Claisen Condensation

The Claisen condensation (different from  Claisen rearrangement) is a C-C bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base (like sodium ethoxide), resulting in a β-keto ester or a β-diketone.  It is named after Rainer Ludwig Claisen (German Chemist), who first published his work on the reaction in 1881.

The base used must not interfere with the reaction by undergoing nucleophilic substitution or addition with a carbonyl carbon. For this reason, the conjugate sodium alkoxide base of the alcohol formed (like sodium ethoxide if ethanol is formed) is often used, since the alkoxide is regenerated. In some cases LDA (lithium diisopropylamide) a non nucleophilic base is used (e.g. mixed claisen condensation)

The alkoxy portion of the ester must be a relatively good leaving group. Methyl and ethyl esters, which yields methoxide and ethoxide, respectively, are commonly used.

The driving force is the formation of the stabilized anion of the β-keto ester. If two different esters are used, an essentially statistical mixture of all four products is generally obtained, and the preparation does not have high synthetic utility.

However, if one of the ester partners has enolizable α-hydrogens and the other does not (e.g., aromatic esters or carbonates), the mixed reaction (or crossed Claisen) can be synthetically useful. If ketones or nitriles are used as the donor in this condensation reaction, a β-diketone or a β-ketonitrile is obtained, respectively.

The use of stronger bases (like sodium amide or sodium hydride) instead of sodium ethoxide, often increases the yield.

Mixed Claisen Condensation (Reaction between enolizable ester or ketone and a nonenolizable ester)

Intramolecular Claisen Condensation (Reaction where a molecule with two ester groups reacts intramolecularly, forming a cyclic β-keto ester.  This is also called as Dieckmann Condensation)

Mechanism for Ketone and aldehyde reduction by NaBH4 to alcohol

Sodium borohydride is a salt which is made up of a sodium cation (Na+) and a borohydride anion (BH4-) The sodium ion plays no important role in the reaction, so we will ignore it (ions like sodium and potassium are seldom directly involved in reactions. They are present merely to maintain charge balance so that stable compounds can be added to reaction mixtures. They are often called spectator ions.) The borohydride ion is the important player in this process, and it is the B-H bond that we want to examine.

From periodic it is understood that both boron and aluminum are metals with relatively low electronegativities. Each is less electronegative than carbon, and since hydrogen has about the same electronegativity as carbon we can conclude that the B-H bond is polarized with the boron positive and the hydrogen negative. So B-H bond effectively serves as a source of hydride ion (:H-). This is given below.

 Mechanism of aldehyde to alcohol conversion

 Below attack by a nucleophile at the carbonyl carbon, followed by protonation of the carbonyl oxygen.

The same mechanism applies to the reduction of ketones by sodium borohydride and to reactions of carbonyl groups with lithium aluminum hydride. In case of lithium aluminum hydride, the reagent itself highly reactive with water, so the water is added after the lithium aluminum hydride has reacted.

Lithium diisopropylamide (LDA)-Preparation and usage

Lithium diisopropylamide is the chemical compound with the formula [(CH₃)₂CH]₂NLi.  Generally abbreviated LDA, it is a strong base used in organic chemistry for the deprotonation of weakly acidic compounds. The reagent has been widely accepted because it is soluble in non-polar organic solvents and it is non-pyrophoric. LDA is a non-nucleophilic base. Potassium diisopropylamide (KDA) is a similar compound, but it has a potassium cation instead of a lithium cation.  LDA is cheaper than KDA and is more widely used.

Preparation:

In the preparation of lithium diisopropylamide (LDA), the only other product is the gaseous alkane butane.  Because of its solubility in THF, LDA is a widely used base for enolate anion formation. In this application one equivalent of diisopropylamine is produced along with the lithium enolate, but this normally does not interfere with the enolate reactions and is easily removed from the products by washing with aqueous acid.

                

(2R,5S)-2-tert-Butyl-5-methyl-1-aza-3-oxabicyclo[3.3.0]octan-4-one: In a 250-mL, round-bottomed flask equipped with a magnetic stirrer, 18.3 mL (0.131 mol) of diisopropylamine is mixed with 120 mL of dry tetrahydrofuran (THF) under argon. At −78 °C bath temperature, 88.6 mL of a 1.6 M solution of butyllithium (0.142 mol) in hexane is added and the mixture is allowed to warm to room temperature for 20 min. After the mixture is recooled to −78 °C, the lithium diisopropylamide (LDA) solution is added over a period of 20 min to a solution of 20.0 g (0.109 mol) of (2R,5S)-2-tert-butyl-1-aza-3-oxabicyclo[3.3.0]octan-4-one in 600 mL of dry THF in a 1-L, round-bottomed flask, precooled to −78 °C. Tetrahydrofuran (20 mL) is used to rinse the 250-mL flask. After keeping the resulting solution at −78 °C for 45 min, 8.8 mL (0.142 mol) of iodomethane   is added over a period of 10 min. The resulting mixture is allowed to warm to 0 °C over a period of 3 hr, and 300 mL of a saturated aqueous solution of ammonium chloride is added. After separation, the organic layer is washed with 300 mL each of saturated aqueous solutions of sodium carbonate and brine. Each aqueous layer is extracted twice with 200 mL of ethyl acetate. The combined organic layers are dried over magnesium sulfate and the solvent is removed in a rotary evaporator at ca. 15 mm. Traces of solvent are removed by drying the residue at 60 °C/0.05 mm for 2 hr under an oil pump vacuum to yield19.8–20.5 g (0.100–0.104 mol, 93–95%) of the desired product. It is used directly in the next step.

Reference: Organic Syntheses, Coll. Vol. 9, p.626 (1998); Vol. 72, p.62 (1995)

Stability:

Since i-Pr₂NLi is a sufficiently strong base to deprotonate and cleave solvents such as Et₂O, THF, and especially DME and HMP [(Me₂N)₃PO] at temperatures above 0 ^oC, it is not practical to prepare stock solutions of i-Pr₂NLi in these solvents. However, we have found that if commercial solutions of n-BuLi in hexane are diluted with additional hexane or pentane and then treated with 1 molar equiv of i-Pr₂NH, stable solutions of i-Pr₂NLi (0.5-0.6 M) in hexane or hexane-pentane mixtures are formed. Provided that these hexane solutions are not cooled or concentrated to induce the irreversible separation of solid i-Pr₂NLi, they may be standardized (titration with 2,2'-bipyridyl indicator) and stored at 25 ^oC without deterioration for weeks. Thus, it is especially convenient to prepare solutions of i-Pr₂NLi for reactions by adding a known volume of the stable hexane solution to the desired volume of cold (<O ^oC) ethereal solvent such as Et₂0 or THF.

Mechanism (LAH reduction nitrile to amine)

Below is the mechanism of the reduction of an nitrile to amine using LiAlH4 (LAH).  I have kept it simple by not going into much details.

 Transfer of a hydride ion from lithium aluminum hydride to the carbon atom of the nitrile generates an imine intermediate, which is in equilibrium with the corresponding imino alanate.

 The imino alanate converts to the amino alanate after adddition of an additional hydride ion.

Hydrolysis yields the primary amine.

Mechanism (LAH reduction ester to alcohol)

Below is the mechanism of the reduction of an ester to alcohol using LiAlH₄ (LAH).  I have kept it simple by not going into details.

Step 1: The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl group of the ester. Electrons from the C=O move to the electronegative O creating the tetrahedral intermediate a metal alkoxide complex.

Step 2: The tetrahedral intermediate collapses and displaces the alcohol portion of the ester as a leaving group, in the form of the alkoxide, RO^-. This produces an aldehyde as an intermediate.

Step 3: Now we are reducing an aldehyde.  The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl group of the aldehyde. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.

Step 4: This is the work-up step, a simple acid/base reaction. Protonation of the alkoxide oxygen creates the primary alcohol product from the intermediate complex.