Understanding the Aldol Condensation Reaction Using NMR

The Thermo Scientific picoSpin 45 NMR spectrometer is a useful tool for teaching through the aldol condensation reaction. In a number of undergraduate organic teaching programs, probably the first exposure that students have to NMR as an analytical tool is the aldol condensation reaction.

Aldol Condensation Reactions

Aldol condensation reactions signify an essential class of reactions for the formation of carbon-carbon bonds. An aldol reaction involves the condensation of two carbonyl compounds to form a ß-hydroxyaldehyde or ß-hydroxyketone, the aldol product.

The typical aldol reaction involves self condensation of the reactant ketone or aldehyde wherein one molecule adds to the other of the same type. An example of a self-condensation aldol reaction is shown in Figure 1, with acetaldehyde as the sole reactant.

Here 3-hydroxybutanal is obtained by adding acetaldehyde to another acetaldehyde reactant molecule to form the aldol (aldehyde-alcohol) product.

Figure 1. Aldol self-condensation of acetaldehyde

Under base-catalyzed conditions the aldol reaction proceeds through an enolate ion as shown in Figure 2.

Figure 2. Base-catalyzed production of the enolate ion in the aldol self-condensation reaction (R = H, alkyl, phenyl)

The resonance stabilized enolate is then subjected to nucleophilic addition to the carbonyl carbon of another aldehyde or ketone molecule, forming a new C-C bond and an alkoxide ion as shown in Figure 3.

Figure 3. Nucleophilic addition of enolate anion to the carbonyl group (R = H, alkyl, phenyl)

In the next step ß-hydroxy aldehyde or ketone is formed by reaction with water, and the reaction is completed by dehydration of the alcohol group in a strong base, resulting in the loss of water and the formation of an α,ß-unsaturated product as shown in Figure 4.

Figure 4. Formation of the aldol product and dehydration to an a,ß-unsaturated carbonyl product

Similar self condensation reactions take place for ketones and derivatized ketones and aldehydes as long as there is an enolizable proton at the a carbon position.

Crossed aldol reactions between ketones and aldehydes form mixed condensation products. One compound’s enolate ion is subjected to nucleophilic addition to the carbonyl carbon of a different compound. Normally crossed condensation products are not desirable as they cause a mixture of products and bring down the yield of a desired product.

Figures 5 and 6 show a case where an aromatic benzaldehyde, aldehyde, is substituted for the alkylaldehyde as a reactant.

Figure 5. Crossed aldol condensation reaction, producing the a,ß-unsaturated ketone dibenzalacetone

Figure 6. Crossed aldol condensation reaction, producing the a,ß-unsaturated ketone chalcone

Derivatives of the parent reactant molecules acetophenone and benzaldehyde can include a range of R, R¹ and R² functional groups, such as methyl (-CH₃), methoxy (-OCH₃), chloro (-Cl), bromo (-Br), amino (-NH₂), hydroxy (-OH), nitrile (-CN), etc. and in a number of positions round the phenyl ring. The hydroxy group will show concentration, temperature and solvent polarity dependence that complicates interpretation.

Also there are complications in the amino group spectrum because of spin coupling of the proton with the nitrogen nucleus, the varying exchange rate of the labile amino proton and the electric quadrupole moment of the 14N nucleus.

A new peak in a proton NMR spectrum is not introduced by halogen substitution but will impact splitting patterns and peak position on the aromatic protons. Only the methoxy and the methyl groups introduce non-overlapping, new resonance lines in the parent molecule spectrum enabling straightforward interpretation.

¹H NMR – A Qualitative Lesson

It is a simple task to identify the key peaks in the ¹H NMR spectra of the reactants in the aldol reactions of Figures 5 and 6. Both the methyl ketone and aldehyde protons produce only one resonance line each, hence making them easy to monitor. NMR spectra can be determined on pure samples or by using using an aliquot of the reaction mixture.

The picoSpin 45 NMR spectrometer is suitable for initial qualitative analysis of neat mixtures and samples providing students the chance to determine the quality of their starting materials, establish the mixture’s stoichiometry, identify the main functional groups undergoing chemical transformation and obtain valuable hands-on experience using NMR in the lab.

Since the capillary cartridge can be easily flushed and refilled, it can be used using a three to four hour organic chemistry experiment. The reaction mixture of students can be sampled several times at a number of stages through the experiment, obtaining spectra as the reaction proceeds and determining a spectrum of the isolated product. ¹H NMR spectra shown here were obtained with a 90-degree pulse angle, 750 ms acquisition time, 10–20 s recovery delay, and an average of 9 or 49 scans.

Figures 7 and 8 show spectra of reactants 4-methoxybenzaldehyde and 4-methylbenzaldehyde. The aldehydic proton produces a lone signal because of a lack of the neighboring proton. Diamagnetic anisotropy results by circulation of p electrons of the carbonyl (C=O) bond induced along the transverse axis by the applied field, resulting in strong e-shielding of this lone proton.

Figure 7. NMR spectrum of 4-methoxybenzaldehyde (neat, 25 scans)

Figure 8. NMR spectrum of 4-methylbenzaldehyde (neat, 25 scans)

This information has been sourced, reviewed and adapted from materials provided by Thermo Fisher Scientific – Materials & Structural Analysis.

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