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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 α hydrogen ) perform a condensation reaction with compounds of the form Z-CH 2-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. CH 3Z. 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. The Knoevenagel Reaction is a modified version of the aldol reaction. The reaction serves particularly for the chain extension of more aromatic aldehydes. Much less work on the Knoevenagel condensation involving ketones has been done because ketones are generally very unreactive towards Knoevenagel condensation. A secondary amine is used as

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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,βunsaturated acids or compounds is a general use of Knoevenagel condensation.

e.g. I

RCHO + CH2(CO2C2H5)2

base

RCH=C(CO2C2H5)2 + H2O base

II

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

CH(CO2C2H5)2

RCH

+ H2O

CH(CO2C2H5)2 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:

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II). this enol reacts with the aldehyde, and the resulting aldol undergoes subsequent baseinduced 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: CH 2Cl2 (5:95). The melting point of  obtained crystals and mixed melting point were measured.

Results

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Melting point of the prepared crystals (Cinnamic acid) = 118 - 120 C 0 0 Mixed melting point = 120 - 122 C -

Weight of the crystals = 1.52 g

5.60cm

4.90cm 4.80cm

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-----------TLC plate----------

Calculations C6H5CHO(l) + CH2(COOH)2(s)

C6H5CH=CHCOOH(s) + CO2(g) +H2O(l)

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Used moles of malonic acid

= =

-

Used moles of benzaldehyde

= =

1.0g x 98 -1 104.06 gmol 100 0.009 mol 0.3 ml x 1.05 gml -1 106.12 gmol 0.003 mol

-1

x

99 100

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 0.44 g

Actual yield

=

0.38 g

% yield of Cinnamic acid

=

0.38 g x 100 0.44 g

-

-1

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=

86.4%

o Rf  Values (Retention values)

-

Solvent front

Distance travelled by recrystallized product Rf value

Distance travelled by standard commercial Cinnamic acid Rf value

= 5.6 cm = 4.9 cm 4.9cm = 5.6cm = 4.8 cm 4.8 cm = 5.6 cm

=

0.88

=

0.86

Discussion Distance from Baseline travelled by Solute

In this experiment, Knoevenagel Distance from Baseline travelled by Solvent 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 the addition of an acid. Thus adding HCl leads to form white precipitate of Cinnamic acid. Rf Value

=

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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)

Malonic acid Benzaldehyde Cinnamic acid

104.06 106.12 148.15

Solid 1.05 -

98% 99% 100%

132-134

b.p. (0C)

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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/knoevenagelcondensation.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)

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