Stoichiometric Methods

This is the first example of a reaction for which the presence of a chelating ligand was observed to facilitate rather than retard metal-catalysed epoxidation (Gao et al., 1987). It was found that the use of molecular sieves greatly improves this process by removing minute amounts of water present in the reaction medium. Water was found to deactivate the catalyst. All these developments led to an improved catalytic version that allows a five-fold increased substrate concentration relative to the stoichiometric method. Sensitive water-soluble, optically active glycidols can be prepared in an efficient manner by an in situ derivatisation. This epoxidation method appears to be competitive with enzyme-catalysed processes and was applied in 1981 for the commercial production of the gypsy moth pheromone, (-1-) disparlure, used for insect control (Eqn. (25)). 

In electroanalysis, the techniques are pre-eminently based on processes that take place when two separate poles, the so-called electrodes, are in contact with a liquid electrolyte, which usually is a solution of the substance to be analysed, the analyte. By means of electrometry, i.e., by measuring the electrochemical phenomena occurring or intentionally generated, one obtains signals from which chemical-analytical data can be derived through calibration. Often electrometry (e.g., potentiometry) is applied in order to follow a reaction that goes to completion (e.g., a titration), which essentially represents a stoichiometric method, so that the electrometry merely acts as an end-point indicator of the reaction (which means a potentiometric titration). The electrochemical phenomena in electroanalysis, whether they take place in the solution or at the electrodes, are often complicated and their explanation requires a systematic treatment of electroanalysis. 

For more than a century, stoichiometric methods were presumed in the preparation of benzonitriles in laboratory and industry. These particularly include the Rosenmund-von Braun reaction of aryl halides, the diazotization of anilines and subsequent Sandmeyer reaction, and the ammoxidation. Because of (over)stoichiometric amounts of metal waste, lack of functional group tolerance, and harsh reaction conditions, these methods do not meet the criteria of modern sustainable synthesis. 

Recently, the iron-promoted Barbier-type addition of alkyl halides to aromatic aldehydes has been reported (Equation (26)).326 According to the proposed mechanism, the initial step is the formation of an alkyl radical, which can be reduced to the corresponding carbanion. This carbanion nucleophile can react, while coordinated to the iron pentacarbonyl complex, with the corresponding aldehyde. This stoichiometric method is limited with respect to substrate scope and yield. The same authors have also developed the Reformatsky-type addition of cr-halosub-stituted carbonitriles to aldehydes and ketones in the presence of iron pentacarbonyl.3... 

Several stoichiometric methods for transition metal-promoted transformations of allenes have been studied, involving metals such as iron [77] and titanium [78, 79]. The titanium-mediated reactions developed by Sato and co-workers have probably the greatest synthetic impact, as exemplified by the conversion of silylated allene 150 to 1,4-diene 152 (Scheme 14.38) [78],... 

An alternative technique to the stoichiometric method for measuring gas solubilities has evolved as a result of the development of extremely accurate microbalances. 

Catalytic processes using diazo chemistry and stoichiometric methods with Fischer carbenes are complimentary for the introduction of a substituted carbene into a molecule. For methylene addition, however, there is no viable alternative to the modified Simmons-Smith reaction. Ring-closing metathesis, and its ROMP counterpart, have matured so fast that even now they rank among the most useful synthetic methodologies in organic chemistry. 

Another variation of the stoichiometric method involves loading known amounts of gas and IL into the cell and then increasing the pressure (at constant temperature) until all the gas dissolves in the liquid and, consequently, the vapor phase disappears. Using different loadings of the gas, one can determine the solubility at various different pressures and temperatures. Mercury was used as the pressurization fluid by Peters and coworkers to determine gas solubilities in ILs [4]. Maurer and coworkers used a similar method, but they introduced and withdrew additional known amounts of the IL to pressurize or depressurize the mixture and observe the phase change [5]. 

Even considering only the example of the proline family of aldol catalysts, it is dear that there will soon be hundreds of cases of organocatalysts described in the literature. Direct, organocatalytic aldol reactions do not yet have the generality of traditional stoichiometric methods, which can offer predictable results for a wide variety of substrates. However, companies already offer to screen substrates against panels of up to 200 enzymes to find the optimum biocatalyst for a reaction, and the same approach could be applied to identify rapidly the best organocatalyst for a process. 

Sometimes the analyte is in such low concentration that it is impossible to isolate. It can be noted from equations (17.1) and (17.3) that it is not necessary to know Ax and As individually if their ratio can be determined. To achieve this, a reproducible reaction can be conducted on the labelled standard (analytical blank) and, in an identical fashion, on the sample in order to obtain the same quantity of derivatised compound. Thus the sub-stoichiometric method is similar to the immunochemical method for trace analysis. 

Like epoxides, chiral non-racemic aziridines are useful synthetic intermediates [3, 71], and a number of methodologies have been developed for their asymmetric synthesis [3, 6, 14, 72, 73]. Although several groups have developed stoichiometric methods using chiral ylides [16, 20, 22, 74, 75], catalytic asymmetric ylide azir-idinations remain relatively rare. In fact, the first catalytic aziridination with an ylide was only reported ten years ago [76]. Progress in this area is reviewed in the following section. 

Stoichiometric methods for measuring total carboxyl content depend on the exchange between a cation in solution and the solid cellulose substrate in its free-acid form ... 

The crucial additive is 3A or 4A molecular sieves. Without their addition, products of 39-80% ee are obtained, reactions proceed slowly and to only 50-60% conversion. In control experiments it was determined42 that water irreversibly destroys the catalyst in the long term but that activity can be preserved if molecular sieves are added before or shortly after all the components. As in the case of the stoichiometric method, aging of the catalyst prior to addition of the fourth component gives higher enantioselection. 

Reaction times with the catalytic method are comparable to those obtained with the stoichiometric method and Z-disubstituted allylic alcohols can be efficiently epoxidized at —20 JC in 1 -4 hours using just 5% titanium(IV) isopropoxide and 6-7.5% tartrate (Table 4). The method is especially useful for epoxidation of alcohols that react only very slowly under normal conditions. In particular, Z-disubstituted allylic alcohols (Table 4) react at useful rates only if the reaction is warmed to —10 °C. In the catalytic procedure the absence of large quantities of titanium salts and tartrate minimize epoxide opening that would be a problem in the stoichiometric procedure at this temperature. A similar situation exists for unsymmetrical disubstituted allylic alcohols (Table 4) which are also prone to opening under the conditions of the stoichiometric method. 

In addition to simplifying the workup procedures, use of catalytic amounts of the titanium-tartrate complex in the epoxidation of low molecular weight alcohols makes in situ derivatization of the crude epoxy alcohol feasible (Table 5)42, Catalytic epoxidation and in situ derivatization allowed the preparation of glycidol, an epoxy alcohol accessible only in very low yield by the stoichiometric method. The in situ derivatization method also makes possible the enhancement of enantiomeric excess through crystallization. Derivatives of low molecular weight alcohols, such as the 4-nitrobenzoates, undergo significant enantiomeric enrichment upon crystallization (Table 5). 

Mas, V., Kipreos, R., Amadeo, N., and Laborde, M. Thermodynamic analysis of ethanol/ water system with the stoichiometric method. International Journal of Hydrogen Energy, 2006, 31 (1)> 21. 

One stoichiometric method that avoids the use of an expensive chiral auxiliary and allows for the use of nonpyrophoric bases is based on diketopiperazine chemistry. The use of this system as a chiral auxiliary is associated with a method that was developed for the preparation of the sweetener aspartame. At the same time, we were looking at the alkylation reactions of amino acid derivatives and dipeptides. These studies showed that high degrees of asymmetric induction were not simple, were limited to expensive moieties as the chiral units, and required the use of large amounts of lithium [25,26]. The cyclic system of the diketopiperazine has been used successfully by other investigators [27,28], and we also chose to exploit the face selectivity of this unit. L-Aspartic acid was chosen as the auxiliary unit because it is readily available and cheap. All of the studies were performed with sodium as the counterion because it is a more cost-effective metal at scale. Finally, we concentrated in the use of aldehydes rather than alkyl halides to allow for a general approach and so as not to limit the reaction to reactive alkyl halides. 

Compared to reductions the oxidation reactions constitute an area that is still relatively unexplored from a large-scale point of view. In spite of the enormous efforts which have been spent on basic research, applications at scale are still scarce. The reasons for this could be that the asymmetric procedures currently at hand are deemed to be inefficient, that the types of functional group interconversions addressed with oxidations are far less in demand than is the case for reductions, or the existence of competitive stoichiometric methods (mostly based on the use of metal oxides and salts, such as fTO, and KM 1104) that are considered to be sufficient for most purposes. Another factor that needs to be included is the intrinsic difficulty in designing a catalyst that is stable under the relatively aggressive oxidative conditions (compare reactivity of [H] and [O]). Nonetheless, the capabihty of enantioselective oxidations has been unambiguously proven at the manufacturing level in enough cases to make this approach a viable option for commercial production (see Sections 2.2 and 2.3). 

Major commodity chemicals produced by epoxidation are ethylene oxide and propylene oxide. Epoxybutene is an important intermediate, but is no longer produced on a large scale. The general subject of epoxides has been reviewed, including properties and preparation by stoichiometric methods [Ij. Reliable production and price data are not available for most epoxides because they are used captively, and only available market values for some commodity chemicals will be presented. 

In summary, epoxides are produced not only as endproducts, but also as intermediates because they are valuable building blocks in synthetic organic chemistry [82-84] (Table 1.3). Until recently, epoxide intermediates were produced by direct oxygen transfer to olefins by a variety of stoichiometric methods. Recently, considerable efforts have been made to conduct the transformations selectively under catalytic conditions. Because epoxides are reactive substances, they can undergo diverse transformations by reactions with acids and bases, and their reactivity has been exploited to form a diverse range of products by so-called click chemistry [85,86], which combines the breadth of combinatorial methods with the precise synthesis of organic chemistry. 

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