02

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CHEM 43293

Experiment No. 02

Knoevenagel Condensation :

Synthesis of Cinnamic

acid

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Date

_–

01/19/2012

Experiment No.

_–

02 Experiment Title

_–

Knoevenagel Condensation: Synthesis of Cinnamic

acid

Introduction

In organic synthesis one of the most well known reactions for C-C bond formation is the Knoevenagel condensation. This reaction has been widely used for the synthesis of

intermediate such as coumarin derivatives which are useful in perfumes, cosmetics and bioactive compounds. In addition, there has been considerable interest on Knoevenagel condensation product because of their widespread application including inhibition of antiphosphorylation of EGF-receptor and antiproliferative activity.

As a result of their importance from a pharmacological, industrial and synthetic point of view, Knoevenagel condensation has been extensively studied and several methods for the Knoevenagel condensation have been reported. Generally, these methods includes both

homogeneous condition (liquid-phase system) catalyzed by base such as pyridine, piperidine, ethylene diamines or corresponding ammonium salts DMAP or organocatalyst such as

glycine, L-poroline and alanine. Unfortunately many of these methods have some drawbacks, such as use of expensive, use of stoichiometric, amount of reactant, low yields, extended time and lack of geometry.

The Knoevenagel Reaction is where aldehyde or ketones, (which don't normally contain αhydrogen) perform a condensation reaction with compounds of the form Z-CH₂-Z'

or Z-CHR-Z'. The Z groups are electron withdrawing groups, such as CHO, COR, COOH, COOR, CN, NO2, SOR, SO2R, SO2OR or similar groups. The protons attached to this

Methylene group are very much acidic and can be removed by weaker bases such as amine to provide sufficient concentration of enolate ions to react with aldehydes and some ketones. However, if a strong enough base is used then the reaction can be performed on compounds possessing only one Z group, i.e. CH3Z. Plus, other active hydrocarbons can be used, such as

CHCl3, cyclopentadienes, to name a couple. In reality, any compound that contains a C-H

bond that can be removed by a base can be used.

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the base usually, as it allows partial deprotonation of a 1,3-dicarbonyl compound but not of a normal aldehyde, so self-condensation of the aldehyde is not a problem.

Basic Knoevenagel reaction

Mechanism

The knoevenagel reaction in its simplest form is the condensation of malonic acid (or its analogs) with aldehydes and ketones in the presence of an amine as the base catalyst. Such way the condensation of carbon acid compounds with (especially) aldehydes to afford α,β-unsaturated acids or compounds is a general use of Knoevenagel condensation.

e.g.

Reaction (I) is favored by using equivalent amounts of aldehyde and ethyl malonate in the presence of pyridine whereas reaction (II) (via Michael addition) is favored by using excess of ethyl malonate in the presence of piperidine and when aldehyde is aliphatic.

The mechanism of this reaction has been the subject of much discussion. When a tertiary base (e.g., pyridine), is used as catalyst, then the mechanism is believed to be similar to that of the aldol condensation. When a primary or secondary base is used as

catalyst, the mechanism may still follow the same as of tertiary base catalyzed reaction, but a complication arises from the fact that carbonyl compounds can form addition products with such bases and these addition products may therefore be intermediates in the reaction.

- In this example, aldehyde and diethylmalonate undergo Knoevenagel condensation with piperidine as the base.

I). an enol intermediate is formed initially:

I RCHO + CH2(CO2C2H5)2 base RCH=C(CO2C2H5)2+ H2O

II RCH=C(CO2C2H5) + CH2(CO2C2H5)2

base CH(CO2C2H5)2

+ H2O

RCH

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II). this enol reacts with the aldehyde, and the resulting aldol undergoes subsequent base-induced elimination:

 A reasonable variation of the mechanism, in which piperidine acts as organocatalyst, involves the corresponding iminium intermediate as the acceptor:

-

The first step is that the base will attack a aldehyde molecule at the carbonyl position, and this is helped by the product being a stable iminium salt, stabilized by the weak acid.

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 The Doebner Modification, which is possible in the presence of carboxylic acid groups, includes a pyridine-induced decarboxylation which is followed by heating.

Materials & Instruments

 Malonic acid  Pyridine  Piperidine  Benzaldehyde  HCl (6M)  EtOAc  Methylene dichloride

 Conical flasks & Erlenmeyer flask  Measuring cylinders & Beakers  Refluxing apparatus

 Buchner funnel  Balance

 Melting point apparatus  Desiccators

 Dropper  pH papers  TLC plates

Procedure

Malonic acid (1.0g) was placed in a small conical flask, pyridine (1ml) and 2-3 drops of piperidine were added into it under a fume hood and mixed well. Then benzaldehyde (0.3ml) was added to mixture. This mixture was refluxed sing water jacketed condenser on a sand bath for 1and ½ hours.

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The reaction mixture was then allowed to cool to room temperature and the reaction mixture was transferred to an Erlenmeyer flask containing ice cold water (~20ml). The reaction flask was rinsed with ice cold water (2x~5ml) and added to the same Erlenmeyer flask. HCl (6M) was added in small portions to the above solution until a white precipitate formed and the solution was weakly acidic to pH papers.

The solid crude was filtered at the pump using Buchner funnel and washed with cold water. The product was recrystallized with small amount of hot water and obtain crystals were dried by gently pressing between two filter papers and leaving in a desiccators.

The yield was measured. TLC plate was run with recrystallized product and Cinnamic acid to check the identity using the eluent as EtOAc: CH2Cl2 (5:95). The melting point of

obtained crystals and mixed melting point were measured.

Results

- Melting point of the prepared crystals (Cinnamic acid) = 1180- 1200C - Mixed melting point = 1200- 1220C

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---TLC

plate---Calculations

C

6

H

5

CHO

(l)

+ CH

2

(COOH)

2(s)

C

6

H

5

CH=CHCOOH

(s)

+ CO

2(g)

+H

2

O

(l)

- Used moles of malonic acid = 1.0g x 98 104.06 gmol-1 100 = 0.009 mol

- Used moles of benzaldehyde = 0.3 ml x 1.05 gml

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x 99 106.12 gmol-1 100 = 0.003 mol

According to the calculations, the limiting reagent of the reaction is Benzaldehyde. Hence, the theoretical yield of Cinnamic acid = 0.003 mol x 148.15 gmol-1

= 0.44 g - Actual yield = 0.38 g

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= 86.4%

o

Rf

Values (Retention values)

Discussion

In this

experiment, Knoevenagel

condensation was carried

out using benzaldehyde and malonic acid, under pyridine as the organic tertiary base and piperidine as organic base catalyst which help in the formation of imminium form of benzaldehyde.

The Doebner modification is occurring here, in which the condensation followed by

heating results in α, β-unsaturated monocarboxylic acid, which here is the Cinnamic acid. Mixing of malonic acid, pyridine and piperidine should be performed under a fume hood as pyridine and piperidine are strong toxic bases that may cause complications after inhaling. The refluxing was then carried out on a sand bath; sand bath is required to provide high heat homogeneously. As most of used reactants and also the product have higher boiling points it is better to use a sand bath. In the refluxing process, condensation occurs and whiles the decarboxylation also takes place. Produced Cinnamic acid is in salt form in the basic medium of reaction mixture. Hence Cinnamic acid can be released by

Rf Value=

Distance from Baseline travelled by Solute Distance from Baseline travelled by Solvent

- Solvent front = 5.6 cm

- Distance travelled by recrystallized product = 4.9 cm

Rf value = 4.9cm = 0.88

5.6cm Distance travelled by standard commercial Cinnamic acid = 4.8 cm

Rf value = 4.8 cm = 0.86

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As the yield is low amount, it is appropriate to use Hirsh funnel for separation. Cinnamic acid can be easily recrystallized using hot water. Melting point of obtained crystals was lower than pure Cinnamic acid, mostly due to moisture (inadequate drying) and impurities. According to TLC results, recrystallized product (0.88) and standard Cinnamic acid (0.86) had mostly the similar Rf values which confirmed the crystals to be Cinnamic acid.

Conclusion

-

Percentage yield of Cinnamic acid = 86.4%

Appendix

- Physical constants Compound Mol. Wt. (g/mol) Density (g/mL) Assay m.p. (0C) b.p. (0C) Malonic acid 104.06 Solid 98%

Benzaldehyde 106.12 1.05 99%

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Reference

1. http://www.arkat-usa.org/get-file/19026/ CY-1086LP published mainmanuscript.pdf (2012/01/22) 2. http://www.chem.shef.ac.uk/level-3/project-2001/knoevenagel_reaction.html (2012/01/22) 3. http://www.organic-chemistry.org/namedreactions/knoevenagel-condensation.shtm(2012/01/22) 4. http://www.chemtube3d.com/Enolates%20with%20aldehydes%20and%20ketones%2 0(Aldol%20Reaction)%20-%20Knoevenagel%20condensation.html (2012/01/21)