The presence of two, or even three, electron-withdrawing groups on a single carbon atom makes the remaining proton(s) sufficiently acidic (pKa 10–15) that even mild bases can lead to complete enolate formation. Bases of the strength of alkoxides (pKa of ROH = ca. 16) cannot deprotonate simple carbonyl compounds (pKa 20–25) completely, but readily generate anions stabilized by more than one electron-withdrawing group. The most important enolates of this type are those of 1,3-dicarbonyl (or β-dicarbonyl) compounds. The resulting anions are alkylated very efficiently. This diketone is enolized even by potassium carbonate, and reacts with methyl iodide in good yield. Carbonate is such a bad nucleophile that the base and the electrophile can be added in a single step.

Among the β-dicarbonyls two compounds stand out in importance—diethyl (or dimethyl) malonate and ethyl acetoacetate. You should make sure you remember their structures and trivial names.

With these two esters, the choice of base is important: nucleophilic addition can occur at the ester carbonyl, which could lead to transesterification (with alkoxides), hydrolysis (with hydroxide), or amide formation (with amide anions). The best choice is usually an alkoxide identical with the alkoxide component of the ester (that is, ethoxide for diethyl malonate, methoxide for dimethyl malonate). Alkoxides are basic enough to deprotonate between two carbonyl groups but, should substitution occur at C=O, there is no overall reaction. In the fi rst example below the electrophile is the allylic cyclopentenyl chloride, and the base is ethoxide in ethanol—most conveniently made by adding one equivalent of sodium metal to dry ethanol. The same base is used in the second alkylation, of ethyl acetoacetate with butyl bromide.

Various electron-withdrawing groups can be used in almost any combination with good results. In this example an ester and a nitrile cooperate to stabilize an anion. Nitriles are not quite as anion-stabilizing as carbonyl groups so this enolate requires a stronger base (sodium hydride) in an aprotic solvent (DMF) for success. The primary alkyl tosylate serves as the

These doubly stabilized anions are alkylated so well that it is common to carry out an alkylation between two carbonyl groups, only to remove one of them at a later stage. This is made possible by the fact that carboxylic acids with a β-carbonyl group decarboxylate (lose carbon dioxide) on heating. The mechanism below shows how. After alkylation of the dicarbonyl compound the unwanted ester is first hydrolysed in base. Acidification and heating lead to decarboxylation via a six-membered cyclic transition state in which the acid proton is trans ferred to the carbonyl group as the key bond breaks, liberating a molecule of carbon dioxide. The initial product is the enol form of a carbonyl compound that rapidly tautomerizes to the more stable keto form—now with only one carbonyl group. Using this technique, β-keto esters give ketones while malonate esters give simple carboxylic acids (both ester groups hydrolyse but only one can be lost by decarboxylation). Decarboxylation can occur only with a second carbonyl group appropriately placed β to the acid, because the decarboxylated product must be formed as an enol.

The alkylation of ethyl acetoacetate with butyl bromide <was done with the expressed intention of decarboxylating the product to give hexan-2-one. These are the conditions for this decarboxylation: the heating step drives off the CO₂ by increasing the gear ing on the entropy term (ΔS‡) of the activation energy (two molecules are made from one).

Esters are much easier to work with than carboxylic acids, and a useful alternative procedure removes one ester group without having to hydrolyse the other. The malonate ester is heated in a polar aprotic solvent—usually DMSO—in the presence of sodium chloride and a little water. No acid or base is required and, apart from the high temperature, the conditions are fairly mild. The scheme below shows a dimethyl malonate alkylation (note that NaOMe is used with the dimethyl ester) and removal of the methyl ester.

The mechanism of decarboxylation is a rather unusual type of ester cleavage reaction. The bond that breaks is not the MeO–CO bond but instead the O–alkyl bond: the reaction is an SN2 substitution of carboxylate by Cl⁻.

Chloride is a poor nucleophile, but it is more reactive in DMSO, by which it cannot be solvated. And, as soon as the carboxylate is displaced, the high temperature encourages (entropy again) irreversible decarboxylation. The other by-product, MeCl, is also lost as a gas. The ‘decarboxylation’ (in fact, removal of a CO₂Me group, not CO2) is known as the Krapcho decarboxylation. Because of the SN2 step, it works best with methyl malonate esters.

We have only looked at single alkylations of dicarbonyl compounds, but there are two acidic protons between the carbonyl groups and a second alkylation is usually possible. Excess of base and alkyl halide gives two alkylations in one step. More usefully, it is possible to intro duce two different alkyl groups by using just one equivalent of base and alkyl halide in the first step.

With a dihaloalkane, rings can be formed by two sequential alkylation reactions: this is an important way of making cycloalkanecarboxylic acids. Even the usually more difficult four-membered rings can be made in this way.

اخر الاخبار

اخبار العتبة العباسية المقدسة

شعبةُ الحرم الشريف تستبدلُ ستائر أبواب حرم مرقد أبي الفضل العباس (عليه السلام)

شعبة التوجيه الديني النسوي تستهل برنامجها العاشورائي السنوي بعدد من المجالس العزائية

لليوم الثاني من المحرم.. توافد المواكب على مرقدي الإمام الحسين وأخيه أبي الفضل العباس (عليهما السلام)

العتبة العباسية المقدسة تهيئ بواباتها لاستقبال المواكب الحسينية

المزيد

الآخبار الصحية

دراسة تكشف علاقة خطيرة بين عمر الأم وصحة مولودها

دراسة تحذر.. اضطراب نوم بسيط قد يسبب الموت المبكر ؟

الاستحمام بالماء الساخن.. راحة مؤقتة وأضرار دائمة للبشرة

ماذا يحدث للجسم عند تخطي وجبة الإفطار؟

المزيد

الآخبار التكنلوجية

كيف تساعد الصيانة الوقائية في الحفاظ على كفاءة التكييف في سيارتك ؟

في ظاهرة غريبة حيرت العلماء.. كوكبنا قد يسجل أقصر يوم في التاريخ هذا الصيف!

السد الصيني العملاق يعيق دوران الأرض ويغيّر شكلها ؟

السعودية تطلق 10 تجارب علمية إلى محطة الفضاء الدولية

المزيد

مواضيع ذات صلة

The Claisen ester condensation and other self-condensations

Problems with acylation at carbon

Cross-condensations

The aldol reaction

Nitroalkanes are superb nucleophiles for conjugate addition

A variety of electrophilic alkenes will accept enol(ate) nucleophiles

Conjugate addition of silyl enol ethers leads to the silyl enol ether of the product

Enamines are convenient stable enol equivalents for conjugate addition

Alkali metal (especially Na, K) enolates can undergo conjugate addition

1,3-Dicarbonyl compounds undergo conjugate addition

Using Michael acceptors as electrophiles

Conjugate addition to enones gives enolates regiospecifically