The chemistry of enolate ions – Reactions with alkyl halides

The chemistry of enolate ions – Enolate ion reactions with alkyl halides

The chemistry of enolate ions – Alkylations - Enolate ion reactions with alkyl halides

Enolates are reactive nucleophiles. Although the major enolate Lewis contributor shows concentration of electron density on the electronegative oxygen (Fig. I.1) when it reacts as a nucleophile, it behaves like the electron density is concentrated on the α-carbon next to carbonyl group.

Fig. I.1: Enolate ion resonance contributors. Although the major contributor is resonace structure I when it reacts as a nucleophile structure II is more reactive.

However, from the resonance forms shown in Fig. I.1, it is clear that enolates are capable of reacting as both carbon and oxygen nucleophiles (resonance structures II and I respectively). Enolates react with alkyl halides, aldehydes/ketones and esters and these reactions are shown below:

 

Reactions of enolates with alkyl halides

Enolates are reactive nucleophiles and react with alkyl halides by the SN2 and E2 mechanism. The electrophiles (alkyl halides in this case) need to be SN2 reactive and this means that react in the order (Fig. I.2):

 

Fig. I.2: Alkyl halides react with the enolates in the order methyl > allyl > benzyl > primary > secondary.

      

Primary, benzylic and allyl alkyl halides are among the best alkylating agents. More branched halides tend to prefer to undergo unwanted E2 elimination reactions. Tertiary alkyl halides are practically unreactive for enolate alkylation.

Since enolates react as nucleophiles with alkyl halides the following rules must be obeyed for the SN2 reaction to occur:

  • Electrophiles –alkyl halides in this case - cannot be tertiary
  • The leaving group X in the alkyl halide RX must be a good leaving group (-Br, -I, OTs, OMs or OTf)
  • The nucleophile – enolate anion – must be a good nucleophile
  • The solvent must be an aprotic polar solvent

Note: If the electrophile is tertiary then an E2 reaction occur (enolates are moderate bases)

Let us examine the reaction of cyclohexane-1,3-dione with ethyl iodide. The reaction product is an alkylated diketone at the 2 position (2-ethylcyclohexane-1,3-dione) (Fig. I.3).

 

Fig. I.3: Reaction of the enolate anion generated from cyclohexane-1,3-dione in the presence of NaOCH3 with an alkyl halide ethyliodide.

 

    

The basic steps of the above reaction mechanism are as follows (Fig. I.3):

  • The CH3O- anion (base) attacks the most acidic H (the –H atom between the two carbonyls). Electrons of the C-H bond make a double bond (π bond) and electrons of the C=O bond move to oxygen
  • The nucleophilic C=C π bond attacks carbon of the C-I bond in CH3CH2I and the very good leaving group –I leaves.  Alternatively, the resonance structure of the corresponding enolate can be drawn and the electron-pair on the α-carbon to the carbonyl group attacks the C-atom having the –I leaving group. In the same step, electrons on the oxygen atom move back to remake a π bond. The result is a new C-C bond (alkylation) in-between the 2 carbonyl atoms.

 

Note: An important consideration that affects all alkylations – like the ones presented above - is the choice of base:

  1. A strong base can be selected to deprotonate the starting material completely. There is complete conversion of the starting material to the anion before addition of the electrophile (i.e. an alkyl halide, halogen…), which is added in a subsequent step. The choice of a strong base is practically more demanding but the electrophile and base never meet each other, so their compatibility is not a concern.
  2. A weaker base may be used in the presence of the electrophile. The weaker base will not deprotonate the starting material completely and therefore only a small amount of anion will be formed but that small amount will react with the electrophile. This choice is easier practically (mixing the starting material, base and electrophile) but works only if the base and electrophile are compatible.

 

In general, the reaction conditions and the base must be chosen with care since an enolate tends to react with another enolate ion by attacking the C=O carbon forming dimers (aldol condensation) or polymers. The condensation problem described above (enolate reacting with unenolized carbonyl under basic conditions) does not exist if there is no unenolized carbonyl compound present. This can be achieved by choosing the following:

  • an enolate anion that will be sufficiently stable to survive until the alkylation is complete
  • a sufficiently strong base (pka at least 3 or 4 units higher than pka of the carbonyl compound) that will ensure that all of the starting carbonyl will be converted into the corresponding enolate.

 

Is there such a sufficiently strong base for making enolates?

One of the best bases for making enolates is LDA made from diisopropylamine and butyl lithium. The reaction is shown in Fig. I.4. LDA came into general use in the 1970’s but today more modern species  are used such as lithium isopropylcyclohexylamine (LICA) and lithiumtetramethylpiperidide (LTMP) which are even more hindered and less nucleophilic as a result. LDA will deprotonate virtually all ketones and esters that have an acidic proton to form the corresponding lithium enolates rapidly, completely, and irreversibly even at low temperatures (-78 C) required for some of these reactive species to survive. Therefore, any possibility for condensation reactions (enolate reacting with unenolized carbonyl) is minimized.

Fig. I.4: Synthesis of diisopropylamine lithium (LDA) from diisopropylamine and butyl lithium. LICA and LTMP are often used today as bases instead of LDA since these are even more hindered and less nucleophilic minimizing the possibilities for side reactions.

What is the mechanism of the alkylation of lithium enolates when react with alkyl halides?

The reaction of these lithium enolates with alkyl halides is one of the most important C-C bond-forming reactions in chemistry. Carbon-carbon bond formation is important since this is the basis for the construction of the molecular framework of organic molecules by synthesis.

The mechanism of the reaction is SN2 in which the carbon nucleophile displaces a halide (from the electrophile, alkyl halide RX) with inversion of configuration at the alkylating group. The mechanism is the same as the one described in Fig. I.3 except that the base is LDA instead of CH3O-.

Note: The electrophile (RX) can also be any unhindered electrophile with a good leaving group X (such as X= OTs, OMs or OTf).

Relevant Posts

Carbocations: Factors affecting their stability

Carbocations and factors affecting instability

Carbocations: Stability. formation and reactions

References
  1. A.J. Kresge, Pure Appl. Chem., 63, 213 (1991)
  2. B. Capon, The Chemistry of Enols, Wiley, NY, 307–322 (1990)
  3. S.E. Biali et al., J. Am. Chem. Soc. 107, 1007 (1985).
Key Terms
carbonyl compounds, keto-enol reaction, keto form, enol form, α-hydrogen, enolization, enolates, tautomerism

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