One important condensation reaction is the aldol condensation, which usually
involves .... This experiment illustrates several of the principles of green chemistry
.
Student Handout
ALDOL CONDENSATION References:
1. Doxsee, K.; Hutchison, J.E. Green Organic Chemistry: Strategies, Tools, and Laboratory Experiments Pacific Grove, CA: Brooks/Cole, 2004. 2. List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 23952396. 3. Gröger, H.; Wilken, J. Angew. Chem. Int. Ed. 2001, 40, 529-532. 4. Cauble, D.F.; Krische, M.J. Chemtracts—Org. Chem. 2002, 15, 380-383. 5. Rothenberg, G.; Downie, A.P.; Raston, C.L.; Scott, J.L. J. Am. Chem. Soc. 2001, 123, 8701-8708.
Compounds that contain the carbonyl group display a surprisingly diverse range of reaction chemistry, and the discovery and study of such reactions form the heart of much modern synthetic organic chemistry. Often when a nucleophile forms a bond with a carbonyl carbon, the mechanism proceeds in such a way that a molecule of water is released. Because of this formation of water, such reactions were first known as condensation reactions. As research provided greater insight into mechanistic pathways, the condensation label was eventually applied to virtually any nucleophilic acyl addition or substitution in which two compounds combine or are "condensed" into a single molecule. These reactions are valuable because they result in more elaborate carbon skeletons, and they frequently result in the generation of a new chirality center.
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When a new chirality center forms during the course of a reaction, the resulting product might consist of a 50%-50% (or racemic) mixture of enantiomers, or the amount of one enantiomer might exceed the amount of the other enantiomer. In the latter situation, it is useful to measure this enantiomeric excess (ee). If the specific rotation of one of the enantiomers is known, polarimetry can be used to determine ee. [You will use this technique for determining ee in this project.] The technique can be unreliable, however, because rotation values vary with solvent and temperature, and uncertainty in the concentration contributes to uncertainty in the specific rotation value. The most reliable data correlate the optical rotation with an independent analytical determination of ee. Sometimes certain hydrogen atoms in the enantiomers (e.g., a hydrogen bonded at the chirality center) are magnetically and chemically inequivalent and can be distinguished in the 1H NMR spectrum. Integration of these signals can also allow determination of ee. Integration, however, can carry noticeable experimental error because different relaxation times can lead to different peak intensities. A pulse delay is necessary to account for any differences in relaxation time. Another way to find ee is to separate the enantiomers from each other and measure the individual amounts. Chemists used to routinely accomplish this task by treating the enantiomeric mixture with a chiral reagent, thereby forming a diastereomeric mixture. Because diastereomers have different chemical and physical properties, these mixtures could be resolved by one of several means. For example, one diastereomer might crystallize while the other remained in solution. Once separated, the diastereomers were treated with a reagent to remove the added group so the original enantiomers could be recovered. A second method for separating enantiomers is to treat the mixture with an achiral reagent followed by an enzyme that selectively
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catalyzes the reverse reaction to re-form one of the enantiomers. Once separated, the compound that does not react with the enzyme can be treated to re-form the other enantiomer. The preferred technique for determining ee is chiral HPLC (refer to the background information on chromatography). This method permits the separation of the enantiomers without any prior chemical treatment of the mixture. Chiral HPLC requires a column packed with chiral material. The two enantiomers interact differently with this chiral stationary phase and, therefore, have different retention times. Integration of the resolved peaks allows the determination of ee. One important condensation reaction is the aldol condensation, which usually involves the reaction between two molecules of aldehydes or ketones in the presence of base to form βhydroxycarbonyl compounds (Scheme 1). (The name “aldol” is a contraction of aldehyde and alcohol, which are the two functional groups in the simplest condensation product.) These compounds are readily dehydrated, sometimes under the initial reaction conditions, to form α,βunsaturated carbonyl compounds. The reaction requires that at least one of the starting aldehydes or ketones have α-hydrogens. Crossed aldol reactions involve two different aldehydes or ketones. The Claisen-Schmidt modification of the aldol condensation involves the reaction between a ketone with α-hydrogens and an aldehyde.
O R
C
CHR
+
R
O
O
C
C
CH2 R
R
O C CH2 R H CH R R
O
+
R
C
OH CH R
C CH2 R R
Scheme 1. Mechanism of Base-Promoted Aldol Condensation The catalytic asymmetric aldol condensation is a fundamental C-C bond forming reaction in biology, too. In contrast to laboratory methods that require a base to form an enolate, biological systems use enzymes, class I and class II aldolases, to catalyze the direct aldolization 6
of two unmodified carbonyl compounds. Whereas class II aldolases use a zinc co-factor, class I aldolases take advantage of an enamine mechanism that involves the ε-amino group of an activesite lysine residue (Scheme 2). This amino group forms an imine with the ketone of dihydroxyacetone-3-phosphate (DHAP). The imine tautomerizes to an enamine, which adds to the aldehyde of glyceraldehyde-3-phosphate (G3P) as the imine re-forms. Finally, the imine undergoes hydrolysis to liberate the β-hydroxy adduct.
O
OH
2-
O 2OPO3
O3 PO OH
Class I aldolase
2-
O3 PO DHAP
OH
Lys(aldolase)
N
Lys(aldolase)
OH
2-
N 2-
2OPO3
O3 PO OH
OH
O3 PO
OH (imine)
OH Lys(aldolase)
tautomerization
OH OPO32-
O G3P
NH 2-
O3 PO
OH (enamine)
Scheme 2. Catalytic cycle of direct aldol condensation with a class I aldolase If simple organic molecules can act like these enzymes, such processes would allow the cost-effective manufacture of chiral building blocks on an industrial scale. These organic catalysts should not only function like an enzyme, but should also show easy availability in
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either enantiomeric form at comparably low prices. The molecules should have low molecular weight, be easily separated from the product, and be easily recovered after work-up without racemization. Recently, chemists have found that L-proline, a naturally-occurring amino acid, can function as a small-molecule asymmetric class I aldolase mimic. The proposed enamine mechanism of the proline-catalyzed aldol condensation involves an iminium ion intermediate rather than an imine (Scheme 3). O
O
OH CO2 H
N
R
H
H
N
HO
CO2 OH
N
CO2
R tautomerization
H2 O CO2 H
N N
CO2 OH O
R R
H
H O R
H
N O
O
H
Scheme 3. Proposed catalytic cycle of direct aldol condensation with L-proline
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During the addition of the enamine to the aldehyde, the rigid pyrrolidine ring of the enamine and an intermolecular hydrogen bond between the carboxylate group of the enamine and the aldehyde oxygen both contribute to the enantioselection. If the amino group of the proline is nucleophilic enough to form an enamine, why is it not basic enough to simply remove an α-proton from the acetone and catalyze the aldol condensation that way? One reason is that proline also contains a carboxylic acid. Protons of carboxylic acids are more acidic than α-protons of ketones. If the amino group were going to act as a base, it would deprotonate the carboxylic acid. The carboxylic acid also activates the ketone carbonyl, so nucleophilic addition is more favorable. In general, an enamine mechanism is more likely when the catalyst contains two or more functional groups that can act in concert (e.g., one as an acid/electrophile, the other as a base/nucleophile). Because isobutyraldehyde has an α-hydrogen, one might expect that it could combine with proline to form an enamine that would condense with another molecule of isobutyraldehyde or with acetone, but no such reaction products are observed. One explanation is that the proline is statistically more likely to encounter acetone molecules because the acetone is used in large excess. Another explanation is that even if an enamine were to form from isobutyraldehyde, the two methyl groups would sterically hinder the addition of the enamine to another carbonyl compound. The product of the aldol condensation between acetone and isobutyraldehyde also contains α-hydrogens, yet it does not undergo a second condensation. If the product were to form an enamine with proline, steric effects would make that enamine less reactive than the enamine from acetone. Therefore, any remaining isobutyraldehyde is more likely to react with the acetone-derived enamine.
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This experiment illustrates several of the principles of green chemistry. The reaction proceeds at ambient temperature and pressure and requires neither an inert atmosphere nor purification and drying of the reagents. The reagents require no modification. The promoter is used in catalytic rather than stoichiometric amount. Moreover, the catalyst is theoretically obtainable from renewable sources, biodegradable, and readily available in both enantiomeric forms. The water-solubility of the catalyst allows for easy removal from the reaction mixture. Furthermore, when only one enantiomeric product is desired, an enantioselective process generally offers a higher atom economy. Condensation reactions, by following an addition mechanism, also have an inherently higher atom economy. However, this experiment also illustrates some of the trade-offs involved in green chemistry. The most glaring example is that the acetone is used in large excess so as to function as both reagent and solvent and to suppress side reactions, such as dehydration of the adduct or self-condensation of the isobutyraldehyde. This large excess leads to poor overall atom economy and effective mass yield. In addition, the acetone is volatile and flammable. Another volatile and flammable organic solvent, ether, is used for extracting the product from the reaction mixture. The separated aqueous layer contains not only the proline catalyst but also NaCl and possibly some unreacted acetone and isobutyraldehyde. Finally, the reaction proceeds slowly. Product does not begin to appear for about 24 hours, and at least 48 hours are necessary to obtain an appreciable yield. For a process to be recognized as green, it ultimately needs to be viable in an industrial setting. The time limitation alone calls into question the viability of this process. Procedure Because isobutyraldehyde is an irritant and some aldol products can trigger allergic reactions in individuals, you are strongly encouraged to wear gloves when performing these
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experiments. Acetone, isobutyraldehyde, and diethyl ether are flammable, so open flames should be avoided. Conduct operations in a fume hood whenever possible. Aldol Procedure To a 25-mL one-neck round-bottom flask equipped with a magnetic stir bar and a stopper or rubber septum, add 1.0 mL (0.79 g, 0.011 mol) of isobutyraldehyde, 14 mL (11 g, 0.19 mol) of acetone, and 0.23 g (0.0020 mol) of L-proline. Magnetically stir the reaction mixture at room temperature in a fume hood for one week. Dilute the mixture with 50 mL of saturated aqueous NaCl solution and transfer to a separatory funnel. Extract the mixture with diethyl ether (1 x 15 mL). Dry the separated organic layer over MgSO4, remove the drying agent by gravity filtration into a clean, dry, weighed 50-mL one-neck round-bottom flask, and remove the solvent by rotary evaporation. Analyze your compound by IR, 1H NMR, 13C NMR, and polarimetry. If your product is a solid, measure a melting point. Assess the purity of your product. If necessary, purify the product. Once you have isolated pure product, calculate your percent yield, atom economy, efficiency, effective mass yield, and cost for the experiment. Estimation of Enantiomeric Excess A literature reference for the specific rotation of the enantiopure R aldol adduct is not available. On the other hand, there are two literature reports of specific rotations for mixtures of which the R enantiomer is the major component: Specific Rotation
Enantiomeric Excess
+61.7
96%
Reference List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395-2396
+43.4
61%
Ramachandran, P.V.; Xu, W.-c.; Brown, H.C. Tetrahedron Lett. 1996, 37, 4911-4914
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We also know that a racemic mixture (ee = 0%) will show no rotation. Use all three data points to generate a graph of ee vs. specific rotation with a linear fit. Use the equation of the straight line to solve for the ee that corresponds with the average specific rotation of your product mixture. Round your result to the nearest whole percent. Additional Work Perform at least one of the following tasks: 1.
Repeat the procedure using a smaller amount of catalyst and analyze the outcome.
2.
Repeat the procedure using a smaller amount of acetone and analyze the outcome.
3.
Repeat the procedure using D-proline as the catalyst and analyze the outcome.
4.
Repeat your procedure using a different aldehyde (e.g., benzaldehyde) and analyze the outcome.
5.
Repeat your procedure using a different ketone (e.g., acetophenone) and analyze the outcome.
6.
Repeat your procedure using one equivalent of acetone and 10 mL of water as the solvent and analyze the outcome.
7.
Repeat the procedure, but maintain the reaction mixture at reflux temperature for 2 h instead of room temperature for one week. Analyze the outcome.
8.
Oxidize your product to a diketone (with instructor approval of the procedure).
9.
Reduce your product to a diol (with instructor approval of the procedure).
10.
Other (with approval of the instructor).
Clean-up: All reaction products should be placed into properly labeled vials and submitted to the instructor. All aqueous solutions and spent drying agent can be flushed down the drain with copious amounts of water. All organic solutions should be placed into the appropriate solvent
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waste container. Melting point capillaries, Pasteur pipets, tlc plates, and tlc capillaries should be placed into the broken glass receptacle. Filter paper can be placed into the regular trash. Clean your glassware, and wash your hands. Questions Answer the following questions in your lab notebook: 1.
Was the original reaction enantioselective? If so, which enantiomer was major?
2.
What other possible condensation products might have formed?
3.
What was green about the initial procedure?
4.
What was not green about the initial procedure?
5.
How might the initial procedure be made greener?
6.
What was the outcome of your second reaction?
7.
What was green about your second procedure?
8.
What was not green about your second procedure?
9.
How might your second procedure be made greener?
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