Aldol Condensation

In many undergraduate organic teaching programs, the aldol condensation reaction is the first exposure students have to NMR as an analytical tool. While the technical aspects of executing the aldol reaction are not difficult, the analysis of products is more challenging since this is frequently a student’s first time using NMR instrumentation, interpreting NMR spectra and evaluating the outcome of their synthetic efforts. Because of the simplicity of its design and ease of use, the aldol condensation lab is a good entry point for applying the Thermo Scientific™ picoSpin™ 45 spectrometer in a teaching laboratory.

Aldol condensation reactions represent an important class of reactions for forming carbon-carbon bonds. In the aldol reaction, two carbonyl compounds are condensed to form a β-hydroxyaldehyde or β-hydroxyketone – the aldol product. The classic aldol reaction is a “self-condensation” of the reactant aldehyde or ketone where one molecule adds to another of the same type. An example of a self-condensation aldol reaction is shown in Figure 1, using acetaldehyde as the sole reactant. Here, the aldol product, 3-hydroxybutanal, is the result of adding acetaldehyde to another acetaldehyde reactant molecule to form the aldol (aldehyde-alcohol) product.

Figure 1. Aldol self-condensation of acetaldehyde

When carried out under base-catalyzed conditions, the aldol reaction proceeds via an enolate ion (Figure 2). The resonance stabilized enolate then undergoes nucleophilic addition to the carbonyl carbon of another aldehyde or ketone molecule, forming a new C-C bond and an alkoxide ion (Figure 3).

Figure 2. Step 1 – Base-catalyzed production of the enolate ion in the aldol self-condensation reaction (R = H, alkyl, phenyl)

Figure 3. Step 2 – Nucleophilic addition of enolate anion to the carbonyl group (R = H, alkyl, phenyl)

The β-hydroxy aldehyde or ketone is then formed in the next step by reaction with water, and the reaction is finalized by dehydration of the alcohol group in a strong base, resulting in the loss of water and the formation of an α,β-unstaturated product (Figure 4).

Figure 4. Step 3 and 4 – Formation of the aldol product and dehydration to an α,β-unsaturated carbonyl product

Similar self-condensation reactions will occur for ketones, as well as derivatized aldehydes and ketones, so long as an enolizable proton at the α carbon position exists.

Crossed aldol reactions between aldehydes and ketones result in the formation of mixed condensation products. Here, the enolate ion of one compound undergoes nucleophilic addition to the carbonyl carbon of a different compound. Crossed-condensation products are usually undesirable since they result in a mixture of products, and reduce the yield of a desired product. Careful selection of starting materials where only one reactant has an enolizable α hydrogen can minimize the formation of mixtures. This is illustrated in Figures 5 and 6 where an aromatic aldehyde, benzaldehyde, is substituted for the alkylaldehyde as a reactant.

Figure 5. Crossed aldol condensation reaction, producing the α,β-unsaturated ketone dibenzalacetone

Figure 6. Crossed aldol condensation reaction, producing the α,β-unsaturated ketone chalcone

Derivatives of the parent reactant molecules benzaldehyde and acetophenone can include a variety 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 various positions around the phenyl ring. Due to intermolecular hydrogen bonding, the hydroxyl group will show temperature, concentration and solvent polarity dependence, which complicates interpretation. Similarly, complications will arise in the spectrum of the amino group due to spin coupling of the proton with the 14N nucleus. Halogen substitution does not introduce a new peak in a proton NMR spectrum but will affect peak positions and splitting patterns on the aromatic protons. Only the methyl and methoxy groups introduce new, non-overlapping resonance lines in the parent molecule spectrum, which affords straightforward interpretation.

1H NMR – A Qualitative Lesson

It is easy to identify the prominent peaks in the pre-synthesis 1H NMR spectra of the reactants in the aldol reactions of Figures 5 and 6. Both the aldehyde proton and methyl-ketone protons produce only one resonance line each, thus making them simple to monitor. NMR spectra can be measured on pure samples or using a portion of the premeasured reaction mixture.

The picoSpin 45 NMR spectrometer is ideal for preliminary qualitative analysis of neat samples and mixtures, giving students the opportunity to determine the quality of their starting materials, establish the stoichiometry of their mixture, identify the predominant functional groups which will undergo chemical transformation, and gain valuable hands-on experience using NMR in the lab. Because the picoSpin-45 sample capillary can be quickly flushed and refilled, it can be used repeatedly throughout the course of a 3-4 hour organic chemistry lab experiment. Students can sample their reaction mixture multiple times at various stages throughout their experiment, obtaining NMR spectra as the reaction proceeds and measuring an NMR spectrum of their isolated product. 1H NMR spectra shown below were taken with a 90-degree pulse angle, 750 ms acquisition time, 6 s recovery delay, and are an average of 16 or 36.

picoSpin-45 spectra of reactants 4-methoxybenzaldehyde and 4-methylbenzaldehyde are shown in Figures 7 and 8. The aldehydic proton produces a lone signal due to a lack of neighboring proton. Diamagnetic anisotropy arises from circulating π electrons of the carbonyl (C=O) bond induced along the transverse axis by the applied field, giving rise to strong deshielding of this lone proton. In the spectrum of 4-methoxybenzaldehyde, the aldehyde proton appears as a singlet at 9.90 ppm, while for 4-methylbenzaldehyde this same signal is at 10.08 ppm.


Figure 7. NMR Spectrum of 4-Methoxybenzaldehyde (neat, 16 scans).

The protons of the methoxy methyl group experience deshielding due to carbon bonding to an electronegative oxygen atom and shift down field, producing a singlet at 3.79 ppm. There are four aromatic protons that are in two different chemical environments, generating a characteristic doublet of doublets splitting pattern. Protons ortho (position 2 and 6) to the aldehyde are in the deshielding zone of the carbonyl bond, whereas protons in the meta position (3 and 5) move up field due to resonance shielding by the adjacent methyl ester.


Figure 8. NMR Spectrum of 4-Methylbenzaldehyde (neat, 16 scans).

Ring currents in the aromatic group produce similar anisotropy, deshielding the in-plane protons of the benzene ring. Lower symmetry, arising from asymmetric para disubstitution of the benzene ring, affects the chemical environment for protons in the ortho (2 and 6) and meta (3 and 5) positions, giving rise to a doublet of doublets signal. The ortho protons, further deshielded by the adjacent aldehyde group, appear down field (δ7.81), while the meta protons appear up field (δ6.95) with respect to a center frequency of δ7.38 – each proton being split by one nearest neighbor proton, giving rise to a doublet of doublets signal.

Integration of peak areas reveals an expected 1:4:3 proton ratio for both 4-methoxybenzaldehyde and 4-methylbenzaldehyde.


Figure 9. NMR Spectrum of Acetophenone (neat, 16 scans).

Like the substituted benzaldehydes in Figures 7 and 8, the proton NMR spectrum of acetophenone (Figure 9) exhibits multiple peaks in the 7.3-8.2 ppm region, but the splitting pattern is complicated by overlap of signals from five benzylic protons in three different chemical environments.  At first glance, the signal pattern in the aromatic region appears as a doublet of triplets signal, but closer scrutiny of the splitting pattern and asymmetric signal intensity reveals overlapping multiplicities. Protons in positions 2 and 6 are each split by neighboring protons in positions 3 and 5, producing doublet signals. The proton in the para position is split by two adjacent and identical protons into a triplet signal and overlaps strongly with the doublet signal from the meta protons. Ortho protons shift farther down field due to deshielding by the aldehyde group, and their  signal is resolved more easily.


Figure 10. NMR Spectrum of 4′-Methylacetophenone (neat, 16 scans, * impurity).

The three methyl protons on the ketone experience less shielding and shift to ~2.6 ppm, producing only a single peak. Peak area integration shows a 3:5 ratio. By comparison, the reactant acetone would produce a similar signal and chemical shift (s,δ 2.5) but with an integral area  equivalent to the six homotopic protons for the absorption peak.

Substitution by a methyl group in the para position in 4′-methylacetophenone (Figure 10) clears up issues with overlapping signals in the aromatic region, showing only ortho and meta protons being split by each other. Adding a methyl group on the benzene ring introduces an additional alkyl signal (δ2.34) near the keto-methyl signal (δ2.50), but this is clearly resolved in the spectrum.


Figure 11. NMR Spectrum of 4′-Methoxyacetophenone in CDCl3 (1.08 M, 36 scans).

Replacing the methyl substituent in the para position of 4′-methylacetophenone with a methoxy group in 4′-methoxyacetophenone (Figure 11) separates the two methyl groups by shifting the methoxy methyl downfield 3.79 ppm. The solid sample 4′-methoxyacetophenone was dissolved in CDCl3 at a concentration of 1.08 M and its spectrum, measured at 40 °C. Considering the concentration of the 4′-methoxyacetophenone solution and sample volume within the spectrometer’s RF coil, we are measuring signal arising from approximately 38 nano-moles of material. The crossed aldol reaction product trans-chalcone, derived from the combination of benzaldehyde with acetophenone is shown in Figure 12. The solid sample was dissolved in acetone-d6 containing 1% TMS at a concentration of 1.22 M. The spectrum consists of two overlapping signal groups; one set of signals arises from phenyl protons and a second set of signals from vinyl protons. The olefinic protons, Hα and Hβ, are positioned α and β to the carbonyl of this α,β-unsaturated ketone and appear at 7.50 ppm and 7.80 ppm. It is known that under normal solvent conditions the mesomeric effect produces inductive deshielding at the α-carbon position due to the electron-withdrawing effect of the carbonyl, and assignment of the low field signal at δ 7.80 to Hα is plausible. However, complexation of the α,β-unsaturated ketone in solvents such as DMSO-d6 gives rise to steric encumbrance, holding rigid the molecular confirmation and making Hα more accessible the phenyl ring; A similar effect may exist in acetone as well. This solvent effect causes an anomalous chemical shift whereby the Hα and Hβ protons exchange positions, placing the β proton downfield with respect to the α proton signal. Hence, unambiguous assignment of the two signals to either the Hα or Hβ protons is not possible without further analysis. Evidence of H-H coupling across the olefinic bond is difficult to discern due to heavy overlap with the phenyl proton signals.

Protons on the phenyl ring adjacent to the carbonyl group are expected to shift downfield relative to phenyl ring protons on the vinyl side. The low frequency doublet-of-doublets signal centered at 8.21 ppm thus belongs to the keto phenyl protons, while the high frequency signals centered around 7.54 ppm can be attributed to the vinyl side phenyl protons. Symmetric and asymmetric substitution at both the 4 and 4′ positions can simplify the aromatic region.

This simple analysis is an excellent opportunity for students to learn about substituent effects, splitting patterns, sample preparation and dilution.


Figure 12. NMR Spectrum of trans-chalcone in CDCl3 (1.22 M, 49 scan)


University of Colorado at Boulder Organic Chemistry Undergraduate Laboratory, (

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J-C. Lien, S-C. Chen, L-J. Huang and S-C. Kuo Solvent Effect of Dimethyl Sulfoxide on the Chemical Shifts of
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