{"id":6122,"date":"2014-06-17T11:39:16","date_gmt":"2014-06-17T18:39:16","guid":{"rendered":"http:\/\/blogs.reed.edu\/chemistry201-202-test\/?page_id=6122"},"modified":"2025-01-17T16:27:57","modified_gmt":"2025-01-18T00:27:57","slug":"background","status":"publish","type":"page","link":"https:\/\/blogs.reed.edu\/chemistry201-202-lab-ref-manual\/experiments\/experiment-8-synthesis-and-purification-of-diastereomers-sodium-borohydride-reduction-of-a-chiral-ketone\/background\/","title":{"rendered":"Synthesis and Purification of Diastereomers: Background"},"content":{"rendered":"\n

A single compound can exhibit many types of isomerism. Even when the compound’s structure is relatively simple, chemical transformations may lead to unexpected mixtures of isomers. The following sections discuss possible stereochemical outcomes for ketone reduction, and spectroscopic methods for distinguishing stereoisomers.<\/p>\n\n\n\n

General stereochemical principles<\/h3>\n\n\n\n

As you will see, the reduction of a ketone carbonyl can result in a number of stereochemical scenarios depending on the exact structure of the starting ketone.<\/p>\n\n\n\n

The first and most straightforward example (1) is the reduction of a symmetric ketone, such as acetone. This reaction gives a single achiral product.<\/p>\n\n\n

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\"reduction<\/a><\/figure><\/div>\n\n\n

A second example (2) illustrates the selective reduction of a ketone carbonyl group and the creation of a new chiral atom. The newly formed chiral center is the only chiral center in the product and two outcomes, S<\/em> and R<\/em> enantiomers, are possible. In this case, the carbonyl carbon in the reactant is said to be prochiral<\/i>, indicating that it can become a chiral center after a specific reaction, in this case, reduction.<\/p>\n\n\n

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\"reduction<\/a><\/figure><\/div>\n\n\n

The conversion of an achiral starting material into an optically active product is possible, but only if optically active reagents are used. Sodium borohydride is an achiral reagent, and optically inactive, so it necessarily reduces ethyl acetoacetate to a 50:50 racemic <\/i>mixture of chiral alcohols. However, when the reduction is carried out with Baker’s yeast, the S<\/i>-alcohol is produced in 90% optical yield instead (note: optical yield = %major enantiomer – %minor enantiomer). Baker’s yeast is able to achieve this outcome because it contains chiral enzymes called dehydrogenases<\/em>. Like sodium borohydride, dehydrogenases are capable of catalyzing the selective reduction of the ketone carbonyl group in ethyl acetoacetate. The ester carbonyl group is not altered. Because yeast contains only one enantiomer of each type of dehydrogenase enzyme, these enzymes can be labeled as optically active reagents.<\/p>\n\n\n\n

Before we leave example (2), you might wonder how chemists are able to distinguish the outcomes of these experiments. Recall that enantiomers possess identical chemical and physical properties. For example, the NMR spectra of the pure S<\/em> and pure R<\/em> alcohols are identical. And so are the NMR spectra of the 50:50 and 95:5 product mixtures! The traditional method for identifying enantiomers and mixtures of enantiomers is to measure their optical rotation<\/em> of plane-polarized light. Enantiomers rotate light by the same amount, but in opposite directions. The racemic<\/em> 50:50 mixture obtained from the NaBH4<\/sub> reduction does not rotate plane-polarized light and is optically inactive<\/em>. The 95:5 S:R<\/em> mixture obtained from yeast is optically active<\/em>: [a]D<\/sub> = +38.6o<\/sup>.<\/p>\n\n\n\n

A third carbonyl reduction scenario, and the one you will explore in this experiment, involves the reduction of a molecule that contains a prochiral ketone and an additional chiral center (3). The products of the reduction all contain two chiral centers, so one must keep track of both enantiomeric and diastereomeric relationships between product molecules.<\/p>\n\n\n

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\"reduction<\/a><\/figure><\/div>\n\n\n

The diastereomers in (3) are distinguished by the labels cis<\/i> and trans<\/i> that indicate the relative positions of the hydroxyl and “lone” methyl groups. The diastereomers possess different relative configurations (they are neither superimposable nor mirror-images), and also different chemical and physical properties which makes them relatively easy to detect and identify in our laboratory.<\/p>\n\n\n\n

Although the starting ketone in (3) is a chiral molecule, you will use a racemic mixture of the ketone in your experiment. As a result, your experiment will generate racemic mixtures of the cis<\/i> and trans<\/i> products. (Note: it is the habit of organic chemists to draw only one of the two possible enantiomers when depicting racemic compounds. In this particular case, each product has been drawn with the lone methyl group “down” even though the products with the methyl group “up” are present in equal amounts.) If we had provided you with an optically active sample of 3,3,5-trimethyl-cyclohexanone, as shown in (4), you would have still obtained the same 60:40 ratio of trans<\/em> and cis<\/em> diastereomers as in (3), but each diastereomer would now be optically active. (Can you see why?)<\/p>\n\n\n

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\"reduction<\/a><\/figure><\/div>\n\n\n

Properties of trans <\/i>and cis <\/i>3,3,5-trimethylcyclohexanol<\/h3>\n\n\n\n

In this experiment, 3,3,5-trimethylcyclohexanone (1<\/strong>), a racemic ketone with one chiral center, is reduced with sodium borohydride to produce two alcohols, trans <\/i>2<\/strong> and cis <\/i>3<\/strong>.<\/p>\n\n\n\n

In order to understand the relative chemical and physical properties of these two diastereomers it is useful to know the conformational preferences of these molecules. One analysis is shown in the following figure (you might want to refresh your knowledge of the conformational analysis of cyclohexanes: see Sorrell<\/i>, section 3.3).<\/p>\n\n\n

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\"cyclohexanol<\/a><\/figure><\/div>\n\n\n

Two chair conformations are possible for the starting ketone, and two conformations are also possible for each product. One way to differentiate between these conformers is to watch the 5-methyl group. Conformers 1e<\/strong>, 2e<\/strong>, and 3e<\/strong>, contain an equatorial<\/i> 5-methyl group, while conformers 1a<\/strong>, 2a<\/strong>, and 3a<\/strong>, contain an axial<\/i> 5-methyl group.<\/p>\n\n\n\n

We assume that the 5-methyl group always prefers to be in an equatorial<\/i> position (in other words, ‘e<\/strong>‘ conformers are preferred). The energy difference between an equatorial and axial methyl group is 1.8 kcal\/mol. This energy is known as the methyl group’s A-value<\/i> and is often used as an indication of steric bulk.<\/p>\n\n\n\n

The hydroxy group also prefers to be in an equatorial position, however, its A-value is only 0.7 kcal\/mol. (This makes sense since a hydroxy group has less steric bulk than a methyl group.)<\/p>\n\n\n\n

Since two groups change places when the conformers interconvert, we might try to predict the lower energy conformer by adding A-values together. This suggests that cis <\/i>3e<\/strong> is more stable than 3a<\/strong> by 2.5 kcal\/mol (= 1.8 + 0.7). It also suggests that trans <\/i>2e<\/strong> is more stable than 2a<\/strong> by 1.1 kcal\/mol (= 1.8 – 0.7) even though 2e<\/strong> places the hydroxy in an axial orientation.<\/p>\n\n\n\n

To summarize, this conformational analysis of the two diastereomeric alcohols suggests that the trans<\/i> alcohol, 2<\/strong>, will tend to keep the OH axial, while the cis<\/i> isomer, 3<\/strong>, will have an equatorial OH.<\/p>\n\n\n\n

It is well documented that functional groups in an axial orientation are sterically more hindered than their equatorial counterparts. The enhanced accessibility of an equatorial hydroxy group can be seen from the following facts:<\/p>\n\n\n\n