Atom efficient catalytic processes

The ultimate greening of fine chemical synthesis is the replacement of multistep syntheses by the integration of several atom-efficient catalytic steps. For example. Figure 9.9 shows the new Rhodia, salt-free caprolactam process involving three catalytic steps. The last step involves cyclization in the vapor phase over an alumina catalyst in more than 99% conversion and more than 99.5% selectivity. 

Metal-catalyzed substitution reactions involving propargylic derivatives have not been studied in much detail until recently [311, 312]. In this context, the ability shown by transition-metal allenylidenes to undergo nucleophilic additions at the Cy atom of the cumulenic chain has allowed the development of efficient catalytic processes for the direct substitution of the hydroxyl group in propargylic alcohols [313]. These transformations represent an appealing alternative to the well-known and extensively investigated Nicholas reaction, in which stoichiometric amounts of [Co2(CO)g] are employed [314-317]. 

The useful procedures began to be developed with the recognition that by initial activation of the allylic position with an electronegative atom, direct oxidative addition with Pd° can give the key ] -allyl intermediate. Spontaneous recycling then leads to an efficient catalytic process (equation 47). 

The Hashmi phenol synthesis is another example of a perfect atom-economical reaction. Hashmi and coworkers reported this transformation for the first time in 2000, and have been actively working on improving and developing more efficient catalytic processes ever since. As a result of this work, they have reported several extremely active catalytic systems for this transformation. In 2011, they reported TONs of 1900 and 1860 using catalysts VI and VII, respectively, in a comparative study between the use of KITPhos and SPhos ligands in the gold-catalysed phenol synthesis (Scheme 16.14). ... 

Similarly, a catalytic route to indigo was developed by Mitsui Toatsu Chemicals (Inoue et al, 1994) to replace the traditional process, which dates back to the nineteenth century (see earlier), and has a low atom efficiency/high E factor (Fig. 2.15). Indole is prepared by vapour-phase reaction of ethylene glycol with aniline in the presence of a supported silver catalyst. The indole is selectively oxidised to indigo with an alkyl hydroperoxide in the presence of a homogeneous molybdenum catalyst. 

The same reasoning applies to the synthesis of pure enantiomers as to organic synthesis in general processes should be atom efficient and have low E factors, i.e. involve catalytic methodologies. This is reflected in the increasing attention being focused on enantioselective catalysis, using either enzymes or chiral metal complexes. 

During a chemical reaction, chemical bonds between atoms are broken and new bonds are formed. The efficiency of a catalyst consists in its ability to favour the electron transitions which occur when bonds are dissolved and formed. A knowledge of the distribution and concentration of the electrons in the catalyst therefore plays a predominant role in the interpretation of catalytic processes 1 I2). To determine the importance of the surface bonds of a catalyst in the elementary step of a catalytic reaction, we have to change the distribution of the electrons over the quantum states of the bonds at the surface of the solid. The electron distribution must be altered where the reacting atoms may take notice of it, i.e. at the surface where the reaction occurs or very close to it, but not in the bulk. 

A catalytic version of the Zn( 11)-mediated enantioselective addition of alkynylides to aldehydes was documented after the stoichiometric process [19]. Initially, the reaction was reported to proceed using 22 mol % N-methylephedrine, 20 mol % Zn(OTf)2, and 50 mol % Et3N to furnish the product alcohols in yields and enantioselectivity only marginally lower than in the original stoichiometric version (Eq. 15). The key difference between the stoichiometric and the catalytic procedures is the elevated temperature (60 °C) for the catalytic process. Because the reaction can also be conducted under solvent-free conditions, ensuring a process with a high atom economy and volumetric efficiency (Eq. 16). Under these conditions, the reactions can be conducted with substantially lower catalyst loading (Eq. 17) [13]. 

Because ibuprofen has been a successful drug on the market for almost 30 years with no patent protection since 1985, there is a widespread competition for commercial production of this product throughout the world. As a result, several practical and economical industrial processes for the manufacture of racemic ibuprofen (14) have been developed and are in operation on commercial scales.38 Most of these processes start with isobutylbenzene (15) and go through an isobutylstyrene3 4 or an acetophenone intermediate.42 The most efficient route is believed to be the Boots-Hoechst-Celanese process, which involves 3 steps from isobutylbenzene, all catalytic, and is 100% atom-efficient (Scheme 6.1).43 44... 

The conventional Grignard reaction (Fig. 2, route I) would generate both a stoichiometric amount of halide waste and a stoichiometric amount of metal waste. It also requires multistep synthesis of the halides. On the other hand, an alternative Grignard-type reaction via catalytic C-H activation in water (Fig. 2, route II) would preclude the use of flammable organic solvents and also avoid the wasteful process of drying them. Obviously, it would provide a cleaner solution for organic synthesis and provide a theoretical 100% atom-efficiency. 

The atom utilization [13-18], atom efficiency or atom economy concept, first introduced by Trost [21, 22], is an extremely useful tool for rapid evaluation of the amounts of waste that will be generated by alternative processes. It is calculated by dividing the molecular weight of the product by the sum total of the molecular weights of all substances formed in the stoichiometric equation for the reaction involved. For example, the atom efficiencies of stoichiometric (Cr03) vs. catalytic (02) oxidation of a secondary alcohol to the corresponding ketone are compared in Fig. 1.1. 

---