Solvent-Free Aldol Condensation

Discovery Experiment Solvent-Free Aldol Condensation 

Some but not all organic reactions proceed well in the absence of solvent(s). Develop a solvent-free protocol for the aldol reaction using solid sodium or potassium hydroxide as the base. The reaction can be successfully performed on a 5-10 mmol scale, using an equivalent of base. Bear in mind that the base should be finely divided, so it should first be crushed with a mortar and pestle. In addition, the condensation partners should be mixed thoroughly before the base is added. The reaction should take no more than 20-25 minutes, and the mixture should be acidified to pH 5 with 10% HCI prior to isolation of the product. Characterize the product by its melting point and using spectroscopic techniques. 

Possible combinations that you might use include acetophenone with either 4-methylbenzaldehyde or 4-chlorobenzaldehyde, 1-indanone with either 4-phenylcyclohexanone or 3,4-dimethoxybenzaldehyde, 4-phenylcyclohexa-none with 3,4-dimethoxybenzaldehyde, and 3,4-dimethoxybenzaldehyde with 3,4-dimethoxyacetophenone. Self-condensation of 4-methylbenzaldehyde is also a possibility. Consult with your instructor before undertaking any experiments. 

Neutralize the ethanolic filtrates with dilute hydrochloric acid, and flush them down the drain. Place the dichloromethane solution from the bromine test for unsaturation in a container for halogenated organic liquids. 

Compute the equilibrium constant, for the reaction of equimolar amounts of acetophenone, C H5COCH3, and hydroxide ion to generate the enolate ion. The pKg values of the ketone and of water are 19.0 and 15.7, respectively. 

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Chemoselective, Solvent-free aldol Condensation Reactions... 

Raston. C.L. Scott. J.L. Chemoselective, solvent-free aldol condensation reaction. Green Chem. 2000. 2. 49-52. 

Discovery Experiment Solvent-Free Aldol Condensation... 

Some aldol condensation reactions proceed more efficiently and stereoselectively in the ab.sence of solvent than in solution [18]. When the solvent-free aldol reaction is carried out in an inclusion complex with a chiral host complex, diastereo-and enantioselective reactions occur, although enantioselectivity is not high [18]. 

One of the most thoroughly investigated aldol condensations is the selfcondensation of acetone. This is an important industrial reaction for the production of diacetone alcohol (DA) (Scheme 11), which is valuable as a chloride-free solvent and an intermediate in the synthesis of industrially important products such as mesityl oxide (MO), isophorone, methyl isobutyl ketone, and 3,5-xylenol. The reaction is exothermic, with the yield of DA decreasing with increasing reaction temperature it is usually performed with NaOH or KOH as a basic catalyst 118). 

Catalysis in reaction systems with undissolved substrates and products is not restricted to biocatalysis. High yields in sobd-state synthesis, sohd-to-sohd reactions, and solvent-free systems have also been reported for aldol condensation, Baeyer-Villiger oxidation, oxidative coupling of naphthols, and condensation of amines and aldehydes [1, 2]. 

When aliphatic nitro compounds are used instead of aldehydes or ketones, no reduction occurs, and the reaction has been referred to as a Tollens reaction (see 16-43). However, the classical condensation of an aliphatic nitro compound with an aldehyde or ketone is usually called the Henry reaction or the Kamlet reaction, and is essentially a nitro aldol reaction. A variety of conditions have been reported, including the use of a silica catalyst, Mg—A1 hydrotalcite, a tetraalkylam-monium hydroxide,proazaphosphatranes, " or an ionic liquid.A solvent free Henry reaction was reported in which a nitroalkane and an aldehyde were reacted on KOH powder. Potassium phosphate has been used with nitromethane and aryl aldehydes. The Henry reaction has been done using ZnEt2 and 20%... 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

For example, onium ion-tagged prolines have been synthesized and their catalytic activity in direct asymmetric aldol condensation was initially studied in molecular solvents.The observed superior performance of IL-proline relative to Peg-proline or free proline, in terms of yields and enantiomeric excess, evidenced that the ionic moiety in IL-proline plays more than a silent or simply supporting role in the reaction (Scheme 4.4). ... 

Salehi, R, Dabiri, M., Zolfigol, M.A. and Fard, M.A.B. 2004. Silica sulfuric acid as an efficient and reusable reagent for crossed-aldol condensation of ketones with aromatic aldehydes under solvent-free conditions. J. Braz. Chem. Soc. 15(5) 773-776. 

Chalcones (123) are commonly prepared by Claisen-Schmidt or aldol condensation. An important way to synthesize chalcones (123) is the Friedel-Crafts acylation involving treatment of acid chlorides (121) with arenes (122). Such a protocol for the synthesis of chalcones (123) was developed by More et al. (2012) using nano-ZnO heterogeneous catalyst under solvent-free conditions at room temperature (Scheme 9.38). Arenes (122) of all sorts, activated as well as unactivated, reacted smoothly to afford the chalcones (123) in excellent yield. High regioselectivity was observed during the course of reaction, which occurred selectively at the para-position of OMe, Br, Me, and Cl. 

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