Green Chemistry – Aspects for the Knoevenagel Reaction

Knoevenagel condensation is a classic C-C bond formation reaction in organic chemistry (Laue & Plagens, 2005). These condensations occur between aldehydes or ketones and active methylene compounds with ammonia or another amine as a catalyst in organic solvents (Knoevenagel, 1894). The Knoevenagel reaction is considered to be a modification of the aldol reaction; the main difference between these approaches is the higher acidity of the active methylene hydrogen when compared to an -carbonyl hydrogen (Smith & March, 2001).


Introduction
Knoevenagel condensation is a classic C-C bond formation reaction in organic chemistry (Laue & Plagens, 2005).These condensations occur between aldehydes or ketones and active methylene compounds with ammonia or another amine as a catalyst in organic solvents (Knoevenagel, 1894).The Knoevenagel reaction is considered to be a modification of the aldol reaction; the main difference between these approaches is the higher acidity of the active methylene hydrogen when compared to an -carbonyl hydrogen (Smith & March, 2001).
Figure 1 illustrates the condensation of a ketone (1) with a malonate compound (2) to form the Knoevenagel condensation product (3), which is then used to form the ,-unsaturated carboxylic compounds (3) and (4) (Laue & Plagens, 2005).Subsequent to the first description of the Knoevenagel reaction, changes were introduced using pyridine as the solvent and piperidine as the catalyst, which was named the Doebner Modification (Doebner, 1900).The Henry reaction is another variation of the Knoevenagel condensation that utilises compounds with an -nitro active methylene (Henry, 1895).The general mechanism for the Knoevenagel reaction, which involves deprotonation of the malonate derivative (6) by piperidine (5) and attack by the formed carbanion (8) on the carbonyl subunit (9) as an aldol reaction that forms the product (10) of the addition step is illustrated in Fig. 2.After the proton transfer step between the protonated base (7) and compound (10), intermediate (11) forms and is then deprotonated to (12), which forms the elimination product (13) in the last step.

Green chemistry and new synthetic approaches
In the past two decades, classic organic chemistry had been rewritten around new approaches that search for products and processes in the chemical industry that are environmentally acceptable (Okkerse & Bekkum, 1999;Sheldon et al., 2007).With the emergence of Green Chemistry, a term coined in 1993 by Anastas at the US Environmental Protection Agency (EPA), a set of principles was proposed for the development of environmentally safer products and processes: waste prevention instead of remediation; atom efficiency; less hazardous/toxic chemicals; safer products by design; innocuous solvents and auxiliaries; energy efficiency by design; preference for renewable raw materials; shorter syntheses; catalytic rather than stoichiometric reagents; products designed for degradation; analytical methodologies for pollution prevention; and inherently safer processes (Anastas & Warner, 2000).
Consequently, many classic reactions, such as the Knoevenagel reaction, have been studied based upon the green chemistry perspective, which is very important in the context of the pharmaceutical industry.Currently, two indicators are used to evaluate environmental acceptability of products and chemical processes.The first is the Environmental factor (E factor), which measures the mass ratio of kg of waste to kg of desired product, as described by Sheldon in 1992(Sheldon, 2007).The second indicator is a measure of atom economy www.intechopen.comGreen Chemistry -Aspects for the Knoevenagel Reaction 15 based on the ratio of the molecular weight of the desired product to the sum of the molecular weights of all stoichiometric reagents.This indicator enables the evaluation of atom utilisation in a reaction (Trost, 1991).As illustrated in Table 1, the pharmaceutical industry produces 25->100 kg of waste per kg of drug produced, which is the worst E factor observed among the surveyed industrial sectors (Sheldon, 2007).This result is problematic as the pharmaceutical market is among the major sectors of the global economy, accounting for US $ 856 billion in 2010 (Gatyas, 2011a).
Entacapone ( 40) is a catechol-O-methyltransferase (COMT) inhibitor used in combination with L-DOPA for the treatment of Parkinson's disease (Mukarram et al., 2007).This combination prevents L-DOPA degradation through COMT inhibition.As illustrated in Fig. 10, this drug ( 40) is synthesised in yields of 73.0% from aldehyde (41) and methylene compound (42) in ethanol with a piperidine catalyst (Mukarram et al., 2007).The examples illustrated above for selected drug syntheses emphasise the on-going necessity of finding new approaches to carry out classic reactions that are essential to developing environmentally responsible products and chemical processes.Some new, green approaches are presented below.

Microwave-promoted Knoevenagel reactions
Microwave irradiation is a method used to speed up reactions with potential uses under the guidelines of Green Chemistry principles.Microwave radiation utilises wavelengths of 0.001 -1 m and frequencies of 0.3 -300 GHz.When a polar organic reaction is irradiated in a microwave, energy is transferred to the sample, and the result is an increase in the rate of reaction.The transference of energy from microwave radiation to the sample is accomplished through dipolar polarisation and conduction mechanisms (Lidström et al. 2001;Loupy, 2002).As illustrated in Fig. 11, the coumarinic derivative ( 42) is produced in yields of 75.0% after eight minutes of irradiation.This reaction was carried out using aldehyde (43) and methylene compound (44) and was catalysed by piperidine without solvent present (Bogdal, 1998).Following the Knoevenagel condensation, the transesterification reaction to form the ring quickly occurs.There are many examples in the literature involving the use of microwave radiation to promote Knoevenagel reactions.In these examples, several different aldehydes, methylene compounds and catalysts were used for the syntheses involving cinnamic acids on silica gel (Kumar et al., 2000), ammonium acetate (Kumar et al., 1998;Mitra et al., 1999) and lithium chloride as catalysts (Mogilaiah & Reddy, 2004).

Clays as catalysts for Knoevenagel reactions
Clays are abundant in nature, and their high surface area, utility as supports and ionexchange properties have been exploited for catalytic applications (Dasgupta & Török, 2008;Varma, 2002).As shown in Fig. 12, the product of Knoevenagel reaction (45) from the reaction between ninhydrin (46) and malononitrile (47) can be formed in yields of 85.0% after five minutes.This reaction was carried out at room temperature without solvent using K10 as a catalyst (Chakrabarty et al., 2009).Other Knoevenagel reactions between aromatic aldehydes and malononitrile (47) have also performed successfully without solvent using calcite or fluorite catalysts prepared using a ball mill (Wada & Suzuki, 2003).

The use of ionic liquids in Knoevenagel reactions
In recent years, ionic liquids (ILs) have attracted increasing interest as environmentally benign solvents and catalysts due to their relatively low viscosities, low vapour pressures and high thermal and chemical stabilities (Hajipour & Rafiee, 2010;Wasserscheid & Welton, 2002).ILs have been successfully used in a variety of reactions.

Catalysis of Knoevenagel reactions using biotechnology
Historically, microorganisms have been of enormous social and economic importance (Liese et al., 2006).In the pharmaceutical industry, companies are using biotechnology to develop 901 medicines and vaccines targeting more than 100 diseases (Castellani, 2001a).In 2010, 26 new treatments were approved, and five of these treatments were based on biotechnology (Castellani, 2001b).
Using a biotechnology-based approach, coumarin (50) was produced in yields of 58.0% when the reaction was catalysed by alkaline protease from Bacillus licheniformis (BLAP) in a DMSO:H 2 O (9:1) solvent at a temperature of 55 0 C (Fig. 14) (Wang et al., 2011).Because cells are chemical systems that must conform to all chemical and physical laws, whole microorganisms may be used (Alberts et al., 2002).Figure 15 illustrates examples of other Knoevenagel products ( 52) and ( 53) resulting from reactions between benzaldehyde (9) and methylene compounds ( 44) and ( 19) that were catalysed by baker's yeast.These reactions were carried out under mild conditions, e.g., room temperature and in ethanol as the solvent, with moderate to good yields (Pratap et al., 2011).

Knoevenagel reactions in water
Water as a solvent is not only inexpensive and environmentally benign but also provides completely different reactivity (Li & Chen, 2006).It has been suggested that the effect of water on organic reactions may be due to the high internal pressure exerted by a water solution, which results from the high cohesive energy of water (Breslow, 1991).
As illustrated in Fig. 16, the Knoevenagel reaction product ( 55) is formed in yields of 97.0% when condensation between aldehyde (56) and malononitrile (47) was carried out in water at a temperature of 65 0 C in the absence of catalyst (Bigi et al., 2000).The product of the reaction between vanillin (58) and ethyl cyanoacetate (54) was formed in yields of 84.5% in water at room temperature (Fig. 17) (Gomes et al., 2011) approximately 90 minutes, producing yields of 95.0% (Ratan, 2007).Thus, it's clear that there are green approaches for carrying out organic reactions in water to prepare compounds of industrial interest.
Entacapone (40), a COMT inhibitor drug whose synthesis is illustrated above in Fig. 10, is another example of the synthesis of important industrial compounds using green conditions.As shown in Fig. 18, Knoevenagel reaction product ( 59) is formed in yields of 88.0% after two hours under reflux in water with piperidine as a catalyst (McCluskey, 2002).There are others examples of Knoeveganel reactions carried out in water that are catalysed by L-histidine and L-arginine (Rhamati & Vakili, 2010).Isatin compounds (61) can also be produced in water at room temperature after fifteen minutes in yields of 75.0% (Fig. 19) (Demchuk, 2011).( Amantini, 2001).When the prenylated phenolic aldehyde (65) reacts with methylene compound (66) in water at room temperature for three hours, Knoevenagel intermediate (67) forms, which then reacts to form Diels-Alder product ( 63) and ( 64) in yields of 75.0% at a 16:1 ratio (Amantini, 2001).63) and ( 64).

Ultrasound-catalysed Knoevenagel reactions
The application of ultrasound waves triggers high-energy chemistry, which is thought to occur through the process of acoustic cavitation, i.e., the formation, growth and implosive collapse of bubbles in a liquid.During cavitational collapse, intense heating of the bubbles occurs (Suslick, 1990).
The piperidine-catalysed reaction between piperonal (69) and malonic acid (35) at room temperature with pyridine as the solvent was carried out under ultrasound irradiation, and Knoevenagel reaction product (68) formed in yields of 91.0% after three hours (Fig. 21) (McNulty et al., 1998).When carried out under reflux conditions, the same reaction forms the Knoevenagel reaction product in yields of 52.0% after three hours (McNulty et al., 1998).Figure 22 illustrates reactions between benzaldehyde (9) and coumarin ( 71) that can also be conducted in water under ultrasound irradiation at a temperature of 40 0 C for 90 minutes, forming product (70) in yields of 88.0% (Method B) (Palmisano et al., 2011).In the absence of ultrasound irradiation, formation of product (70) occurs in yields of 62.0% under anhydric conditions (Method A) (Palmisano et al., 2011).

Solvent-free Knoevenagel reactions
As mentioned previously, the reduction or elimination of volatile organic solvents in organic syntheses is one of the main goals in green chemistry.Solvent-free organic reactions result in syntheses that are simpler and less energy-intensive, and these conditions also reduce or eliminate solvent waste, hazards, and toxicity (Tanaka, 2003).

Knoevenagel reactions using solid phase organic synthesis
An innovative and important field of organic synthesis involves the use of solid phase organic synthesis (Czarnik, 2001).This new methodology was introduced by Merrifield in 1963 when he used it to synthesise amino acids (Merrifield, 1963).Solid phase organic synthesis uses insoluble polymers that covalently bond organic substrates to the solid surface until the synthesis is complete, at which point the compound of interest is separated from the solid matrix (Czarnik, 2001).
This approach has been used to synthesise coumaric compound (79) from the reaction of aldehyde (81) and methylene compound (80) bonded to Wang resin.The reaction was complete after sixteen hours under Doebner conditions, as illustrated in Fig. 25 (Xia et al., 1999).Solid phase Knoevenagel reactions were also utilised to produce triphostin protein tyrosine kinases inhibitors.As illustrated in Fig. 26, the piperidine-catalysed reaction between 4hydroxybenzaldehyde ( 22) and a resin-bonded methylene compound (83) was carried out using DMF:MeOH (10:1) as the solvent over a period of twelve hours (Guo et al., 1999).

Conclusions
As illustrated by the examples presented herein, classic reactions such as the Knoevenagel condensation can be modernised through new approaches related to Green Chemistry.Particularly in the area of drug synthesis, these new approaches have been being very useful in the development of more environmentally supportable products and chemical processes in the pharmaceutical industry, which works with compounds with high added values.

Acknowledgments
The author is grateful to FAPEG, INCT-INOFAR and UFG for financial support.

Fig. 3 .
Fig. 3.A Knoevenagel condensation used during the synthesis of atorvastatin (14).In addition to atorvastatin (14), many others drugs and pharmacological tools use the Knoevenagel reaction during their syntheses.Figure4illustrates the synthesis of pioglitazone (17), a benzylthiazolidinedione derivative approved as a drug for the