Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 328

Brief Organic Chemistry

Summer 2004

Lecture Notes: 7 July

© R. Paselk 2004
 
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Enolate and Carbonyl Condensation Reactions, cont.

Condensation reactions

In condensation reactions the carbonyl compound acts both as electrophile and as nucleophile. That is an enolate carbanion attacks a carbonyl carbon to form a C-C bond. We will look at two important condensation reactions, the Aldol Condensation and the Claisen Condensation, both of which are important in biological systems.

Aldol Condensation Reaction: When acetaldehyde is treated with a strong base (e.g. HO- or CH3CH2O-) in alcohol a rapid, reversible condensation occurs, the Aldol Reaction:

This base catalyzed reaction occurs via the mechanism below:

Notice that the catalyst consumed in the first step (it became alcohol solvent) is regenerated in the last step (from alcohol solvent).

The aldol reaction favors condensation for monosubstituted acetaldehydes (with 2 alpha-hydrogens) but favors cleavage (breaking the aldol into aldehydes or ketones) for disubstituted acetaldehydes (with 1 alpha-hydrogen) or ketones.

Aldol Dehydration: The acidity of the alpha-carbon makes beta-dehydration of aldols an easy reaction. (This is of course quite different than the chemistry of normal alcohols.) This conjugated enone synthesis is catalyzed by both acids and bases.

Acid catalysis:

Base catalysis:

Dehydration generally occurs under slightly more vigorous conditions, such as higher temperature, than the condensation reaction. Thus at higher temperature in base the aldol reaction will go directly to the conjugated enone without any isolation of the aldol intermediate.

Claisen Condensation Reaction: This reaction is very similar to the aldol condensation, but it is done with esters instead of aldehydes. As a consequence the product will be a ketone instead of an alcohol because it is easier to lose an alcohol than a hydrogen!

The mechanism is shown below:

Like an aldehyde, an ester has an acidic alpha-carbon. Thus we see the same kind of attack as was seen with the aldol condensation. The difference is in the relaxation of the intermediate. Where the aldol has a hydrogen on the alkoxy carbon (a very poor leaving group), the oxo-ester has an alcohol group which is a good leaving group. Thus the alkoxy oxygen goes to a keto oxygen with the loss of the alcohol group.

Diekmann Condensation Reaction: This is an intramolecular Claisen condensation giving a five or six membered ring.

 

Just for fun - not covered Summer 2004

Malonic Ester Synthesis: The malonic ester synthesis is a particularly important carbonyl alkylation reaction. It is an excellent method for preparing substituted acetic acids. It also illustrates some interesting chemistry. The net result of the reaction is to take two of the three carbons of malonic acid

and to add them to the alkyl chain of an alkyl halide in a multi-step process:

In the first step of this reaction malonic ester is reacted with a strong base such as sodium alkoxide to give the enolate ion (note that the solvent and the catalyst are the same alcohol as in the ester since exchange may take place):

Next the enolate can attack an alkyl halide to give the alkylated malonic ester:

(This and the previous step can be repeated to give the dialkylated derivative.)

The alkylated malonic ester can now be hydrolysed:

But the resulting diacid will now spontaneously decarboxylate (lose carbon dioxide):

(Why should this occur? Because there is a very good leaving group, CO2, on an acidic alpha-carbon.)

The overall reaction can then be written as:

 

Carbohydrates

There are four major families of biomolecules: the carbohydrates, the amino acids/proteins, the purines & pyrimidines/ nucleic acids, and the lipids. The first three families are characterized by their functional groups/structures:

We will focus on the carbohydrates and the amino acids.proteins. Our purposes in looking at this material is to familiarize you with these biomolecules, and to review the physical properties and chemistries of the characteristic functional groups and structures.

Carbohydrates: The carbohydrates have the common empirical formula: (CH2O)n. The appearance of the formula would seem to indicate a compound of hydrated carbon, hence the name. In fact carbohydrates have at least one carbonyl group and two hydroxy groups for each residue. Thus the smallest carbohydrate has three carbons.

Note that there are a total of three 3-C sugars: the D & L chiral isomers of glyceraldehyde (2,3-Dihydroxypropanal) and dihydroxyacetone (1,2-Dihydroxypropanone).

You should review the drawing and meaning of Fischer structures. You should be able to tell if two Fischer structures represent the same chirality. For the remainder of this course we will generally refer to the chiralities of biomolecules using the older, D, L convention. This is not because biologists are backward (they may very well be, but that's not the reason!). Rather its because the D, L designation is based on the actual structure of the molecules by functional group, rather than the artificial, but very useful, designation based on prioritizing by atomic weight. What do I mean by functional group? If you look at glyceraldehyde we can use it as the basis of the D, L system. Thus in a Fischer structure of a similar molecule we would line it up so the most oxidized group (in this case the C=O) is in the same relative position as shown. Next we would put the next group, -OH (or for an amine, -NH-) in the same orientation as shown. If the H's for the two structures now line up, they have the same configuration (D in our example), if not, then they are of opposite configurations!

Aldehyde sugars such as glyceraldehyde are known as aldoses while ketone sugars such as dihydroxyacetone are known as ketoses.

Aldoses: We will look at the aldoses first. All of the D aldoses with up to 6 carbons are shown in Table 16.1 of your text, while all of the D ketoses with up to 6 carbons are shown in Table 16.2. {overheads} Whether a sugar is D or L is strictly determined by its configuration around the penultimate carbon. Thus there will be an equal number of L aldoses with the yellow color-coded hydrogen to the left instead of the right in the Fischer structure (notice that the sugars are conventionally drawn with the carbonyl carbon nearest the top).

Notice that there will be fewer ketoses, since there are no chiral ketotrioses.


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Last modified 7 July 2004