An important part of our efforts towards a more environmentally friendly, green chemistry is aimed at a reduction of the use of organic solvents. Usually, organic solvents are used in much larger quantities than the solutes they carry and have a tendency to escape into the environment through evaporation and leakage. A lot of research is currently devoted to the replacement of organic solvents by a less environmentally hazardous one. Nature's own solvent, water, is ideally suited for this purpose owing to its non-toxic character. Its enormous abundance on this planet makes water a cheap and readily accessible alternative.
The increased focus on water in synthetic organic chemistry during the past few decades has
resulted in a large number of reactions that can now be performed successfully in an aqueous medium. Among these reactions are allylation reactions, the aldol condensation, the Michael addition, the Mannich reaction, indium-mediated allylation and Grignard-type additions and the benzoin condensation. Surprisingly, also notoriously solvent-insensitive reactions such as the Claisen rearrangement and the 1, 3-dipolar cycloaddition can benefit dramatically from an aqueous medium. Perhaps the most striking and unexpected example of a reaction that benefits from the use of an aqueous solvent system is the Diels-Alder reaction.
Why water:
Advantages:
1. Not flammable, toxic or explosive
2. Cheapest solvent on the planet
3. Highest heat capacity of all liquid (4.19 J/gC)
4. Solation of organics facile through extraction
5. Low volatility aids recycling.
Drawbacks:
1. Metals difficult to remove
2. Removing organics before disposal can also be difficult
3. High heat capacity=lots of energy for distillation
Water is essential for life and an interesting molecule in chemistry Organic reactions in aqueous media have attracted much attention, firstly because water induces unique reactivity and selectivity which are not observed for reactions in organic media, and secondly because use of water as a solvent will reduce use of harmful organic solvents and may lead to the development of environmentally friendly chemical processes. Since the discovery of water-compatible Lewis acids, we have been investigating the development of efficient organic reactions in aqueous media.
Water-accelerated reactions-
On water reactions are a group of organic reactions that take place as an emulsion in water and that exhibit unusual reaction rate acceleration compared to the same reaction in an organic solvent or compared to the corresponding dry media reaction.
The rate acceleration is found in certain Claisen rearrangements. In one typical example of this reaction at room temperature the chemical yield was found to be 100% on water after 120 hours compared to 16% with the same reaction in toluene or 73% in the neat reaction.
Enhanced reactivity is also found in cycloadditions. The reaction of quadricyclane with DEAD is a 2σ + 2σ + 2Ï€ cycloaddition that on water takes place within 10 minutes at room temperature with 82% yield. The same reaction in toluene takes 24 hours at 80°C with 70% yield. An emulsion reaction in fluorinated cyclohexane takes 36 hours and the neat reaction takes even longer (48 hours).
Other reactions with apolar reactants such as Ene reactions and Diels-Alder reactions also exhibit rate accelerations. it involves hydrogen bonding and the presence of a small amount of dissolved solute. This reaction type is of interest to green chemistry because it greatly reduces the usage of organic solvents, reaction product isolation is relatively easy, and it increases the yields and chemical purity with little extra expenditure, if not less.
SPECIAL EFFECTS OF WATER ON DIELS-ALDER REACTIONS:
In general, the use of an aqueous medium increases the rate of Diels-Alder reactions significantly as compared to all organic solvents. In extreme cases accelerations can exceed a factor of 10 000 [7]. In addition, aqueous solvents tend to enhance the selectivity of the reaction. More specifically, the generally observed preference for the formation of the endo cycloadduct is even more pronounced in water. Also, the regioselectivity and diastereofacial selectivity tends to increase in aqueous media.
This pattern strongly suggests that in water, a hydrogen-bond donating solvent par excellence, the Diels-Alder reaction benefits not only from enforced hydrophobic interactions but also from hydrogen-bonding interactions. The small size of water molecules allows efficient interaction with hydrogen-bond acceptors by forming more hydrogen bonds than protic organic solvents.
the use of water as a solvent for the Diels-Alder reaction is not merely an environmentally friendly alternative, but has considerable additional advantages in the form of significant water-induced increases in rates and selectivities. Possibilities exist for further rate enhancements and even for enantioselective catalysis by using (chiral) Lewis-acid catalysts in an aqueous medium. Despite these obvious benefits water is still not always the solvent of choice for the Diels-Alder reaction. The poor water solubility of many Diels-Alder reactants and the difficulties in achieving efficient interaction between Lewis-acid catalyst and substrate are major obstacles. The use of micelles and low concentrations of cosolvents might provide ways around these obstacles eventually transforming the Diels-Alder reaction into a clean and green process.
Examples
A coupling reaction between an indole and quinine takes place at room temperature without catalyst in water in 82% chemical yield even though reactants and products are insoluble in this medium. The reaction is much less efficient in homogeneous systems such as dichloromethane, toluene and acetonitrile or even the solvent free reaction or even the water reaction but now at 50°C
In this reaction the alkyne methyl 2-octynoate reacts with triphenylphosphine to an intermediate zwitterionic allenolate, a dipolarophile for the 1,3-dipole 2-phenylnitrone. The primary regioselective [3+2] dipolar cycloaddition product then rearranges to a -dihydroisoxazole with regeneration of the phospine. This reaction only takes place in water with lithium chloride added even though the reactants do not dissolve in this medium. In organic solvents such as toluene or dichloromethane no reaction takes place.
Reaction in presence of water
An alternative classification with broader scope is suggested by Yujiro Hayashi as he describes certain organocatalytiy Aldol reactions as taking place in the presence of water. The observed effect in these reactions is not rate acceleration (that would be On Water) but happens to be increase in enantioselectivity.
In the context of organocatalysis both concepts of on-water reactions and in-the-presence-of-water reactions have been criticized in 2007 as not so environmentally friendly by Donna Blackmond. According to Blackmond, separation of reaction product from the water phase usually requires organic solvent anyway and in reported aqueous systems the water phase can in reality be less than 10% of the total reaction mixture with another component forming the actual solvent. Blackmond also notes that in reported instances, the observed rate-acceleration in presence of water is in fact due to water suppressing reaction deactivation
Water-compatible reactions:
Lewis acid catalysis has attracted much attention in organic synthesis as it often affords access to unique reactivity and selectivity under mild conditions. Although various kinds of Lewis acids have been developed and applied in industry, these Lewis acids must be generally used under strictly anhydrous conditions, as the presence of even a small amount of water interferes with the reactions due to preferential reaction of the Lewis acids with water rather than the substrates. In contrast to this, rare earth and other metal complexes have been found to be water-compatible. Furthermore, Bi(OTf)3- and Ga(OTf)3-basic ligand complexes have also been found to be stable in water, and have been used as water-compatible Lewis acids. This application is particularly significant, as Bi(OTf)3 and Ga(OTf)3 themselves are unstable in the presence of water, but are stabilized by the basic ligands. This observation has led to the development of a new approach to Lewis acid catalysis in which Lewis acids that are generally unstable in the presence of water are rendered amenable to aqueous systems when combined with basic ligands. In particular, the use of chiral basic ligands leading to new types of water-compatible chiral Lewis acids may enable a wide range of asymmetric catalysis in aqueous media.
Some Research
Catalytic Asymmetric Mannich-Type reaction in aqueous media.
Asymmetric Mannich-type reactions are one of the most important methods to obtain optically active nitrogen-containing compounds. We have developed a catalytic system for this type of reactions in aqueous media.
2.Three Component Aza-Diels-Alder Reactions in Water
Three component reactions using aldehydes, amines, and indoles (Aza Friedel Crafts reactions) produce byproducts predominantly in organic solvents. On the other hand, we found that the desired indole derivatives could be obtained successfully by using catalytic amount of C9H19COOH in water as a sole solvent. The desired products can be intermediates of biologically active compounds.
Grignard reaction:
The Grignard reaction is an organometallic chemical reaction in which alkyl- or aryl-magnesium halides (Grignard reagents) act as nucleophiles and attack electrophilic carbon atoms that are present within polar bonds (e.g. in a carbonyl group as in the example shown below) to yield a carbon-carbon bond, thus altering hybridization about the reaction center.The Grignard reaction is an important tool in the formation of carbon-carbon bonds and for the formation of carbon-phosphorus, carbon-tin, carbon-silicon, carbon-boron and other carbon-heteroatom bonds.
The disadvantage of Grignard reagents is that they readily react with protic solvents (such as water), or with functional groups with acidic protons, such as alcohols and amines. In fact, atmospheric humidity in the lab can dictate one's success when trying to synthesize a Grignard reagent from magnesium turnings and an alkyl halide. One of many methods used to exclude water from the reaction atmosphere is to flame-dry the reaction vessel to evaporate all moisture, which is then sealed to prevent moisture from returning. However, though the reagents still need to be dry, ultrasound can allow Grignard reagents to form with less stringent regard to the amount of water in the reaction mix by activating the surface of the magnesium such that it consumes any water present.
Another disadvantage of Grignard reagents is that they do not readily form carbon-carbon bonds by reacting with alkyl halides via an SN2 mechanism.
Stereoselective reactions in aqueous media:
In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during the non-stereospecific creation of a new stereocenter or during the non-stereospecific transformation of a pre-existing one. The selectivity arises from differences in steric effects and electronic effects in the mechanistic pathways leading to the different products. Stereoselectivity can vary in degree but it can never be total since the activation energy difference between the two pathways is finite. However, in favorable cases, the minor stereoisomer may not be detectable by the analytic methods used. And in aqueous media is called Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water (H2O) are split into hydrogen cations (H+) (conventionally referred to as protons) and hydroxide anions (OH−) in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by step-growth polymerization. Such polymer degradation is usually catalysed by either acid, e.g., concentrated sulfuric acid (H2SO4), or alkali, e.g., sodium hydroxide (NaOH) attack, often increasing with their strength or pH.
Types:-
Hydrolysis is a chemical process in which a certain molecule is split into two parts by the addition of a molecule of water. One fragment of the parent molecule gains a hydrogen ion (H+) from the additional water molecule. The other group collects the remaining hydroxyl group (OH−).
The most common hydrolysis occurs when a salt of a weak acid or weak base (or both) is dissolved in water. Water autoionizes into negative hydroxyl ions and positive hydrogen ions. The salt breaks down into positive and negative ions. For example, sodium acetate dissociates in water into sodium and acetate ions. Sodium ions react very little with hydroxyl ions whereas acetate ions combine with hydrogen ions to produce neutral acetic acid, and the net result is a relative excess of hydroxyl ions, causing a basic solution.
However, under normal conditions, only a few reactions between water and organic compounds occur. In general, strong acids or bases must be added in order to achieve hydrolysis where water has no effect. The acid or base is considered a catalyst. They are meant to speed up the reaction, but are recovered at the end of it.
Acid-base-catalyzed hydrolyses are very common; one example is the hydrolysis of amides or esters. Their hydrolysis occurs when the nucleophile (a nucleus-seeking agent, e.g., water or hydroxyl ion) attacks the carbon of the carbonyl group of the ester or amide. In an aqueous base, hydroxyl ions are better nucleophiles than dipoles such as water. In acid, the carbonyl group becomes protonated, and this leads to a much easier nucleophilic attack. The products for both hydrolyses are compounds with carboxylic acid groups.
Perhaps the oldest example of ester hydrolysis is the process called saponification. It is the hydrolysis of a triglyceride (fat) with an aqueous base such as sodium hydroxide(NaOH). During the process, glycerol is formed, and the fatty acids react with the base, converting them to salts. These salts are called soaps, commonly used in households.
Moreover, hydrolysis is an important process in plants and animals, the most significant example being energy metabolism and storage. All living cells require a continual supply of energy for two main purposes: for the biosynthesis of small and macromolecules, and for the active transport of ions and molecules across cell membranes. The energy derived from the oxidation of nutrients is not used directly but, by means of a complex and long sequence of reactions, it is channeled into a special energy-storage molecule, adenosine triphosphate (ATP).
The ATP molecule contains pyrophosphate linkages (bonds formed when two phosphate units are combined together) that release energy when needed. ATP can undergo hydrolysis in two ways: the removal of terminal phosphate to form adenosine diphosphate (ADP) and inorganic phosphate, or the removal of a terminal diphosphate to yield adenosine monophosphate (AMP) and pyrophosphate. The latter is usually cleaved further to yield two phosphates. This results in biosynthesis reactions, which do not occur alone, that can be driven in the direction of synthesis when the phosphate bonds have undergone hydrolysis.
In addition, in living systems, most biochemical reactions, including ATP hydrolysis, take place during the catalysis of enzymes. The catalytic action of enzymes allows the hydrolysis of proteins, fats, oils, and carbohydrates. As an example, one may consider proteases, enzymes that aid digestion by causing hydrolysis of peptide bonds in proteins. They catalyze the hydrolysis of interior peptide bonds in peptide chains, as opposed to exopeptidases, another class of enzymes, that catalyze the hydrolysis of terminal peptide bonds, liberating one free amino acid at a time.
However, proteases do not catalyze the hydrolysis of all kinds of proteins. Their action is stereo-selective: Only proteins with a certain tertiary structure will be targeted. The reason is that some kind of orienting force is needed to place the amide group in the proper position for catalysis. The necessary contacts between an enzyme and its substrates (proteins) are created because the enzyme folds in such a way as to form a crevice into which the substrate fits; the crevice also contains the catalytic groups. Therefore, proteins that do not fit into the crevice will not undergo hydrolysis. This specificity preserves the integrity of other proteins such as hormones, and therefore the biological system continues to function normally.
Hydrolysis of amide links:
In the hydrolysis of an amide into a carboxylic acid and an amine or ammonia, the carboxylic acid has a hydroxyl group derived from a water molecule and the amine (or ammonia) gains the hydrogen ion.
A specific case of the hydrolysis of an amide link is the hydrolysis of peptides to smaller fragments or amino acids.
Many polyamide polymers such as nylon 6,6 are attacked and hydrolysed in the presence of strong acids. Such attack leads to depolymerization and nylon products fail by fracturing when exposed to even small amounts of acid. Other polymers made by step-growth polymerization are susceptible to similar polymer degradation reactions. The problem is known as stress corrosion cracking.
Regioselective reactions in aqueous media
A regioselective reaction is one in which one direction of bond making or breaking occurs preferentially over all other possible directions. Reactions are termed completely (100%) regioselective if the discrimination is complete, or partially (x%), if the product of reaction at one site predominates over the product of reaction at other sites. The discrimination may also semi-quantitatively be referred to as high or low regioselectivity.
Indium-mediated highly regioselective reaction of prop-2-ynyl bromides with acyl cyanides in aqueous media
Indium-mediated reaction of acyl cyanides 1 with prop-2-ynyl bromides 2 in aqueous media occurs regioselectively to afford either allenic 3 or propargylic ketones 4 depending on the γ-substituent of the prop-2-ynyl bromide under the mild conditions
Ester synthesis in aqueous media in the presence of various lipases
The ability of seven lipase preparations to catalyse methyl ester synthesis in aqueous media was compared and the synthesis reaction (esterification or alcoholysis) determined. Three behaviours were observed: three enzymes catalysed ester synthesis by esterification of free fatty acids and one enzyme catalysed alcoholysis but the other three lipases did not catalyse a net ester synthesis under the conditions tested. The three groups also differed by the influence of methanol on the hydrolysis reaction. The first group was not significantly inhibited up to the highest methanol concentration tested (5 M). Hydrolysis in the presence of the enzyme of the second group was increasingly inhibited with increasing methanol concentrations. In the presence of the third group, hydrolysis was 40 to 50% inhibited for all the concentrations tested (0.2-5 M).
glycerol ester hydrolases are characterized by their ability to catalyse the hydrolysis of triacylglycerols and, under certain conditions,ester production by esterification, alcoholysis, acidolysis or inter-esterification. Although most of the published studies of lipase-catalysed ester synthesis have been peIformed in non-aqueous media, some lipases have been shown to catalyse ester synthesis in aqueous media In the presence of alcohol in the aqueous phase, esters can be produced by two mechanisms : a direct transfer of acyl groups fiom an acyl
donor ester by alcoolysis, or the esterification of free fatty acids, eventually resulting from the hydrolysis of an acyl donor ester.
Regioselective Propargylation of Aldehydes with Propargyl Bromide
Mediated by Sn-In in Aqueous Media under
Tin-indium were employed in the propargylations of various aldehydes with propargyl
bromide in the presence of SnCl2 and C6H5(CH3)3NBr under microwave irradiation to afford thecorresponding homopropargyl alcohols exclusively in high yields. All the reactions were completed smoothly in predominantly aqueous media in 200 seconds only.
Water used to control regioselectivity
"Organocatalyzed Highly Enantioselective Direct Aldol Reactions of Aldehydes with Hydroxyacetone and Fluoroacetone in Aqueous media: The Use of Water to Control Regioselectivity"
C-C bond formations in aqueous media
A calcium vanadate apatite (VAp) acts as a high-performance heterogeneous base catalyst for various carbon-carbon bond-forming reactions such as Michael and aldol reactions in aqueous media. No vanadium leaching was detected and the catalyst was readily recycled with no loss of activity.
C-C bond formation reactions between (benzamidomethyl)triethylammonium chloride (1) and some carbon nucleophiles were performed smoothly in aqueous media, under mild reaction conditions and ambient temperature. Mono-C-alkyl and di-C-alkyl derivatives were obtained without using a catalyst. Crystals of the products were easily isolated by simple filtration, in moderate yields and with no apparent contamination due to the formation of O-alkyl products
Carbon-carbon bond formation is the essence of organic synthesis and provides the foundation for generating more complicated organic compounds from the simpler ones. In the latest decade, there has been increased recognition that organic reactions can proceed well in aqueous media and offer advantages over those occurring in organic solvents. Organic syntheses in water have attracted much attention, not only because unique reactivity is often observed in water but also because water can significantly shorten the synthetic route, increase product selectivity and reduce the volatile organic consumption.
In this trend, Manabe and Kobayashi ade a step forward in palladium-catalyzed allylic substitution with carbon nucleophiles as one of the most important and useful carbon-carbon bond-forming reactions. They disclosed a new catalytic system for substitution in aqueous medium. Also, the key of the catalytic system was the use of a catalytic amount of a carboxylic acid, which greatly accelerates the reactions.
Recently, similar catalyzed nucleophilic reactions were reported, but polar organic solvents were used as a medium. Allylic substitution of alcohols with some C-nucleophiles such as β-diketones, catalyzed by Pd - complexes, gives an excellent result for forming new C-C bonds . Pd-complexes also were found to catalyze nucleophilic benzylic substitution of benzylic esters, with high generality In this reactions two different types of products were demonstrated, mono-C and di-C substituted products. Catalytic allylation with anilines, nitrogen compounds and 1,3-dicarbonyl compounds takes place with Pd-complex and H-mont (or other solid Bronsted acid) as a catalyst. Direct substitution of alcohols with allyl-, propargyl- and alkynyl- silanes catalyzed by InCl3 or with active methylene compounds catalyzed by Pd-complexes was also reported as a good synthetic approach that gives moderate to high yields of the products.
Literature data for the C-C bond formation by the SN2 reactions of enolate intermediates in aqueous medium are sparse. This motivated our research to be primary focused on investigating the possibility for building new C-C bonds in the reaction of nucleophilic substitution in aqueous media without using a catalyst and secondary, on the synthesis of new benzamidomethyl derivatives, which may have a great application as constituent moieties for the intermediates within the synthesis of different biologically active compounds. It has already been demonstrated in the past and recently. For example, synthesis of benzamidomethyl ester, such as 2-benzamidomethyl-3-oxybutanoates which are used as intermediates in preparation of (2R,3S)-2-benzamidomethyl-3-hydroxybutanoates as chiral building blocks for synthesis of biologically active carbapenems. Also, new 1,3-diketones as synthons for preparation of new pyrazole, isooxazole or diazepine derivatives were synthesized, which had been obtained in the past and recently in the reactions with hydrazines , hydroxylamine or in reactions with phenylenediamines, accordingly. Many of this type compounds can show different microbiological activity. Furthermore, synthesis of new benzamidomethyl cyanacetamides, as synthons for building of quinazolines, pyridinones, chromones and other heterocycles has been performed.
Our previous results show that triethylamino group in (benzamidomethyl)triethylammonium chloride 1 can be easily replaced by different nucleophiles. In aqueous media these reactions were performed relatively fast, under mild conditions, giving almost pure products which can be easily isolated by simple filtration.
we present the formation of C-C bonds in the reactions of nucleophilic substitution between 1 and different carbon nucleophiles, in aqueous media, without using a catalyst.
Process chemistry:
The use of aqueous acidic conditions for the preparation of arylsulfonyl chlorides from diazonium salts in the presence of copper salts, preferably CuCl, together with thionyl chloride as the sulfur dioxide source, has considerable advantages over recommended literature procedures, whereby reactions are carried out in acetic acid with minimisation of water content of the solvent. The method has been shown to be successful for a wide range of electron-deficient and electron-neutral aryl substrates. The sulfonyl chlorides are protected from hydrolysis by their low solubility in water, which results in their direct precipitation from the reaction mixture in good yields (>70%) and high strength (>98% w/w). The aqueous process, which is additionally safer and more robust, can be readily scaled up and has significant environmental benefits.
Industrial applications:
Water in Industry: Hydroformylation
Rurchemie / Rhone-Poulenc hydroformylation oxo process (RCH/RP)
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Homogeneous process where water aids in:
1. Economic heat management
2. Avoiding complicated catalyst recycling
3. Product separation> 600,000 tons/year production
Water in Industry: Palladium Processes:-
Wacker process
1. Biphasic process
2. Cu re-oxidizes Pd
3. O2 stoichiometric oxidant
4. Higher alkenes still being investigated
Telomerization (Kuraray 1-octanol process)
1. Biphasic process
2. Ni catalyzed hydrogenation yields octanol
Water in Industry: Electrochemistry:-
Synthesis of Adiponitrile (Monsanto)
Quaternary ammonium salts (QASs) essential for selectivity
Sodium phosphate-borate electrolyte
Asahi's Sebacic Acid Process
92% yields, 85% to 90% current efficiency
20% aqueous solution of monomethyl adipate neutralized by NaOH
THE END
