compounds with seven-
membered rings
Nomenclature, some important derivatives

1 1 1 1 1
1 H 2
O 2 S N 2 O 2 S 2 Y
2
O S NH
3 3 3

oxepane thiepane azepane 1,2-dioxepane 1,2-dithiepane Y=O 1,2-oxazepane


Y=S 1,2-thiazepane

H
1 1 1 1 1
1 H 2
O 2 S 2 N 2 N N 2 N
2
3
3 3
H
4 4
5
H
oxepine thiepine 1H-azepine 2H-azepine 3H-azepine 4H-azepine
H H H
1
2 1 2 1 1 2
Y N N 2 N
N N
3
3 3 3
N
5
N4
Y=O 1,2-oxazepine 1H-1,2-diazepine 1H-1,3-diazepine 1H-1,4-diazepine
Y=S 1,2-thiazepine

10 11
R Name
9 1

CH3 imipramin
8 2
(CH2)3N antidepressant
7 N 5 3 CH3
6 4
R
carbamazepine
C
dibenzoazepine antiepileptics
derivatives O NH2
10,11
Benzodiazepine derivatives
Sedatohypnotica

CH2CH3 CH3
1 O
6 5 4 CH3 9 NHCH3 1
7 N N
CH3O 2
8
N3 3
7

CH3O 8 N2 Cl 7
5 N Cl N4
9 1 6 4
O

chlorodiazepoxide diazepam
tofisopam
Elenium Seduxen
Grandaxin OCH3 Librium Valium
OCH3

CH3
1 H O O
1
N N

7 7

NO2 N4 Cl 5 N
O
nitrazepam clobazam
Eunochtin Frisium

Grandaxin: anxiolitics free from sedative side-effects (e.g., it can be administered before driving)
(J. Kőrösi at GYKI, EGYT, 1966. Hungarian patent)
Preparation

CH3O CH2CH3 CH2CH3

CH3O CH3
CrO3
CH3O CH3
CH3COOH / H2O O
CH3O O

OCH3

OCH3
OCH3
diisohomogenol H3CO

1/ H2N NH2 . HX

2/ HO

CH2CH3
CH3
CH3O

CH3O N

tofisopam
Grandaxin
OCH3

H3CO
CH3 CH3 O CH3

NH H N N
N Cl
+
Cl H
Cl Cl H2N O NH

POCl3
P2O5

CH3

Cl N

medazepam
Rudotel
O EtO O H O
NO2 NO2 N
EtO C PCl5 C
Zn/HCl
+ CH2 CH2
Cl NH HO C Cl N C N
O O O

O O NaOCH3
EtO C EtO C CH3Br
PCl5
CH2 CH2
HO C Cl C
CH3
O O O
N

N
O
clobazam
Frisium
O
C Cl H O
NH2 N C
ZnCl2
2 + 2
Cl Cl

H
C N
O
Cl

H OH
N N

N H 3O
Cl O H N Cl
HO
Cl
Cl

NH2 O

O + OH
Cl H 2N

Cl
Cl O
NH2 NH2 C CH2Cl NH C
CH2Cl
H2NOH O
O NOH NOH
Cl - H2O Cl - HCl Cl

- HCl
H CH3
NH
N CH2NHCH3 N Cl
N CH2Cl
+ CH3NH2
N N N
Cl Cl
O - HCl Cl
O - CH3NH2 O

NHCH3
N C
CH2Cl

Cl NOH

CH3
H
H NH N
N N CH3
Cl

Cl N Cl N
O O

Chlordiazepoxide
Br O

H O 4 H O H O
N N Br 4
5 NH2 N 5
3 3
6 6
2 2
7 SH 7
OH CH3 O S
O
1 CH3 1

1,4-oxazepine derivative 1,4-thiazepine derivative

O R
R H
NH2 + N O OH H2N O N
+
O R Br
SH + S SH S
Br
SH SCH2COOH S
SOCl2
+ ClCH2COOH O
NH2 NH2
NH
O O O

SH SCH2CH2NH2 S
+ BrCH2CH2NH2
O O
N
Ph Ph Ph

O R R
SH S
+
NH2 RO N
O H O
CH3
N
O N
O CH3 C
C
N Cl N NH Cl
+
S N S
H

O POCl3
Cl C Cl
CH3
NH2 Cl clothiapin
N
antipsychoticum

S N
N
Cl

S
H 3C CH3
N

O O
H O
N (CH3)2NCH2CH2Cl N
OH (CH3CO)2O OCCH3

S K2CO3 S

OCH3 OCH3
diltiazem
antihypertensive agent
for treatment of heart disease
and antiarrhythmics
Heterocyclic compounds with eight-
membered rings
Azocane / Diazocane derivatives
Thiocane derivatives
CH2 CN CH2 CH2 NH2
NH N N
Cl CH2 CN LiAlH4
- HCl

azocane NH2
H3C S C HSO4
NH2
- CH3SH
S-methylthiuronium
hydrogensulfate

NH
CH2 CH2 NH C
N NH2

guanethidin
blood pressure reducing
(antihypertensive) agent

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