Introduction
In the present post, I will describe the aldol condensation reaction between vanillin (4-hydroxy-3-methoxy benzaldehyde) and methyl-ethyl-ketone (2-butanone) to yield the product (E)-1-(4-hydroxy-3-methoxyphenyl)pent-1-en-3-one. The overall reaction can be summarized as follows:
The reaction mechanism is simple and completely identical to the one discussed in my previous post on the Vanillin-acetone aldol condensation. An enolate ion is formed from the deprotonation of the 2-butanone molecule that, by nucleophilic attack to the carbonyl carbon of the non-enolizable vanillin molecule, gives rise to the aldol addition product. Once the beta-hydroxy carbonyl intermediate is formed, an elimination reaction, following an E1cB mechanism, can occur yielding the final highly conjugated compound.
The main difference in this case is represented by the regiochemistry of the reaction that, due to the asymmetric nature of the ketone, can in principle lead to different enolates and, consequently, to different final products. The two hypothetical enolate species that can be formed are represented in the following picture:
The first enolate (1), let’s call it the kinetic enolate, is formed by deprotonation of the methyl group that is less hindered; the second enolate (2), let’s call it the thermodynamic one, is formed by deprotonation of the methylene group and leads to the more substituted alkene-like structure. Under the conditions followed in the procedure described in this post, only the product derived from the “kinetic” enolate is observed.
Experimental part
In an Erlenmeyer flask, 1g of vanillin (6.57mmol, 1eq) is dissolved in 10mL of methyl-ethyl-ketone (110mol, 16.9eq) to give a clear transparent solution to which 10mL of distilled water are added. The addition of water, which induces the formation of a cloudy solution, is followed by the addition of 0.6g of sodium hydroxide (50.0mmol, 7.6eq) which removes the cloudiness and imparts to the solution a yellow/greenish tint. The mixture is left to react under constant stirring for almost 24h at the end of which the solution has assumed a deep orange/brown tint.
To recover the product different attempts have been made in order to obtain a proper crystallization of the product and avoid the formation of an amorphous dark oil. This is not uncommon for this reaction as it has already been discussed in the previous post about the aldolic condensation of vanillin with acetone. The following procedure appears to work reasonably well but a more refined method must be developed.
To the reaction mixture, 100mL of water and 2g of sodium chloride are added. After dilution, the neutralization of the base is initiated using a diluted phosphoric acid solution obtained by diluting 0.6g of concentrated 85% phosphoric acid (5.20mmol, 0.8eq) in 10mL of distilled water. The addition reduces the orange reflexes of the solution imparting a less bright brownish tint to the reaction mixture. Using a solution of hydrochloric acid obtained by diluting 5mL of concentrated 35% acid in 50mL of water the pH of the solution is adjusted until slightly acidic. The formation of yellow crystals is observed with only a modest presence of amorphous blackish oil. The ionic strength of the solution is increased by adding 4g of sodium chloride and the neutralization of the solution is completed using the same hydrochloric acid solution from before. With this approach, the majority of the product is recovered as yellow crystals with minor black oil contamination allowing for easy separation by filtration.
The product was not recrystallized and directly analyzed by 1H and 13C-NMR.
1H-NMR Spectrum
The 1H-NMR spectrum has been recorded using a 500MHz instrument dissolving the sample in chloroform-d. The spectrum is consistent with the molecule deriving from enolate (1) with a triplet at 1.16ppm and a quartet at 2.68ppm compatible with an ethyl group adjacent to a carbonyl group. The singlet at 3.92ppm can be assigned to the protons of the methoxy group directly connected to the ring while the broad singlet at 6.02ppm belongs to the alcoholic proton of the phenol exchanging with the solvent. The trans protons located on the two sides of the double bonds are responsible for the two doublets of peaks at 6.60ppm and 7.49ppm split with a large coupling constant of 16.1Hz. The higher shift can be associated with the proton in $\beta$ to the carbonyl due to the resonance coupling of the electronic structure of the double bond to the carbonyl system. The other aromatic protons fall, together with the residual signal of chloroform, around 7ppm. The fine structure of the aromatic groups of peaks suggests that the doublet of peaks at 7.05ppm is associated with the isolated proton in position 2′ of the ring which is coupled, with a small coupling constant of 1.7Hz, to the proton in the 6′ position. The multiplet associated with the latter falls at 7.09ppm and, thanks to the stronger coupling with the adjacent proton in position 5′, assumes the form of a doublet of doublets. Finally, the doublet of peaks at 6.92ppm can be associated with the proton in position 5′. The residual peaks are either associated with the solvent (as the peak at 7.26ppm associated with chloroform and the broad signal around 1.7pmm associated with water) or small quantities of impurities.
1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 16.1 Hz, 1H), 7.09 (dd, J = 8.2, 1.8 Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 16.1 Hz, 1H), 6.02 (s, 1H), 3.92 (s, 3H), 2.68 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz, 3H).
13C-NMR Spectrum
The interpretation of the 13C-NMR spectrum is less trivial. Firstly, as can be seen, excluding the small peak at 29.69ppm, probably associated with an impurity, a total of 12 peaks are observed as expected. The peak at 201.15ppm can be associated with the carbonyl carbon while the peaks at 8.38, 33.75, and 55.96ppm are probably associated with the carbons of the ethyl group and the methoxide group on the ring. The other peaks in the region going from 110ppm to 150ppm are associated with the benzene ring and the double bond. Assigning these peaks is however not trivial based on the information available and of little diagnostic interest.
