Claisen Condensation(ngưng tụ claisen)

Acetoacetic-Ester Condensation

Claisen Condensation

Summary

• The Claisen condensation is the ester analogue of the Aldol condensation.
• Reagents : most commonly the base would be the alkoxide, R'O^-
• The reaction involves an ester enolate reacting with another molecule of the ester.
• Remember enolates are good nucleophiles and the ester carbonyl C are electrophilic.
• The products of these reactions are b-ketoesters which are important, useful synthetic intermediates.
• Note that the product is the original ester with an acyl group added i.e. an acylation reaction has occurred.
• A simple example of a Claisen condensation is the reaction of ethyl ethanoate which is shown below in two representations:

The Claisen Condensation between esters containing α-hydrogens, promoted by a base such as sodium ethoxide, affords β-ketoesters. 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, e.g. sodium amide or sodium hydride instead of sodium ethoxide, often increases the yield.

The intramolecular version is known as DieckmannCondensation

Translate to Vietnamese:

 Hiểu sơ bộ:

• Là phản ứng giữa 2 ester có α-hydrogen
• Xúc tác: base như EtONa, MeONa,NaNH2,NaH
• Tạo ra sản phẩm trung gian ổn định: anion của β-keto ester
• Sản phẩm tạo ra là β-keto ester
• Khi 2 ester là khác nhau: tạo ra một hỗn hợp 4 sản phẩm β-keto ester

Mechanism of the Claisen Condensation

Example

1.

claisen condensation 

General, Robust, and Stereocomplementary Preparation of α,β-Disubstituted α,β-Unsaturated Esters
H. Nakatsuji, H. Nishikado, K. Ueno, Y. Tanabe, Org. Lett., 2009, 11, 4258-4261.

Translate to Vietnamese:

• NEt3(TEA): Triethylamin, là xúc tác base
• TiCl4: vai trò phản ứng với EtOH tạo ra, thúc đẩy phản ứng xảy ra theo chiều thuận.
  TiCl4 + 4EtOH -----------------> Ti(OC2H5)4 + 4 HCl
• Dung môi CH2Cl2 hoặc toluen: Phải dùng dung môi hòa tan cả 2 chất phản ứng, tạo nên hệ đồng thể thì hiệu suất mới cao( nói đúng hơn phản ứng mới xảy ra)

2.

 Abstract

Thioesters undergo chemoselective soft enolization and acylation by N-acylbenzotriazoles on treatment with MgBr₂·OEt₂ and i -Pr₂NEt to give β-keto thioesters without prior enolate formation. The reaction is conducted using untreated CH₂Cl₂ open to the air. The coupled products can be converted directly into β-keto esters, β-keto amides, and β-diketones under mild conditions.

Direct Carbon-Carbon Bond Formation via Chemoselective Soft Enolization of Thioesters: A Remarkably Simple and Versatile Crossed-Claisen Reaction Applied to the Synthesis of LY294002

G. Zhou, D. Lim, D. M. Coltart, Org. Lett., 2008, 10, 3809-3812.

Translate to Vietnamese:

MgBr₂·OEt₂ and i -Pr₂NEt có vai trò: tránh tạo ra enolate.

3.

Mild and Efficient Pentafluorophenylammonium Triflate (PFPAT)-Catalyzed C-Acylations of Enol Silyl Ethers or Ketene Silyl (Thio)Acetals with Acid Chlorides
A. Iida, J. Osada, R. Nagase, T. Misaki, Y. Tanabe, Org. Lett., 2007, 9, 1859-1862.

Powerful Ti-Crossed Claisen Condensation between Ketene Silyl Acetals or Thioacetals and Acid Chlorides or Acids
A. Iida, S. Nakazawa, T. Okabayashi, A. Horii, T. Misako, Y. Tanabe, Org. Lett., 2006, 8, 5215-5218.

Synthesis of Trifluoromethyl Ketones via Tandem Claisen Condensation and Retro-Claisen C-C Bond-Cleavage Reaction
D. Yang, Y. Zhou, N. Xue, J. Qu, J. Org. Chem., 2013, 78, 4171-4176.

Consecutive Michael-Claisen Process for Cyclohexane-1,3-dione Derivative (CDD) Synthesis from Unsubstituted and Substituted Acetone
D. Sharma, Bandna, A. K. Shil, B. Singh, P. Das, Synlett, 2012, 23, 1199-1204.

"One-Pot" Synthesis of 4-Substituted 1,5-Diaryl-1H-pyrazole-3-carboxylic Acids via a MeONa/LiCl-Mediated Sterically Hindered Claisen Condensation-Knorr Reaction-Hydrolysis Sequence
J.-A. Jiang, C.-Y. Du, C.-H. Gu, Y.-F. Ji, Synlett, 2012, 23, 2965-2968.

Exercises about Claisen condensation

The Claisen Condensation

The nucleophilic carbon of the enolate ion adds to the electrophilic carbon of a molecule of ethyl acetate that has not been deprotonated. A carbon-carbon bond is formed. The reaction produces yet another tetrahedral intemediate as shown in Equation 1.

Since the newly formed tetrahedral center has an electronegative atom attached to it, reformation of the carbonyl group, as shown in Equation 2, is a reasonable process.

         Exercise 1 

Draw the structure of the major product you would expect to be formed in each of the following situations:

        Exercise 3:

An intramolecular version of the Claisen condensation is known as the Dieckmann condensation. Equation 3 shows how this reaction was put to good use as part of the total synthesis of the prostaglandin PGA₂.

Equation 4 offers another example of the Dieckmann condensation that was involved in the synthesis of tropinone, a degradation product that was produced during the determination of the structure of the physiologically active alkaloid atropine.

An early synthesis of cholesterol involved the "mixed Claisen reaction" shown if Equation 5.

      Example 4  :Dieckmann Condensation

      Example 5 :Crossed Claisen Condensation

     Example 6:

The classic Claisen condensation, a self-condensation between two molecules of a compound containing an enolizable ester.

Example 7:

The mixed (or "crossed") Claisen condensation, where one enolizable ester or ketone and one nonenolizable ester are used.

Example  8:

The Dieckmann condensation, where a molecule with two ester groups reacts intramolecularly, forming a cyclic β-keto ester. In this case, the ring formed must not be strained, usually a 5- or 6-membered chain or ring.

Example 9:

The Stobbe condensation ^[5] is a modification specific for the diethyl ester of succinic acid requiring less strong bases.^[6]An example is its reaction with benzophenone:^[7]

A reaction mechanism that explains the formation of both an ester group and a carboxylic acid group is centered around alactone intermediate (5):

Example 10:

Example 11:

  

Example 12:

Example 13:

Example 14:

Example 15:

                                                                           

Example 16:

Example 17:

Example 18:

Mechanism of the Claisen Condensation

Mechanism of the Claisen Condensation

Reaction type : Nucleophilic Acyl Substitution

Summary

• The Claisen condensation is the ester analogue of the Aldol condensation.
• Reagents : most commonly the base would be the alkoxide, R'O^-
• The reaction involves an ester enolate reacting with another molecule of the ester.
• Remember enolates are good nucleophiles and the ester carbonyl C are electrophilic.
• The products of these reactions are b-ketoesters which are important, useful synthetic intermediates.
• Note that the product is the original ester with an acyl group added i.e. an acylation reaction has occurred.
• A simple example of a Claisen condensation is the reaction of ethyl ethanoate which is shown below in two representations:

Step 1: 
First, an acid-base reaction. The alkoxide functions as a base and removes the acidic a-hydrogen giving the reactive ester enolate

Step 2: 
The nucleophilic ester enolate attacks the carbonyl C of another ester in a nucleophilic substitution process giving the tetrahedral intermediate.

Step 3:
The intermediate collapses, reforming the C=O, resulting in loss of the leaving group, the alkoxide, leading to the b-ketoester product.

(nguồn: http://www.chem.ucalgary.ca/courses/351/Carey5th/Ch21/ch21-3-1.html
http://www.mhhe.com/physsci/chemistry/carey/student/olc/graphics/carey04oc/ref/ch21enolatereactions.html)

More than:

The general form of a Claisen condensation is as follows:

The first step involves adding a strong base to an ester to generate an enolate at the a carbon (note that the enolate has an additional resonance structure).

The enolate can then add to another ester molecule by attacking the carbonyl to make the tetrahedral intermediate. The carbonyl reforms with loss of the alcoxy group to make the b-keto ester.

Example of a Claisen condensation:

This is an example of an intramolecular Claisen reaction, called a Dieckmann condensation.

Learn More:

Claisen condensation mechanism

1) Enolate formation

2) Nucleophilic attack

3) Removal of leaving group