Water as Solvent

If a solvent is needed for a reaction the most preferable alternative to organic solvent from a green chemistry perspective is water as the cheapest and most abundant solvent available, non-toxic and not inflammable. Although water provides a unique hydrogen-bond network that can beneficially influence the rate and selectivity in many organic reaction, its use has been strongly limited by the fact that the majority of organic compounds is poor soluble or unstable in this reaction medium.

An increase in solubility of non-polar reactants has been often achieved by pH variation, addition of additives as salts or surfactants and use of water-polar organic cosolvent mixtures and many stereoselective C-C bond forming reactions as well as oxidations and hydrogenations have been performed in these modified aqueous media [10]. However, the use of water as sole solvent remains still very challenging for asymmetric catalysis and, despite of the fact that some aspects of the greenness of water in organocatalysis have been recently questioned [11], it represents a very attractive research field.

In a debate on the most suitable terminology to describe reactions in water Sharpless proposed the term ''on water'' for reactions that take place in an emulsion of insoluble reagents stirred in neat water and display rate acceleration compared to the same reaction performed in organic solvent [12]. The positive effects observed in these conditions for many reactions [13] dismantled the concept of solubility as prerequisite for reactivity and has indicated a new way to organic synthesis. Hayashi suggested to term ''in water'' those reactions in which the reactants are homogeneously dissolved in opposition to ''in presence of water'' for reactions proceeding in a concentrated organic phase influenced by water as second phase, the latter definition also including the situation described as ''on water'' [14].

Since the gain in the use of water as more sustainable solvent needs to be conjugated with synthetic and chiral efficiencies, whose decrease could lead otherwise to an increase in cost and chemical waste, much efforts are continuously devoted to the development of new chiral catalytic systems compatible with water, in some cases driven by the knowledge of enzymatic processes that ''naturally''

occur in water and the study of the relationships between the effects generated by water (hydrogen-bonding, hydrophobicity, acidity) and reactivity and stereose-lection. The de novo design of chiral catalysts specifically targeted to their use in water has been rather unexplored while approaches relying on chemical modifications of yet known active catalysts in order to increase their hydrophilicity or, on the contrary, their hydrophobicity have been mainly investigated.

Water-soluble catalysts allow to fully exploit the properties of water to promote the dissociation of ionic species also providing their effective solvation, to modify the reactivity of Lewis acid species due to its nature of Lewis base, and to serve as acid, base or nucleophilic reagent. Furthermore, selectivity can be finely tuned by pH variation or addition of salts and the catalyst can be easily recovered for its recycle by simple phase extraction, this aspect being very attractive for large scale preparations. Since the use of a water-soluble catalyst can result in decreased activity in consequence of poor interactions with hydrophobic substrates, there is considerable interest also in the design of surfactant-like ligands bearing substit-uents with polar or ionic groups at the end of long aliphatic chains or ligands with adjustable solubility properties, as amine- or polyethylene glycol (PEG)-substituted catalysts whose hydrophilicity can be modulated by pH or temperature changes. On the other side, many organocatalysts have been functionalised with large apolar groups in order to cluster together the catalyst and reagents in the aqueous environment by means of hydrophobic interactions and it has been proposed that in such systems reactions occur in a concentrated organic phase constituted by reagents, catalyst and the formed products [15].

The hydrophilic character of chiral phosphines, the largest group of chiral ligands in transition-metal based catalysis, has been usually increased by the introduction, either on the carbon backbone or at phosphorous atom, of anionic sulphonate, phosphonate or carboxylate substituents that exist in ionic form over a broad range of pH, are stable under a variety of reaction conditions and do not interfere with the catalytic cycle due to their low tendency to bind late transition-metals. Functionalization with protonable basic groups or non-ionic polyhydroxyl or polyether substituents has also been explored for the preparation of water-soluble phosphines.

Despite of the obvious modifications in steric and electronic properties of such ligands with respect to the parent molecules for the presence of water-solubilizing groups, good results have been obtained in different reactions with a large predominance of enantioselective olefin hydrogenation [16]. In most cases the reactions have been performed in homogeneous water-organic cosolvent mixtures or in biphasic systems but a limited number of catalysts was also active in pure water.

Hydrogenation of pharmaceutical intermediate 9 with sulphonated BIPHEMP 5/Ru-catalyst proceeded in water with the same enantioselectivity reported in MeOH [17] (Scheme 3.2a) and also Ru-promoted carbonyl hydrogenation of ethylace-toacetate was effectively carried out in the presence of water-soluble ligand 6c. In water as sole solvent, Rh(I)-complexes with hydroxylated DuPHOS 7a [18] or CHIRAPHOS-analogue 8b promoted hydrogenation of dehydroaminoacids in high

MeO MeQ.

MeO MeQ.

R= H, Ar = m-C6H4SO3"Na+ R = PO3H2, Ar = Ph R = CH2NH2, Ar = Ph R = CH2NHC(=NH)NH2, Ar = Ph

R1 R1

(S,S,S,S)-7a R = CH2OH, R1= H (S,S,S,S)-7b R = Me, R1 = OH

Ar2P

PAr2

(S,S)-8a Ar = m-C6H4SO3"Na+ (S,S)-8b Ar = p-C6H4NMe3+BF4

COO-Et3NH

O COO-Et3NH

in MeOH S/C 40000 98.5% ee in H2O S/C 10000 >99% ee

COOH NHCOMe

Scheme 3.2 Hydrogenations with water-soluble phosphines optical purities. Enhanced reaction rate in comparison with biphasic H2O/AcOEt system was observed with 8b and the presence of trimethylammonium groups in the ligand also facilitated the separation of Rh-catalyst, reused three times without loss of enantioselectivity [19] (Scheme 3.2b).

Asymmetric transfer hydrogénation (ATH) of ketones and imines promoted by Ir(III)- Rh(III)- or Ru(II)-complexes to give the corresponding chiral secondary alcohols and amines is an attractive green process since it avoids the use of hazardous molecular hydrogen using 2-PrOH or formic acid as hydrogen sources. Besides the most popular ligand TsDPEN 10, originally developed by Noyori [20], a variety of diamines and aminoalcohols have been tested for ATH of several

R = H (R,R)-10 TsDPEN R = SO3Na (R,R)-10a R = NH2 (R,R)-10b

Me Me

R = H (R,R)-10 TsDPEN R = SO3Na (R,R)-10a R = NH2 (R,R)-10b

NHSO2

"Vf h2n nhr

"Vf h2n nhr

R = H, R1= Ph (S,S)-13 (R,S)-14 R = Me, R1= Me (S,S)-13a

H2N "NHSO2"%A

R = Me R1 = H, Me, OMe, F, Br R = Et, CH2Br, R1 = H

R NH

R = Me, Et, i-Pr Scheme 3.3 Asymmetric transfer hydrogenations in water

68-97% 90-99% ee aromatic and heteroaromatic substrates in 2-PrOH or HCOOH/triethylamine with excellent performances in many cases [21]. Functionalization of TsDPEN with sulphonic [22, 23] or aminic [24] groups has led to water-soluble ligands whose complexes retained high enantioselectivity in ATH of ketones and cyclic imines with HCOONa as hydrogen source in neat water sometimes containing low amount of a surfactant to facilitate substrate solubilisation (Scheme 3.3). Derivatization of TsDPEN with hydrophilic polyethylene glycol (PEG) gave soluble polymer-supported ligands [25, 26] and ruthenium complex of 11 displayed excellent performances and recyclability in ATH of several ketones under aqueous conditions, being active without loss of enantioselectivity for up to

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