Organic Chemistry - Carbanions

CARBANIONS

Keto-Enol Tautomerism – Enolization – Reactions and Mechanism	The chemistry of enolate ions – Reactions with alkyl halides

 

Carbanions are species with a complete octet around the carbon atom. A general formula of a carbanion is of the form:

 

 

By definition, every carbanion possesses an unshared pair of electrons and is therefore a base. When a carbanion accepts a proton, it is converted to its conjugate acid. The stability of a carbanion is directly related to the strength of its conjugate acid. The weaker the acid, the greater the base strength and the lower the stability of the carbanion - the greater the reactivity of the carbanion. Less stable carbanions tend to react rapidly with proton donors and hence exist as carbanions for short time.

Carbanion stability has been found to be in this order:

vinyl > phenyl > cyclopropyl > ethyl > n-propyl > isobutyl > neopentyl > cyclobutyl > cyclopentyl

 

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References

1. R. Bruckner, “Advanced Organic Chemistry – Reaction Mechanisms”, 2nd Edition, Elsevier, 2002

2. M.B. Smith & J. March “March’s Advanced Organic Chemistry”, 6th Edition, Wiley-Interscience, 2007

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The chemistry of enolate ions – 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.

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 S_N2 and E2 mechanism. The electrophiles (alkyl halides in this case) need to be S_N2 reactive and this means that react in the order (Fig. I.2):

 

      

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 S_N2 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).

 

 

    

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:

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.
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.

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 S_N2 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).

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Relevant Posts

Carbocations: Factors affecting their stability

Carbocations and factors affecting instability

Carbocations: Stability. formation and reactions

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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).

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Key Terms

carbonyl compounds, keto-enol reaction, keto form, enol form, α-hydrogen, enolization, enolates, tautomerism

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Keto-Enol Tautomerism – Enolization – Reactions and Mechanism

Acid or Base catalyzed Enolization – Reactions and Mechanism

Carbonyl compounds (aldehydes, ketones, carboxylic esters, carboxylic amides) react as electrophiles at the sp² hybridized carbon atoms and as nucleophiles if they contain an H-atom in the α-position relative to their C=O or C=N bonds. This is because this H is acidic and it can be removed by a base leaving behind an electron pair for nucleophilic attacks.    

For most compounds in organic chemistry all the molecules have the same structure – even if this structure cannot satisfactory represented by a Lewis formula – but for many compounds there is a mixture of two or more structurally distinct compounds that are in rapid equilibrium. This phenomenon is called tautomerism.

Tautomerism is the phenomenon that occurs in any reaction that simply involves the intramolecular transfer of a proton. An equilibrium is established between the two tautomers (structurally distinct compounds) and there is a rapid shift back and forth between the distinct compounds.

A very common form of tautomerism is that between a carbonyl compound containing an α-hydrogen and its enol form (Fig. I.1).

Fig. I.1: A keto-enol reaction

 

An enol is exactly what the name implies: an ene-ol. It has a C=C double bond (diene) and an OH group (alcohol) joined directly to it.

Notice that in the above reaction as in any keto-enol reaction there is no change in pH since a proton is lost from carbon and gained on oxygen. The reaction is known as enolization as it is the conversion of a carbonyl compound into its enol.

Notice also that in the above reaction the product is almost the same as the starting material since the only change is the transfer of one proton and the shift of the double bond.

In simple cases (R₂ = H, alkyl, OR, etc.) the equilibrium of the keto-enol reaction lies well to the left (keto structure) (Table I.1). The reason can be seen by examining the bond energies in Table I.2.

 

Compound	Enol Content, %
Acetone	6 * 10-7
PhCOCH3	1.1 * 10-6
CH3CHO	6 * 10-5
Cyclohexanone	4 * 10-5
Ph2CHCHO	9.1
PhCOCH2COCH3	89.2

Table I.1: The enol content of some carbonyl compounds

 

If keto-enol reactions are common for aldehydes and ketones why don’t simple aldehydes and ketones exist as enols?

IR and NMR Spectra of carbonyl compounds show no signs of enols. The equilibrium lies well over towards the keto form (the equilibrium constant k for cyclohexanone is about 10-5).

	Bond (Energy, kJ/mol)			Sum ( kJ/mol)
keto form	C-H (413)	C-C (350)	C=O (740)	1503
enol form	C=C (620)	C-O (367)	O-H (462)	1449

Table I.2: Bond energies in the keto and in the enol form. The keto form is thermodynamically more stable than the enol form by approximately 50 kJ/mol

The approximate sum of the bond energies in the keto form is 1503 kJ/mol while in the enol form 1449. Therefore, the keto form is thermodynamically more stable than the enol form by approximately 50 kJ/mol.

In most cases, enol forms cannot be isolated since they are less stable and are formed in minute quantities. However, there are some exceptions and in certain cases a larger amount of the enol form is present and it can be even the predominant species:

Molecules in which the enolic double bond is in conjugation with another double bond (cases are shown in Table I.1 like Ph₂CHCHO and PhCOCH₂COCH₃)
Molecules that contain two or more bulky aryl groups (Fig. I.2). Compound I in Fig. I.2 (a substituted enol) is the major species in equilibrium (~95%) while the keto form is the minor species (~5%). In cases like this steric hindrance destabilizes the keto form (the two substituted aryl groups are 109° apart) while in the enol form 120° apart.

 

Fig. I.2: A keto-enol reaction. The enol form (I) is the major species in this case since the keto form is destabilized by steric hindrance (the substituted aryl groups are closer in the keto form – the C-C angle is 109° and this is unfavorable due to steric hindrance)

 

Is there experimental evidence that keto-enol reactions are common for aldehydes and ketones?

If the NMR spectrum of a simple carbonyl compound in D₂O is obtained – such as pinacolone’s (CH₃)₃CCOCH₃ – the signal for protons next to the carbonyl group very slowly disappears. The isolated compound’s mass spectrum (after the above mentioned reaction with D₂O is over) shows that those hydrogen atoms have been replaced by deuterium atoms. There is a peak at (M+1)⁺ or (M+2)⁺ or (M+3)⁺ instead of M⁺. The reaction is shown in Fig. I.3: 

Fig. I.3: Evidence for a keto-enol reaction when pinacolone (CH₃)₃CCOCH₃ reacts with D₂O. When the enol form of the pinacolone reverts to the keto form it picks up a deuteron instead of a proton because the solution consists almost entirely of D₂O.

 

What mechanism can be proposed for the above reaction?

Enolization is a slow process in neutral solution, even in D₂O, and is catalyzed by acid or base in order to happen.

In the acid-catalyzed reaction the molecule is first protonated on oxygen and then loses the C-H proton in a second step (Fig. I.4). When the enol form reverts to the keto – since this is an equilibrium process – it picks up a deuteron instead of a proton since the solution is D₂O. 

 

Fig. I.4: The acid-catalyzed keto-enol reaction mechanism. If D2O is the solvent then the α-hydrogens to carbonyl group are replaced by deuterium.

 

In the base-catalyzed reaction the C-H proton is removed first by the base (for example hydroxide ion OH^-, OD^- in our case) and the proton (or D⁺ in our case) added to the oxygen atom in a second step (Fig. I.5).

Fig. I.5: The base-catalyzed keto-enol reaction mechanism. If D2O is the solvent then the α-hydrogens to carbonyl group are replaced by deuterium.

 

Notice that the enolization reactions in Fig. I.4 and Fig. I.5 are catalytic. In the acid-catalyzed mechanism the D⁺ (or H⁺ if water is the solvent) is regenerated at the end (catalyst). In the base-catalyzed mechanism OD^- (or OH^- if water is the solvent) is regenerated at the end (catalyst).

The enolate ion generated from the enol (Fig. I.6) in the base-catalyzed mechanism is nucleophilic due to:

Oxygen’s small atomic radius
Formal negative charge

An enolate ion is an ion with a negative charge on oxygen with adjacent C-C double bond.

 

Fig. I.6: Enolate ion resonance contributors. Although the major contributor is resonace structure I when it reacts as a nucleophile structure II is more reactive.

 

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

Enolates react with alkyl halides, aldehydes/ketones and esters and these reactions are shown in the post entitled “The chemistry of enolate ions – Enolate ion reactions”.

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Relevant Posts

Carbocations: Factors affecting their stability

Carbocations and factors affecting instability

Carbocations: Stability. formation and reactions

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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).

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Key Terms

carbonyl compounds, keto-enol reaction, keto form, enol form, α-hydrogen, enolization, enolates, tautomerism

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