Introduction
Resonance theory is a valuable extension of valence bond theory because it offers chemists a simple and reliable way to rationalize and/or predict the results of many reactions involving conjugated systems. In this topic we will examine a small but important group of reactions of molecules containing a carbonyl group that is conjugated to a carbon-carbon double bond. We encountered this molecular fragment during our discussion of aldol condensations. Figure 1 reviews this reaction sequence. The process begins when a base removes a proton from the a-carbon atom of the aldehyde. This generates a low concnetration of enolate ion A, which reacts with a molecule of acetaldehyde that has not been deprotonated as indicated by the arrows labeled 1, 2, and 3. Protonation of the resulting alkoxide ion B leads to the b-hydroxyaldehyde known as aldol. While it is possible to isolate this compound, it is also easy to dehydrate it; 1,2-elimination of water leads to the a,b-unsaturated aldehyde 2-butenal.
Figure 1
The Aldol Condensation
Now that you know how to prepare them, let's take a look at an important aspect of the chemistry of these molecules.
Nucleophilic Addition Reactions of a, b-unsaturated Systems
Because of the conjugation of the double bond with the carbonyl group, a,b-unsaturated aldehydes and ketones possess two electrophilic carbons, the carbonyl carbon and the b-carbon. Figure 2 shows the familiar resonance interaction between the two functional groups in 2-butenal.
Figure 2
Spread 'em
It is apparent that the carbonyl carbon of 2-butenal is electron deficient, simply by virtue of being bonded to a more electronegative oxygen atom, i.e. the oxygen atom draws electron density away from the carbon atom by virtue of its inductive effect (its greater electronegativity). Structure A emphasizes the fact that the resonance interaction depicted by the arrow labeled 1 reenforces the inductive withdrawl of electron density from the carbon by the oxygen. The development of a positive charge on the carbonyl carbon in A leads to the resonance interaction indicated by the arrow labeled 2. This reduces the electron density at the b-carbon as indicated by the positive charge on that atom in resonance structure B.
While the foregoing discussion should be familiar to you by now, it bears repeating because understanding resonance interactions like those shown in Figure 2 allows you to make predictions about the outcome of many chemical reactions. The prediction that is central to this topic is this: nucleophilic reagents can react with the carbonyl carbon and/or the b-carbon atom of a,b-unsaturated aldehydes and ketones. Which of these alternatives is realized in a given reaction is an issue of kinetic vs.thermodynamic control. Consider the reaction shown in Equation 1.
Of the two products, cyclohexanone is the more stable. This is primarily due to the fact that the carbon-oxygen double bond is an especially stable molecular fragment, considerably more stable than a carbon-carbon double bond. The average bond strength of a carbonyl group in aldehydes and ketones is about 178 kcal/mol, while that of the carbon-carbon double bond in alkenes is approximately 146 kcal/mol.
Exercise 1 Is reaction 1
kinetically controlled or
thermodynamically controlled?
Whether a nucleophile adds to the carbonyl carbon or the
b-carbon of an
a,b-unsaturated system depends in large measure upon the reactivity of the nucleophile. With highly reactive nucleopliles, addition is kinetically controlled and the nucleophile adds to the carbonyl carbon because it is more electron deficient than the
b-carbon. Less reactive nucleophiles are more selective in their choice of bonding partners and prefer to bond to the
b-carbon, producing the more stable product. The change from kinetic to thermodynamic control is clearly illustrated by the product distributions obtained in the reactions of methyl lithium, methyl magnesium bromide, and lithium dimethyl cuprate with 5-methyl-2-cyclohexenone. The nucleophilic reactivity of these reagents is determined primarily by the difference in electronegativity of the methyl carbon and the metal atom to which it is bonded.
Exercise 2 Which is the most electropositive metal?
Li
Mg
Cu
Exercise 3 Which bond is the most polar? C-Li C-Mg C-Cu
Exercise 4 Which reagent should be the least nucleophilic? CH3Li CH3MgBr (CH3)2CuLi
Equation 2 describes the reaction of 5-methyl-2-cyclohexenone with these three organometallic reagents in general terms. Here M stands for the metal atom. The product distribution in these three reactions is summarized in Table 1.
Table 1
Nucleophilic Addition: Kinetic vs. Thermodynamic Control
| Nucleophile | 1,2-Addition | 1,4-Addition |
 |  |
| CH3Li | >99% | <1% |
| CH3MgBr | 79% | 21% |
| (CH3)2CuLi | 2% | 98% |
Note the almost total reversal from kinetic control to thermodynamic control as the nucleophile is changed from the highly reactive methyl lithium to the much less reactive lithium dimethyl cuprate.
Lithium dimethyl cuprate is prepared by the reaction of copper (I) iodide with methyl lithium as shown in Equation 3.
While the preparation of this complex and the determination of its structure are interesting topics in themselves, the key feature about this organometallic reagent is that the methyl groups are nucelophilic. They are less nucleophilic than a methyl group from methyl lithium or methyl magnesium bromide because the electronegativity difference between C and Cu is less than it is between C and Li or C and Mg. Now let's consider another, more familiar, way of assessing the relative reactivities of carbon nucleophiles.
Relative Reactivity of Carbon Nucleophiles
The relative reactivity of a series of carbon nucleophiles may be assessed to a first approximation by comparing the pKa values of their conjugate acids. The weakest acids produce the strongest conjugate bases, i.e. the most reactive nucleophiles. Table 2 presents a list of carbon acids ranked in order of increasing acidity.
Table 2
pKa Values to the Rescue Again
The remainder of this topic will present a variety of reactions that involve the addition of nucleophilic reagents to the b-carbon of an a,b-unsaturated system. These reactions are also called Michael additions or conjugate additions.
Michael Additions
A simple example of the shift from kinetic to thermodynamic control is available in the reaction of the enolate ion derived from methyl isobutyrate with cyclohexenone as shown in Scheme 1.
Scheme 1
Pick Your Poison
A more dramatic example of Michael addition is illustrated in Equation 4, where conjugate addition occurs to the exclusion of 1,2-addition.
Scheme 2 outlines a transformation that constituted the first step in a multi-step synthesis of the steroid estrone.
Scheme 2
Body Builder
The nucleophilic reagent was generated by reacting cuprous iodide with the Grignard reagent derived from vinyl bromide. The divinyl cuprate added to the b-carbon of 2-methylcyclopentenone to produce an enolate ion that reacted with chlorotrimethyl silane to form the silyl enol ether in 89% yield.
A standard method for forming 6-membered rings known as the Robinson annulation (annulation means ring formation) begins with a Michael addition. Scheme 3 outlines the steps involved in this transformation.
Scheme 3
The Robinson Annulation
The sequence begins with the deprotonation of one of the a-carbons of 2-methylcyclohexanone. This is the same as the first step of an aldol condensation. However, the enolate ion, A, generated in the first step adds to the b-carbon atom of the methyl vinyl ketone that is present in the reaction mixture (arrows 4-7) to produce a new enolate ion, B, which abstracts a proton from a water molecule as shown by arrows 8-10. The resultant ketone C is then converted into its enolate D, which cyclizes as shown by arrows 12-14. This generates the b-hydroxyketone E which spontaneously dehydrates to yield the final product F.
Carbon is not the only nucleophilic species to participate in Michael additions. Scheme 4 illustrates an intramolecular Michael addition that played a key step in the first total synthesis of the antibiotic indolizomycin.
Scheme 4
An Intramolecular Michael Addition
Addition of the hydroperoxide anion to the b-carbon of the starting material initiated the flow of electrons indicated by arrows 1-3. Regeneration of the carbonyl group (arrow 4) of the resulting enolate ion was accompanied by an intramolecular nucleophilic substitution reaction as shown by arrows 5 and 6. The resulting epoxide was isolated in 97% yield!
