Minggu, 11 Oktober 2009

Nucleophilic Addition I

Nucleophilic Addition I


Organometallic reagents are compounds which contains carbon-metal bonds.

For the purposes of the discussion that follows, the only compounds we will consider will be ones where M = Li or Mg. When M= Li, the organometallic reagent is called an organolithium reagent. When M = Mg, it is called a Grignard reagent. Historically Grignard reagents were developed before organolithium reagents. In recent years, however, organolithium reagents have taken over the key role that Grignard reagents played as the most versatile source of nucleophilic carbon.

The nucleophilic character of organometallic reagents stems from the fact that the C-M bond is polarized in such a way that the carbon atom is negative while the metal atom is positive.

As the picture above indicates, the carbon-metal bond has "ionic character". In fact, it is useful to think about Grignard reagents and organolithium reagents as sources of negatively charged carbon atoms, i.e. carbanions. Since carbon is not a very electronegative element, it is very reactive when it bears a negative or partial negative charge.

Organometallic Reagents as Bases

In order to appreciate just how reactive carbanions are, consider the series of anions and their conjugate acids shown in Figure 1.

Figure 1

A Comparison of Acid/Base Strengths

(The pK values are approximate.)

Ignoring for the moment the different ways in which chemists write methane and ammonia on the one hand and water and hydrogen fluoride on the other (wierd, huh?), recall that pKa values are a measure of the acidity of a compound. Furthermore, the pKa scale is logarithmic or exponential. Thus, hydrogen fluoride is 1013 times more acidic than water. Similarly, water is 1022 more acidic than ammonia. Knowing the relative acidities of the compounds in Figure 1 means you also know their relative basicities: the amide anion is 1022 more basic than hydroxide ion, which is 1013 times more basic than fluoride ion.

Clearly then, methane is the weakest acid of the four conjugate acids shown in Figure 1, while the methide anion is the strongest base, and, by extension, the best nucleophile. The trend in base strength exhibited by the four anions in Figure 1 is attributed to the difference in nuclear charge of the central atom in each ion: Carbon has 6 protons attracting the lone pair of electrons, nitrogen has 7, oxygen 8, and fluorine 9.

Reagents such as phenylmagnesium bromide and methyl lithium are among the strongest bases there are. Consequently they will deprotonate compounds such as amines, alcohols, and carboxylic acids. Figure 2 presents one reaction that is representative of each of these situations.

Figure 2

Acid-Base Reactions of Organometallic Reagents

Exercise 1 For each reaction if Figure 2, enter the pKa of the two acids in the appropriate text field and calculate the approximate value of the equilibrium constant for the reaction. Remember to enter an exponential such as 1 x 1012 as 10e12.


NH2CH3 CH4 K =


The equilibrium constant for each of these reactions is very large. These reactions all occur extremely rapidly, sometimes explosively! The extreme reactivity of organometallic reagents towards O-H and N-H groups makes these groups incompatible with such strong bases.

Organometallic Reagents as Nucleophiles

Whether an organometallic reagent is classified as a base or a nucleophile depends on whether it forms a bond with a hydrogen atom or a carbon atom. If a reactant contains an electrophilic carbon and does not contain O-H or N-H groups, then an organometallic reagent will act as a nucleophile towards that electrophilic carbon atom. The most common source of electrophilic carbon is the carbonyl group, especially the carbonyl group of aldehydes and ketones. Equations 3 and 4 illustrate the nucleophilic reactivity of phenylmagnesium bromide and methyl lithium towards a simple aldehyde and a simple ketone, respectively.

As these equations emphasize, each of these reactions leads to the formation of a C-C bond. This is the basis of synthetic organic chemistry! A fundamental principle that guides the development of logical approaches to the preparation of new molecules is that carbon-carbon bond formation requires the interaction of molecules which contain carbon atoms of opposite polarity. We have already seen that the C-O bond in a carbonyl group has a bond dipole with the carbon atom being electron deficient. In Equation 4 the carbonyl carbon of propiophenone is highlighted in blue to emphasize its electrophilic character, while the nucleophilic nature of the carbon in methyl lithium is stressed by coloring it red.

Exercise 2 Draw the structure of the major product expected in each of the following reactions:

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Exercise 3 Identify the aldehyde or ketone that was used to prepare the following alcohols. Draw the structure of the alkyl or aryl bromide from which the appropriate organometallic reagent was generated.

Aaldehyde or ketonebromide

B.aldehyde or ketonebromide

C.aldehyde or ketonebromide

Exercise 4 Each of the following alcohols may be prepared from different combinations of organometallic reagents and aldehydes and/or ketones. In each case, one of the reactants, i.e. either an aldehyde or ketone or an alkyl halide, is specified. Draw the structure of the other reactant that you would use to prepare the target alcohol.

A1. alkyl bromide

A2. alkyl bromide

B1. alkyl bromide

B2. aldehyde or ketone

B3. aldehyde or ketone

C1. alkyl bromide

C2. alkyl bromide

D1. aldehyde or ketone

D2. aldehyde or ketone

Reaction Mechanism

The reaction of an organometallic reagent with an aldehyde or ketone embodies the most fundamental reaction of the carbonyl group: nucleophilic addition. The mechanism of the reaction involves two steps: 1. addition of the organometallic reagent to the carbonyl carbon to form a tetrahedral intermediate 2. protonation of the the resulting alkoxide ion. The second step occurs during the work-up of the reaction. Figure 3 summarizes these two steps.

Figure 3

The Mechanism of Nucleophilic Addition to a Carbonyl Group


In the following reactions, the carbon-carbon bond that is formed is indicated in red. Equation 5 describes a Grignard reaction that was used in the first total synthesis of the hormone progesterone. The carbon atoms in the product of reaction 5 are numbered to match their positions in progesterone.

Exercise 5 Using reaction 5 as a model, Polly Ester designed the following synthesis:

Unfortunately, things did not go as planned. One of the products that Polly was able to isolate from the reaction gave the following 1H-NMR data: d, ppm 1.19 (t, 3H), 1.82 (s, 1H), 2.07 (q, 2H). The IR spectrum showed a peak of medium intensity at 2254 cm-1. What is the name of the compound that Polly isolated?

An aromatic Grignard reagent played a key role in the synthesis of monensin, a polyether antibiotic, as shown in Equation 6.

Finally, Equation 7 illustrates three of the final steps in the synthesis of a terpene called D2-8-epicedrene.

The middle step involves the nucleophilic addition of methyl lithium to the carbonyl carbon atom of a ketone. The final step in the synthesis entails dehydration of the 3o alcohol formed in the second step. How would you accomplish this?

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