Thomas Adam Fleming 24176354 taf1g10@soton.ac.

uk Date of practical work: 9th March 2012 Date of report submission: 16th April 2012 Chemoselectivity Aim: The chemoselective synthesis and conformational analysis of two organic compounds

Synthesis A Reaction Scheme:

Experimental Details: The ketone starting material (5 mmol, 1.37 g) was dissolved in THF (12 mL) under stirring. tert-butyl acetoacetate (Potassium hydroxide (40 % w/b, 12 drops) was added to the reaction mixture which was pale yellow in colour. The reaction was set to reflux and turned darker in colour over time. The reaction was monitored by TLC (35 % Et2O / Light petroleum ether):

TLC at t = 45 min Conclusion: Reaction Incomplete

TLC at t = 75 min Conclusion: Reaction complete

All spots were visible under both UV light and following permanganate oxidation. The reaction was terminated after 90 min, the bulk of the solvent removed in vacuo (rotary). The final solvent was removed under high vacuum causing the oil to become an orange foam which was recrystallised from methanol.

Yield: Crude 1.459 g, 3.5 mmol, 71 % Recrystallised 1.06 g, 2.58 mmol, 52 % The recrystallised product was pale and dull in appearance. Melting point: 149.5 151.8 C An IR spectrum was also obtained.

Mechanism of Formation of Compound A:

IR Analysis

/ cm-1 2983 1724 1651 1618 1509 1227

Cause of absorption C-H stretch -CO-O- stretch C=O stretch C=C stretch C=C stretch C-F stretch

Inference Unfunctionalised CH3 groups of tertbutyl Ester Ketone group, lower frequency stretching vibration due to extensive conjugation Carbonyl-conjugated double bond Conjugated aromatic C=C bond Fluorinated compound

The IR spectrum concurs with the proposed structure. Notably, the shift in the ketone carbonyl stretching frequency due to conjugation.

Question 4 Possible products and their mechanistic formation:

Compound D would arise from the formation of deprotonation at the most acidic position (central between the dicarbonyl electronwithdrawing groups) of the tert-butyl acetoacetate to produce a nucleophilic enolate which would attack from the carbon atom central to the dicarbonyl moiety in a 1,4 (conjugate or Michael) fashion at the carbonyl-conjugated double bond of the fluorinated diphenyl compound. Two of these conjugate additions at each double bond, each followed by a reformation of the central carbonyl group through protonation then ketoenol tautomerism would yield compound D.

Distinguishing Spectroscopic Features: IR: Higher wavenumber ketone absorption due to absence of conjugation. 1 H NMR: Absence of geminal/vicinal proton coupling due to absence of non-aromatic rings 13 C NMR: Lower field shift of ketone carbon nuclei due to reduced shielding from absence of conjugation

Compound D is not formed since following the first Michael addition, the intra-molecular enolate attack is by far the more favourable addition since it forms a six-membered ring and is also more likely to occur on an entropic basis since the proximity of an nucleophile within a molecule is more likely to be in a suitable orientation for attack than a separate nucleophile suspended elsewhere in the reaction mixture. Alternate Aldol/Michael Products: Aldol self-addition of acetoacetate compound:

Aldol addition of tert-butyl acetoacetate to fluorinated compound:

Compound B: Reaction Scheme:

Experimental Details: Compound A (0.5 g, 1.22 mol) was dissolved in dioxane (2.5 mL). Concentrated hydrochloric acid (15 drops) was added and the reaction mixture set to reflux over a Bunsen burner for one hour. The reaction was monitored by TLC which was accomplished with mini-workup, partitioning the reaction mixture between diethyl ether and water:

TLC Monitoring (35 % Et2O / Light petroleum ether):

All spots were visible under both UV and after oxidation with KMnO4. Unusual contaminant observed in starting material, although several repeats with fresh eluent and TLC equipment failed to remove this anomaly. Conclusion: Reaction complete. The reaction was allowed to cool, treated with water (5 mL) and the resulting oil purified via trituration then recrystallised from methanol, filtered and dried under vacuum. Yield: 0.591 g, 1.26 mol, 103 % The impossibly high yield is likely due to the presence of methanol which resulted from an unsuccessful recrystallisation. The product was submitted as a gum which crystallised 48 h later, but still had the same mass. MP:

Mechanism:

IR Analysis

/ cm-1 1641, 1617 1575 1507 1228

Cause of absorption C=O stretch C=C stretch C=C, aromatic C-F stretch

Inference Conjugated ketone, ,-unsaturated ,-unsaturated, carbonyl conjugated Aromatic ring Fluorinated compound

The IR spectrum indicates a compound which is consistent with the proposed structure based on mechanistic analysis. The absence of ester absorption bands is indicative of the expected chemical transformation.

H NMR Compound B (CDCl3, 400MHz)

Compound B 3D (left) and flat (right) representations /ppm 7.49-7.45 7.30-7.26 7.10-7.05 7.00-6.96 6.88-6.84 6.17 3.43-3.35 3.01-2.95 2.77-2.72 2.70-2.60 Integral 2H 2H 4H 1H 1H 1H 1H 1H 1H 2H Multiplicity dd dd t d d d m dd dd m
3 3

Coupling Constant/Hz
3

Inference H1 H2 H3 H4 H5 H6 H7 H8 H9 H10 / H11

JH1-H3 = 8.5, 4JH1-F = 5.5 JH2-H3 = 8.5, 3JH2-F = 5.5

JH3-H1/2 = 8.5, 3JH3-F = 8.5

3

JH4-H5 = 16.1 JH5-H4 = 16.1

JH6-H5/11 = 1.5 N/A

JH8-H7 = 4.8, 2JH8-10 = 17.3

JH9-H7 = 4.5, 2JH9-11 = 16.1 N/A

Conclusion: Synthetically, the experiment was successful bar the slow crystallisation of compound B. Analysis of spectroscopic data supported the mechanistic predictions of products formed.

REFERENCES: 1. D. Williams, I. Fleming, Spectroscopic Methods in Organic chemistry, 2002, p 33-41/ 71-76/ 103-111 2. P. Wothers, N. Greeves, S. Warren & J. Clayden, Organic Chemistry, 2008, p 703.