Generation of Nucleophilic Carbon Reagents

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Chapter: Organic Chemistry : Carbon-Carbon Bond Formation Between Carbon Nucleophiles and Carbon Electrophiles

The three major classes of nucleophilic carbon species are organometallic com-pounds, enolate derivatives and related carbanionic compounds, and neutral enol derivatives:


The three major classes of nucleophilic carbon species are organometallic com-pounds, enolate derivatives and related carbanionic compounds, and neutral enol derivatives:

1. Organometallic compounds which contain a carbon–metal bond are the most reactive carbon nucleophiles. In most cases they are also powerful bases and must be prepared and used under strictly anhydrous and aprotic conditions. A very common way to produce organometallic compounds is to reduce alkyl halides with active metals. Grignard reagents and organolithium compounds are routinely produced in this manner. The transformation is a two-electron reduction of the alkyl halide to a carbanion equivalent; the metal is oxidized.

This procedure works well for alkyl, vinyl, and aryl halides and provides a con-venient source of organomagnesium halides and organolithium compounds. In addition, a variety of other metals can be exchanged for lithium in organolithium compounds to give different organometallic compounds of modified reactivity. Reaction of two equivalents of an organolithium compound with a cuprous halide gives a lithium organocuprate in which the carbon–lithium bonds of the organolithium reactant are converted to carbon–copper bonds in the anionic organocuprate. Lithium merely serves to balance the charge of the organocuprate. By a similar exchange, dialkylmercury compounds can be prepared from organo-lithiums and Hg[II] halides.

A second way to make organometallic compounds for use as carbanion nucleophiles is to use halogen–metal exchange. In this process an alkyl halide and an organometallic compound undergo a metathesis reaction to give a new organometallic compound and a new alkyl halide. This process is thought to take place by nucleophilic attack on the halogen atom by the organometallic reagent.

One requirement is that the pKa of the new organometallic compound is lower than the pKa of the starting organometallic. This in essence means that the equilibrium is driven to products by the formation of a more stable anion. This method is commonly used to make vinyl lithiums from vinyl halides and alkyl lithiums and aryl lithiums from aryl halides and alkyl lithiums because the electron pair in an sp2 orbital of a vinyl or aryl lithium compound is more stable than the electron pair in an sp3 orbital of an alkyl lithium.

A method often employed to drive the halogen–metal exchange equilibrium to completion is to employ tert-butyl lithium as the organolithium component. In addition to being the most basic organolithium compound because of the tertiary substitution, conversion of the tert-butyl bromide by-product to isobutylene also occurs under the reaction conditions and drives the exchange equilibrium to completion. Note that two equivalents of tert-butyl lithium are required as one equivalent is used in the halogen–metal exchange and one equivalent is consumed in converting tert-butyl bromide to isobutylene.

2. Enolates and related carbanionic nucleophiles are routinely generated by removal of an acidic proton in a molecule with a base. Carbonyl groups acidify their α protons somewhat and make their removal by a base a common process. However, structural features other than carbonyl groups can also acidify protons bound to carbon and thus facilitate their removal by bases. For example, pKa values for structurally acidified C–H protons include the ones given below.

The pKa’s of commonly used bases are as follows:

By knowing (or estimating) the pKa of a proton to be removed, it is possi-ble to choose a base with a higher pKa in order to have essentially complete conversion to the anionic carbon nucleophile. When these conditions are met, proton exchange occurs readily and a carbon nucleophile is produced. It must be remembered, however, that many bases can serve as nucleophiles. If the structural feature which acidified the C–H proton is an electrophile, then a nucleophilic base cannot be used. For example, butyl lithium (pKa > 45) converts phenylacetylene (pKa 25) smoothly to its conjugate base by proton removal, whereas it reacts as a nucleophile with the carbonyl group of acetophenone in spite of the fact that the α protons of acetophenone have pKa = 21 and are thus more acidic than the terminal proton in phenylacetylene.

To circumvent problems of nucleophilicity, lithium diisopropylamide (LDA), potassium hexamethyldisilylamide (KHMDS), and KH are often employed for proton removal since they are very strong bases (pKa > 35) but relatively poor nucleophiles. Hence they remove protons from acidic C–H bonds but normally do not attack carbonyl groups or other electrophilic centers.

If the C–H proton is highly acidified as in a β-dicarbonyl compound (pKa 10–14) or nitro compounds (pKa = 9–12), weaker bases such as alkoxides (pKa 17) can be used to convert the material completely to its conjugate base, and thus aprotic conditions are no longer required. However, a common protocol to convert dicarbonyl compounds to their enolates in a clean, controllable manner is to use sodium hydride in dry THF.

3. A third major class of carbon nucleophiles is enol derivatives. In general, these are stable compounds that are prepared by one of the functional group transformations outlined in the previous chapter.

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