NMR Spectroscopy in the Undergraduate Curriculum - American

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Chapter 7

Using NMR To Investigate Products of Aldol Reactions: Identifying Aldol Addition versus Condensation Products or Conjugate Addition Products from Crossed Aldol Reactions of Aromatic Aldehydes and Ketones Nanette M. Wachter* Chemistry Department, Hofstra University, Hempstead, New York 11549-1510 *E-mail: [email protected]

Crossed aldol condensation of benzaldehydes with acetophenone is typically part of an undergraduate organic laboratory curriculum. The experiment involves the reaction of the enolate of acetophenone with an aromatic aldehyde generating benzalacetophenone (chalcone). The initially formed β−hydroxyketone rapidly dehydrates to generate an α,β-unsaturated ketone, even under the basic conditions usually employed for the acyl addition reaction. Elimination is favored because of resonance stabilization of the fully conjugated product. However, in the reaction of 2′-hydroxyacetophenone with benzaldehyde, the partially saturated β−hydroxyketone intermediate initially formed can be isolated in moderate to good yield. In a similar experiment, when an excess of acetophenone is treated with 2-pyridine carboxaldehyde, the initially formed α,β-unsaturated ketone undergoes rapid Michael-addition with a second equivalent of the enolate to yield a symmetric diketone. The unanticipated products of both of these reactions contains diastereotopic methylene hydrogen atoms that are easily identifiable and well resolved in the 1H NMR spectrum. Moreover, a COSY experiment clearly demonstrates coupling between the methylene protons with

© 2013 American Chemical Society Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

one another and with the proton of the β-carbon. Each of these experiments highlights concepts taught in organic chemistry using techniques traditionally introduced in an introductory organic laboratory course.

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The Claisen-Schmidt Reaction The aldol addition reaction is an important synthetic method for the formation of carbon-carbon bonds (1–4), and aldol condensations are typically covered in the second semester of the organic chemistry curriculum. An indication of the importance attributed to this reaction is the frequency with which it appears on standardized organic chemistry examinations. In fact, every popular organic chemistry laboratory text has a crossed aldol condensation experiment between an aromatic aldehyde and the enolate of an aromatic ketone that generates trans-chalcone (1,3-diphenyl-2-propen-1-one), or a substituted chalcone (5–8). The Claisen-Schmidt condensation is a crossed aldol reaction between an aromatic aldehyde and either an aliphatic or aryl ketone that produces an α,β−unsaturated ketone (9, 10). Aromatic carboxaldehydes are popular substrates for the reaction because they lack an α−hydrogen and therefore cannot form an enolate anion. While the enolate of the acetophenone could potentially undergo self-condensation, the anion preferentially attacks the carbonyl carbon of the aldehyde because it is more electrophilic than the carbonyl of acetophenone. The crossed aldol experiment that is most typically performed generates an α,β−unsaturated ketone due to rapid elimination of water from the β−hydroxyketone initially formed, as depicted in Scheme 1. The condensation often occurs readily at ambient conditions because the resulting enone is conjugated with both benzene rings (11).

Scheme 1. Crossed aldol condensation of acetophenone with benzaldehyde 92 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Surprisingly, when benzaldehyde is treated with an ethanolic solution of the sodium enolate of 2′-hydroxyacetophenone, as depicted in Scheme 2, the major product obtained after 30 minutes at room temperature is the β−hydroxyketone and not the expected α,β−unsaturated ketone (12). A simple 1H NMR spectrum of the addition product demonstrates that the methylene protons on the alpha carbon are non-equivalent. Diastereotopic protons are not magnetically or chemically equivalent to one another and therefore can be readily observed with modern highfield magnets (13).

Scheme 2. Aldol condensation of 2′-hydroxyacetophenone with benzaldehyde

A more intriguing example of anisochronous methylene protons is observed in the product resulting from the coupling reaction between acetophenone and 2-pyridinecarboxaldehyde (14, 15). As depicted in Scheme 3, when 2-pyridinecarboxaldehyde is treated with the enolate of acetophenone, the major product isolated is the Michael adduct resulting from the reaction of a second equivalent of the enolate with the initially formed chalcone. If two equivalents of acetophenone and sodium hydroxide are used, the conjugate addition product can be obtained in nearly quantitative yield. In this reaction, the initially formed α,β-unsaturated ketone produced from the condensation of the enolate of acetophenone with 2-pyridinecarboxaldehyde rapidly undergoes conjugate 1,4-addition with the excess enolate to produce a symmetrically substituted diketone. The product, 3-(2-pyridinyl)-1,5-diphenyl-1,5-pentanedione, is achiral, yet the methylene protons of the aliphatic chain are nonequivalent as defined by the symmetry criterion of diastereotopic ligands (16).

Scheme 3. Crossed aldol condensation and Michael addition of acetophenone with 2-pyridinecarboxaldehyde 93 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Experimental Overview The synthesis of either compound can be performed in one laboratory period. In the reaction of 2′-hydroxyacetophenone with benzaldehyde, three equivalents of hydroxide are added to ensure that there is sufficient base present, since one equivalent of base will immediately remove the phenolic proton on the acetophenone. Acetophenone, benzaldehyde, 2′-hydroxyacetophenone and 2-pyridinecarboxaldehyde were purchased from Aldrich Chemical Company. The sodium hydroxide solutions were prepared ahead of time. Hazards Sodium hydroxide is caustic and causes severe burns. The concentrated solution should be handled with gloves and appropriate eye protection. Acetophenone, 2′-hydroxyacetophenone, benzaldehyde and 2-pyridinecarboxaldehyde are irritating to the eyes, respiratory system and skin. They should be dispensed in a hood and suitable protective clothing should be worn. Acetophenone, ethanol and benzaldehyde are combustible and must be kept away from sources of ignition. No flames should be present in the laboratory when the experiment is being performed. Hydrochloric acid is corrosive and causes severe burns. Appropriate eye protection should be worn when handling the acid solution.

1-(2′-Hydroxyphenyl)-3-phenyl-2-propenone 0.106 mL (1 mmol) of benzaldehyde is dissolved in 1 mL of 95% ethanol in a 5-mL conical vial equipped with a magnetic spin vane. While stirring, 0.132 mL (1.1 mmol) of 2′-hydroxyacetophenone is added to the reaction vial. An air condenser is attached and 0.500 mL of 6 M aqueous sodium hydroxide is carefully added to the solution. A bright yellow color develops. The mixture is stirred at room temperature for 30 min. During the reaction a light orange precipitate forms. The reaction is quenched by adding 0.5 mL of water then 3 M aqueous HCl dropwise until the mixture is at neutral pH. The solid is collected using a Hirsch funnel and the filter cake is washed with cold ethanol. Recrystallization from 50% ethanol affords the product.

3-(2-Pyridinyl)-1,5-diphenyl-1,5-pentanedione To a 5-mL conical vial equipped with a magnetic spin vane are added 0.10 mL (1.1 mmol) of 2-pyridinecarboxaldehyde, 0.26 mL (2.2 mmol) of acetophenone and 1 mL of 95% ethanol. The solution is stirred at room temperature and 1.0 mL of 2.5 M aqueous sodium hydroxide is added. The solution acquires a golden tint and a white precipitate develops. The mixture is stirred for 15 minutes at room temperature and then poured into a 10-mL beaker containing 2-mL of ice cold 94 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

water. The alkaline reaction mixture is neutralized by dropwise addition of 3 M aqueous HCl. The solid is collected by vacuum filtration and the filter cake rinsed with small portions of cold ethanol. Recrystallization from 95% ethanol affords the product.

Discussion


Aldol Reaction of 2′-Hydroxyacetophenone with Benzaldehyde The crossed aldol reaction between an aromatic aldehyde and ketone typically generates a β-hydroxyketone that readily dehydrates, even at room temperature, to produce a highly-conjugated α,β-unsaturated ketone. Base-promoted dehydration favors formation of a trans substituted double bond due to unfavorable steric interactions in the transition state for the formation of the cis alkene (Figure 1) (11).

Figure 1. Newman projections of aldol adduct conformations for base-promoted dehydration to produce a cis- or trans-alkene.

Under alkaline conditions, the reaction proceeds through an E1cB pathway in which deprotonation of the aldol addition product precedes elimination of the beta hydroxyl group (Scheme 4). In the reaction of 2′-hydroxyacetophenone with benzaldehyde, the ortho hydroxyl group of the addition product is believed to stabilize the enolate thereby slowing the elimination reaction (Figure 2). Since heat promotes dehydration, the chalcone can be obtained in good yield if the reaction is heated for 60 minutes. The two reaction products can be distinguished by their color; the chalcone is bright yellow, while the partially saturated β−hydroxyketone is colorless. 95 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Scheme 4. E1cB pathway for the dehydration of a β-hydroxyketone

Figure 2. Stabilized enolate anion of β-hydroxyketone intermediate. Perhaps of greater interest than the unexpected outcome of the reaction is the anisochrony of the methylene protons in the acyclic chain that connects the aromatic rings. 1H NMR analysis of the white solid obtained in this experiment reveals three signals between 2 and 6 ppm produced by the diastereotopic methylene protons of the α carbon and the β hydrogen of the β−hydroxyketone which are all coupled to one another (Figure 3). This is a classic ABX pattern; each of the three protons on the aliphatic chain gives rise to a doublet of doublets. Typically, rotationally restricted or chiral molecules are employed to depict diastereomerism in undergraduate laboratories (17–19). Indeed, the β carbon of the ketone is a stereogenic center, conferring magnetic anisochrony to the α-methylene protons of the aliphatic chain. Not only are the chemical shifts of the α methylene hydrogen atoms appreciably different from one another, but a rather significant coupling constant for the geminal protons is observed. The relatively large J value is due to π electron donation by the benzoyl moiety (13). It should be pointed out that coupling over two bonds, (i.e., geminal coupling) results in parallel spin polarizations and J, by convention, has a negative sign so 2JHCH = -17 Hz. Geminal couplings are dependent on the H-C-H bond angle and typically range from -5 to -20 Hz for alkanes (13). The vicinal coupling constants between each of the methylene protons with the α-proton are also significantly different resulting in the multiplicities of the hydrogen atom’s signal to appear as a doublet 96 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


of doublets. Splitting diagrams that depict proton-proton coupling are a useful instructional tool to illustrate the effect of the coupling constant magnitude on the multiplicity of the signal. A sample tree diagram that uses the absolute values of the germinal and vicinal coupling constants for the aliphatic hydrogen atoms of the β-hydroxyketone is shown in Figure 4 below.

Figure 3. 1H NMR spectrum of the alkyl region of 3-hydroxy-1-(2′hydroxyphenyl)-3-phenyl-1-propenone depicting the alpha protons at 2.84 ppm (1H, doublet of doublets, J = 17 and 3 Hz) and 3.15 ppm (1H, doublet of doublets, J = 17 and 13 Hz), and the beta proton at 5.62 ppm (1H, doublet of doublets, J = 13 and 3 Hz).

Figure 4. Tree diagrams depicting coupling between the aliphatic protons of 3-hydroxy-1-(2′-hydroxyphenyl)-3-phenyl-1-propenone. 97 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Figure 5. Aliphatic region of COSY of 3-hydroxy-1-(2′-hydroxyphenyl)-3-phenyl1-propenone demonstrating coupling between the geminal α-protons and the β-proton.

Figure 6. HETCOR of 3-hydroxy-1-(2′-hydroxyphenyl)-3-phenyl-1-propenone. 98 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


When a COSY experiment is performed, coupling between the proton on the β carbon to each of the diastereotopic α-hydrogen atoms is clearly evident (Figure 5). The 13C NMR spectrum further supports the presence of two aliphatic carbons in the product and a HETCOR experiment can be performed to demonstrate that the β-carbon is coupled to two protons that are chemically (and magnetically) distinct from one another (Figure 6). Tandem Aldol-Michael Reactions of 2-Pyridinecarboxaldehyde with Acetophenone An even more interesting outcome is obtained from the base-promoted reaction of acetophenone with 2-pyridinecarboxaldehyde. In this reaction, the product isolated is also not the anticipated α,β-unsaturated ketone. The reaction mechanism clearly involves the initial formation of a β-hydroxyketone that does dehydrate to produce an α,β-unsaturated ketone; however, the unsaturated intermediate rapidly undergoes 1,4-conjugate (Michael) addition with a second equivalent of the enolate as depicted earlier in scheme 3. The 2-pyridine ring of the aldolate is believed to facilitate conjugate addition by coordinating with the sodium-enolate complex; in essence, acting as a Lewis base catalyst for the reaction. Lewis bases have been shown to catalyze aldol reactions by altering the aggregation state of the metal enolate (20, 21). In fact, if pyridine is added to the reaction the yield of diketone is dramatically reduced suggesting that pyridine is competing with the 2-pyridinyl chalcone formed for coordinating the sodium enolate. It is perhaps more difficult to recognize the anisochrony of the methylene protons in the symmetric 1,5-diketone obtained in this reaction. Clearly, the product lacks a chiral center. However, closer inspection reveals that the geminal protons are not interchangeable with one another by a symmetry operation. Replacing one of the methylene protons with another substituent generates two stereogenic carbons (Figure 7).

Figure 7. Two new stereocenters form when one of the methylene protons is replaced by a substituent demonstrating that the geminal hydrogen atoms are diastereotopic. Proton NMR clearly demonstrates the non-equivalency of each set of methylene protons in the large geminal couplings observed (2J = -17 Hz) which can be seen in Figure 8. Splitting diagrams similar to those depicted in Figure 4 can be constructed to illustrate proton-proton coupling and the resulting multiplicities of the signals of the aliphatic hydrogen atoms. 99 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Figure 8. Aliphatic region of the H NMR spectrum of 3-(2-pyridinyl)-1,5diphenyl-1,5-pentanedione. Two-dimensional experiments, such as COSY, can also be used to confirm that the methylene protons are not equivalent (Figure 9).

Figure 9. COSY of 3-(2-pyridinyl)-1,5-diphenyl-1,5-pentanedione. 100 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


Conclusions Each of the experiments presented in this chapter highlight concepts discussed in the undergraduate organic chemistry curriculum and the importance of NMR spectroscopy for structural analysis. Since mixed aldol reactions between aromatic aldehydes and ketones typically produce α,β-unsaturated ketones, these experiments are especially useful as guided-inquiry laboratories. Moreover, the pervasiveness of high field instruments in many undergraduate institutions facilitates demonstrations of anisochrony (distinct chemical shifts) of diastereotopic methylene protons. Additionally, theses labs can be used to introduce students to two-dimensional NMR analysis by performing COSY and HETCOR experiments on the products.

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NMR Spectroscopy in the Undergraduate Curriculum - American

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