Studies on Claisen−Schmidt Condensation in the synthesis of some Chalcones

Introduction

Introduction to chalcone

“chalcone” is derived from the Greek word “chalcos”, meaning “bronze”, which results from the
colors of most natural chalcones. Chalcone compounds have a common chemical scaff old of
1,3-diaryl-2-propen-1-one, also known as chalconoid, that exists as trans and cis isomers, with
the trans isomer being thermodynamically more stable.

The chalcone family has attracted much interest not only from the synthetic and biosynthetic
perspectives but also due to its broad interesting biological activities. Therapeutic applications of
chalcones trace back thousands of years through the use of plants and herbs for the treatment of
diff erent medical disorders, such as cancer, infl ammation, and diabetes. Several chalcone-based
compounds have been approved for clinical use. For example, metochalcone was once marketed
as a choleretic drug, while sofalcone was previously used as an antiulcer and mucoprotective
drug
CHALCONES FROM NATURAL SOURCES

Chalcones are the core of many biologically interesting compounds from natural sources and
have attracted substantial research attention for decades. How many natural chalcones have been
isolated and structurally elucidated? The answer to this question depends on how broadly the net
is cast. As in many articles, the term “chalcone” refers generically to chemicals with an α,β-
unsaturated ketone system. Thus, the chalcone family has extensive structural diversity and can
be roughly classifi ed into two categories: simple/classical chalcones and hybrid chalcones with
the core scaff old of 1,3-diaryl2-propen-1-one. Bichalcones, such as rhuschalcone from Rhus
pyroides, contain two chalcone moieties in a single structure. 23 Dihydrochalcones, such as the fl
eminchalcones from Flemingia philippinensis, are a class of compounds with a reduced α,β- 24
unsaturated double bond. Chalcone mimics (e.g., piperlongumines ) and fused chalcones (e.g.,
oxyfadichalcones ) are not structurally traditional chalcones, although they have a similar α,β-
unsaturated ketone system or fused forms derived from chalcones by special biosynthesis
pathways. When searching for the classical chalcone in the well-known chemical databases,
more than 92 000 chalcones can be found in SciFinder and over 1000 of them have biological
data reported in PubChem Therefore, the number of natural chalcones may ultimately not be
countable with certainty. Representative classical chalcones, bichalcones, dihydrochalcones,
chalcone mimics, and fused chalcones isolated from natural sources in recent years and their
potential biological activities are summarized in Table 1. Some of their biological activities and
applications will be discussed in the following sections.
Synthesis of Chalcone.

Review of literature

Chalcone is synthesized by Claisen-Schmidt condensation, which involves the cross-aldol

condensation of aldehydes and ketones with a base or acid catalyst followed by a dehydration
reaction. Chalcone is a common natural pigment and one of the important intermediaries in
flavonoid biosynthesis . In laboratory synthesis chalcone can be made using the Claisen-Schmidt
reaction by reacting acetophenone compounds or their derivatives with benzaldehyde or their
derivatives using strong bases such as NaOH, KOH, Ba(OH) 2, LiOH.2H2O or NaH as catalysts
in polar solvents. Other catalysts that can also be used are sodium phosphate and aluminum-
magnesium hydroxide hydrate. Whereas acid catalysts are usually used such as HCl, AlCl 3, BF3-
Et2O, TiCl4, RuCl3 . Recently, there have been many synthetic studies involving chalcone
compounds. From previous research conducted by chalcone synthesis was carried out without
the use of solvents, this method produced very high product yields. In the study benzaldehyde
and acetophenone were used in the presence of solid NaOH in mortars, with large crude product
yields ranging from 81-94%. In 2014 it was reported that chalcone compound (1,3-diphenyl-2-
propen-1-one) and its derivative 4-methoxychalcone could be synthesized by microwave
irradiation (400 watt power for 9 minutes) with a catalyst acid (bentonite/montmorillonite) and
yield percentage of 1.72% and 5.21%. Several years the synthesis of several chalcone
derivatives was reported by using two methods, namely the conventional method and the
microwave irradiation method.

Chalcone synthesis different approach

The following paragraphs describe some of the important synthesis of chalcones by using
different chemical reactions other than Claisen Schmidt reaction

By Wittig reaction
By Julia Olefination

By Heck Reaction

Suzuki−Miyaura Coupling for Chalcone Synthesis

One-Pot Synthesis of Chalcones

Claisen−Schmidt Condensation: Overview.

The Claisen−Schmidt reaction is named after two pioneering investigators, R. L. Claisen and J.
G. Schmidt, and describes a process in which a benzaldehyde and a methyl ketone are condensed
in the presence of catalysts

The reaction between an aldehyde or ketone having an alpha-hydrogen with an aromatic

carbonyl compound lacking an alpha hydrogen is called the Claisen–Schmidt condensation. - In
cases where the product formed still has reactive alpha hydrogen and a hydroxide adjacent to an
aromatic ring, the reaction will quickly undergo dehydration leading to the condensation product.

Mechanism of the reaction

This reaction is deemed one of the most classical reactions in Organic chemistry. The catalysts
are either strong bases or acids. In the case of base catalysis, the chalcone is generated from the
aldol product via dehydration in an enolate mechanism, while in the case of acid catalysis, it is
generated via an enol mechanism. The main drawback of this reaction is the slow reaction rate;
the reaction typically needs several days for completion. The reaction could also result in a
complex mixture containing the desirable product, byproducts, and sometimes starting materials.
The yield therefore could vary dramatically, depending on the reactants and catalysts, ranging
from <10% to near 100% conversion. Nevertheless, this reaction has been employed in most
publications because of its experimental simplicity and highly efficient formation of the
carbon−carbon double bond with little restriction to the complexity of the molecules. Szell and
co-workers synthesized a series of nitrochalcones and showed that the presence of electron-
donating groups in the aldehyde favored condensation by acids, while electron-withdrawing
substituents favored condensation by base conditions. Generally, the base condition is more
common in chalcone synthesis.

Base Condition The classical Claisen−Schmidt condensation is base-catalyzed with potassium

tert-butoxide, sodium hydroxide, or potassium hydroxide in methanol or ethanol at room
temperature. This reaction has been widely used for the synthesis of hydroxyl-substituted
chalcones, typically with good to excellent yields (60−90%). A group of ferrocenyl chalcones
has been synthesized under the common base (sodium hydroxide) condition In some cases, an
increase in temperature is required, and the base condition also requires modifi cation. For
example, the α-carbon of a ketone is difficult to dehydrate when the ketone is electrophile
substituted. Such a reaction requires refl ux at an elevated temperature or takes a longer time at
room temperature. However, with a nucleophile substitution on the α-position, mild conditions
are generally sufficient

Acid Condition Although base catalysts are generally used for the synthesis of chalcones,
Brønsted acids, Lewis acids, and solid acids have also been utilized as acid catalysts. The most
common application using ethanol saturated with the Brønsted acid HCl is marginally successful,
with only a 10−40% yield. Dry HCl gas has been shown to be more favorable to the reaction
because it acts as not only a catalyst but also a water absorbent. Aluminum chloride (AlCl 3) has
also been used as a Lewis acid for chalcone synthesis. Two moles of acetophenone per mole of
AlCl3 provide the chalcone product in a high yield (73%). The mechanism of the reaction is not
simply the result of the hydrogen chloride evolved by the heating of acetophenone and AlCl 3; an
intermediate of the general type of R−O−Al−R 2 actually promotes the condensation. The
application of boron trifl uoride−etherate (BF3−Et2O) in the condensation was fi rst reported in a
study describing the use of BF3 gas in chalcone synthesis. In 2007, Narender et al. reported the
use of BF3−Et2O to obtain 15 chalcones with 75-96% yields with reaction times of less than 3 h.
Petrov et al. reported that 16 chalcones, including 4- hydroxyl-chalcone were synthesized in a
SOCl2/ethanol system in high yields (73−96%). SOCl2 was used as a convenient alternative to
the gaseous HCl in the condensation, where HCl was generated in situ by the reaction of SOCl 2
with absolute ethanol.

Experimental section
General information
All the commercially available reagents were used as received. Melting points were
measured with a melting point apparatus and are uncorrected. NMR spectra were recorded on
Brucker 400 MHz FT-NMR spectrometer using tetramethylsilane (TMS) as an internal standard.
All experiments were monitored by thin layer chromatography (TLC). TLC was performed on
peractivated self prepared pltes with silical gel-G. After elution, plate was visualized in iodine
chamber.

Synthesis of Chalcone The experiment was started by adding 5 mmol of acetophenone into 5
ml of ethanol in a round bottom flask, then 5 mmol of benzaldehyde was added to the flask. Then
to the mixture was added 60% NaOH solution, the NaOH is added dropwise while stirring with a
stirrer. After adding NaOH the mixture was stirred for 1.5 hours at room temperature. After
mixing, the mixture is allowed to stand for 4 to 6 hours at room temperature. After being allowed
to stand for up to 6 hours the mixture was poured into ice cold water. Then the crude product
formed is filtered and washed with water. Finally pure chalcone is obtained by recrystallisation
with ethanol.

A series of chalcones have been prepared by using differently substituted aromatic aldehydes.
The results are summerised in the following table. The structure of the end product is confirmed
by spectral analyses

Sl No R Product Yield(%)
1 H 3a 85
2 4-Cl 3b 84
3 4-CH3 3c 86
 Sample 1
1
H-NMR (400 MHz, CDCl3)

13
C-NMR (101 MHz, CDCl3)
Spectral data of the compound 3a1,3-diphenyl-2-propen-1-one

Yellow solid; mp 145 −147 0C (d); 1H NMR (400 MHz, CDCl3) δH, 8.03 (d, 1H, CH), 8.01-7.43
(m, 10H, aromatic) 7.53 (d, 1H, CH). 13C NMR (100 MHz, CDCl3) 190.67, 144.9, 138.2, 134.9,
132.9, 130.6, 129.0, 128.7, 128.6, 128.5, 122.14.

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