Synthesis route, atom efficient

In a process developed by Hoffmann La Roche (Roessler, 1996) for the anti-Parkinsonian drug, lazabemide, palladium-catalysed amidocarbonylation of 2,5-dichloropyridine replaced an original synthesis that involved eight steps, starting from 2-methyl-5-ethylpyridine, and had an overall yield of 8%. The amidocarbonylation route affords lazabemide hydrochloride in 65% yield in one step, with 100% atom efficiency (Fig. 2.22). 

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. 

Another elegant example, of palladium-catalysed amidocarbonylation this time, is the one-step, 100% atom efficient synthesis of a-amino acid derivatives from an aldehyde, CO and an amide (Fig. 1.30) [85]. The reaction is used, for example in the synthesis of the surfactant, N-lauroylsarcosine, from formaldehyde, CO and N-methyllauramide, replacing a classical route that generated copious amounts of salts. 

It is instructive to compare the atom economies of the two pathways. Atom economy is a measure of the efficiency of a chemical process, defined in percentage terms as x (formula wt. of atoms utilized)/(formula wt. of all reactants). For the old six-step ibuprofen synthesis the atom economy was only 40% (with MeC02H, EtOH, NaCl, Et0C02H, 2H2O and NH3 as waste). This is dramatically improved to 77% for the new three-step route with only MeC02H as a by-product from the first step. Recovery and use of this increases the atom economy to 99%. Additionally, the catalytic amounts of HF and Pd complex used in the BHC process are recovered and reused, whereas stoichiometric quantities of AICI3 hydrate were produced as waste by the old route. 

The protonation of organo-rare-earth metal species through a-bond metathesis plays a key role in many catalytic applications described below. The high reactivity of rare-earth metals for insertion of unsaturated carbon-carbon multiple bonds [18], in conjunction with smooth o-bond metathesis, allows to perform catalytic small molecule synthesis. This route is atom efficient, economic, and opens access to nitrogen-, phosphorous-, silicon-, boron-, and other heteroatom-containing molecules. The most important catalytic applications of organo-rare-earth metals involving the o-bond metathesis process will be discussed in this review. 

As shown in Figure 12.3, the new route D had the lowest overall mass consump-hon, even though the ee-value and yield for the reduchon step were the lowest. This was compensated by there being fewer steps, a higher atom efficiency and a lower solvent consumphon for the synthesis and exhachon. 

As stated in Chapter 9, the atom efficiency of a reaction sequence is defined as the molecular weight of the desired product divided by the sum of the molecular weights of all of the products of the synthesis, multiplied by 100 to give a percentage figure. Let us look at each route in turn. 

These atom efficiencies are very useful in predicting the likelihood of a commercially attractive synthesis being produced. The very low figure for route C rules it out straight away, the low atom utilisation and the nature of the by-products indicate a serious effluent problem which will add significantly to the process costs. 

Another effect of the progress in molecular catalysis can be found in green chemistry where development of atom-efficient synthesis through new synthetic routes is sought to minimize waste. Greener routes with less unfavorable impact on the environment may be provided by designing proper synthetic methodologies from the outset, based on the information of elementary processes in molecular catalysis... 

In contrast, here a bifunctional initiator is employed and the polymerization order of the two blocks is inverted In a first step, the styrene block is synthesized by atom transfer radical polymerization (ATRP) followed by the addition of lactide via the recently developed organocatalytic ring-opening polymerization, as depicted in Fig. 3.1 [4, 5]. This synthesis route reduces the involved steps and enables a simplified and time-efficient preparation of copolymers with different block compositions. Importantly, both polymerization techniques offer precise and robust control over the copolymer composition, which is an essential requirement to reliably target the double-gyroid s narrow location in phase space [6]. 

Beyond this careful selection of platform chemicals, the production of a number of other polymer building blocks, chemical intermediates, and end products from carbohydrates has been reported. Due to the unique oxygen-rich composition of carbohydrates, their conversion into renewable chemicals that preserve the functional groups is an advantage over the current petroleum and natural gas conversion routes. Biomass conversion with high atom efficiency is a key aspect of the competitive synthesis of chemicals and chemical-based products. 

Synthesis II An alternative route with greater atom economy starts with 4-isobutylacetophenone. (below) Although synthesis II is more atom-efficient than synthesis I, it uses a cyano group, neither atom of which appears in the final product. 

A typical synthesis of complex organic molecules involves multiple reaction steps with intermediate purification of the intermediates. Such synthetic routes require a lot of labor-intensive manipulations and generate a lot of waste (e.g., solvents). With the atom-efficient biosynthetic pathways in cells as a model, several approaches have been developed in order to facilitate synthetic chemistry, such as protecting group-free syntheses [46], one-pot syntheses [47], cascade reactions [48], and multicomponent reactions [49]. More recently, synthetic chemists have been attracted by flow chemistry since it allows to combine all these processes in a single streamlined continuous process (i.e., multistep one-flow synthesis) [50]. Several strategies have been developed. 

In addition to cross-coupling chemistry, one of the most direct routes to the formation of vinyl ethers entails the addition of alcohols and phenols to alkynes. This atom-efficient transformation is referred to as hydroalkoxylation and can be tuned to generate vinyl ethers in excellent yields under very mild conditions. Both intermolecular and intramolecular versions of this reaction are well known, and a vast array of catalysts and conditions has been used for the successful synthesis of vinyl ethers [111, 112]. The following sections will highlight a number of advances in this area with special attention paid to modifications such as the development of fast reactions, green processes, as well as the ability of the reactions to tolerate moisture or air. 

---