Green Chemistry Catalysis And Waste Minimization

Roger A. Sheldon

Delft University of Technology, Delft, The Netherlands


A growing environmental awareness and increasingly stringent environmental legislation have focused the attention of chemical manufacturers on what has become known as sustainable development or green chemistry. A working definition of green chemistry is: Technologies that efficiently utilize energy and (preferably renewable) raw materials and reduce, or preferably, eliminate, the generation of waste and avoid the use of toxic and/or hazardous reagents and solvents. This is actually very close to and has the same meaning as the definition given by the International Union of Pure and Applied Chemistry's (IUPAC's) working party on green chemistry. The emphasis is placed clearly on the reduction (elimination) of waste at the source, that is, primary pollution prevention rather than incremental, end-of-pipe solutions (waste remediation). A direct consequence of this trend toward green chemistry is that traditional concepts of process efficiency, based exclusively on chemical yield, are being replaced by a new paradigm that assigns economic value to eliminating waste and avoiding the use of toxic and/or hazardous chemicals.1-4


Two useful measures of the potential environmental impact of chemical processes are the E-factor,5-7 defined as the mass ratio of waste to desired product, and the

Methods and Reagents for Green Chemistry: An Introduction, Edited by Pietro Tundo, Alvise Perosa, and Fulvio Zecchini

Copyright © 2007 John Wiley & Sons, Inc.

TABLE 9.1 E-factors for Different Segments of the Chemical Industry

Industry Segment

Production (tons)

E-Factor kg Waste/kg Product

Oil refining


ca. 0.1

Bulk chemicals



Fine chemicals






atom efficiency,1'2 calculated by dividing the molecular weight of the product by the sum of the molecular weights of all substances produced in the stoichiometric equation.

A prime cause of high E-factors is the use of stoichiometric inorganic reagents. Fine chemicals and pharmaceuticals manufacture, for example, is rampant with classic stoichiometric technologies that generate copious amounts of inorganic salt as waste. Examples that readily come to mind are stoichiometric reductions with metals (Zn, Fe) and metal hydrides (NaBH4, LiAlH4, and derivatives thereof) and stoichiometric oxidations with permanganate, dichromate, periodate, and so forth. Similarly, processes employing mineral acids (H2SO4, HF), Lewis acids (AlCl3, ZnCl2, BF3), or inorganic bases (NaOH, K2CO3), often in stoichiometric amounts, represent a major source of inorganic waste that cannot easily be recycled. Reactions of this type, widely employed in the fine chemical industry, include Friedel-Crafts acylation mediated by Lewis acids such as AlCl3, sulfona-tions, and diazotizations, to name but a few.

The workup for such reactions involves neutralization and concomitant generation of salts such as NaCl, Na2SO4, and (NH4)2SO4. The elimination of such waste streams and a reduction in the dependence on the use of hazardous chemicals, such as phosgene, dimethyl sulfate, peracids, sodium azide, halogens, and HF, are primary goals in green chemistry.

Table 9.1 contains the values of E-factors (mass ratio of waste to desired product) for different industry segments; most of the processes for fine chemicals and pharmaceuticals, with a very large E-factor, use reagents in stoichiometric quantities, often in combination with environmentally unfriendly solvents. The E-factor is the actual amount of waste formed in the process and includes everything except the desired product, not only the raw materials and reagents involved in the stoichiometric equation but also chemicals used in the workup, for example, acids and bases for neutralization, and solvent losses. Strictly speaking, it should also include the fuel used to generate the energy required to operate the process, but this is often difficult to quantify. Process water is not included, as this leads to E-factors that are not generally meaningful.


The increasing use of catalytic processes can substantially reduce waste at the source, resulting in primary pollution prevention. The theoretical process efficiency


3 PhCH(OH)CH3 + 2 Cr03 + 3 H2S04 -- 3 PhCOCH3 + Cr2(S04)3 + 6 HzO



Atom efficiency = 120/138 = 87%

By-product: HzO

Figure 9.1 Acetophenone synthesis by stoichiometric and catalytic oxidation.

can be quantified by the atom efficiency, the ratio between the molecular weight of the product, and the sum of the molecular weights of all substances produced in the stoichiometric equation. It should be pointed out, however, that the atom efficiency only takes the chemicals appearing in the stoichiometric equation into account.

Figure 9.1 compares the synthesis of acetophenone by classic oxidation of 1-phenylethanol with stoichiometric amounts of chromium oxide and sulphuric acid, with an atom efficiency of 42%, with the heterogeneous catalytic oxidation with O2, with an atom efficiency of 87%, and with water as the only by-product. This is especially important if we consider the environmental unfriendliness of chromium salts: the potential environmental impact of reactions can be expressed by the environmental quotient (EQ), where E is the E-factor (kg waste/kg product) and Q is the environmental unfriendliness quotient of the waste. If Q is

Hydrogénation: 9 Catalyst H\ /0H

100% atom efficient

Carbonylation: H OH Catalyst

100% atom efficient

Oxidation: H OH Catalvst V

87% atom efficient

Figure 9.2 Atom-efficient catalytic processes.

AICI3 -1


AICI3 -1


+ CH3C02H

+ CH3C02H



AICI3 >1 equivalent Solvent (recycle) Hydrolysis of products 85-95% yield

H-Beta, catalytic, and regenerable No solvent No water necessary >95% yield/higher purity

4.5 kg aqueous effluent per kg 0.035 kg aqueous effluent per kg Figure 9.3 Friedel-Crafts acylation of anisole.

1 for NaCl, for example, then for chromium salts Q could be arbitrarily set at, say 100 or 1000. Similarly, clean catalytic technologies can be utilized for hydrogenation of acetophenone and carbonylation of 1-phenylethanol (Figure 9.2), with 100% atom efficiency in both cases.

One way to significantly reduce the amount of waste is to substitute traditional mineral acids and Lewis acids with recyclable solid acid catalysts. A good example of this is the Rhodia process for the synthesis of 4-methoxy acetophenone by Friedel-Crafts acetylation of anisole (Figure 9.3) with acetic anhydride, catalyzed by the acid form of zeolite beta.8 This replaced a traditional Friedel-Crafts acylation using acetyl chloride in combination with more than one equivalent of aluminium chloride in a chlorinated hydrocarbon solvent. The new process requires no solvent and avoids the generation of HCl in both the acylation and the synthesis of the acetyl chloride. The original process generated 4.5 kg of aqueous effluent (containing AlCl3, HCl, chlorinated hydrcarbon residues, and acetic acid) per kg of product. The catalytic alternative generates 0.035 kg of aqueous effluent (i.e., >100 times less), consisting of 99% water, 0.8% acetic acid, and <0.2% other organics per kg of product. Workup consists of catalyst filtration and distillation of the product. Because of the simpler process, a higher chemical yield is obtained (>95% vs. 85-95%) and higher product purity is obtained. Moreover, the catalyst is recyclable and the number of unit operations is reduced from 12 to 3. The conclusion is clear: The new technology is not only cleaner and greener, it also leads to lower production costs than the classic process. An important lesson indeed.

Other important successes have been achieved in developing clean, "green," methods to oxidize alcohols, for example, the Ru/TEMPO (tetramethylpiperidiny-loxyl radical) catalysis, shown in Figure 9.4, for the aerobic oxidation of alcohols.

Conv. (%)

Sel. (%)










Figure 9.4 Aerobic oxidation of primary and secondary alcohols catalyzed by RuCl2 (Ph3P)3/TEMPO in PhCl at 100°C.


Another environmental issue is the use of organic solvents. The use of chlorinated hydrocarbons, for example, has been severely curtailed. In fact, so many of the solvents favored by organic chemists are now on the black list that the whole question of solvents requires rethinking. The best solvent is no solvent, and if a solvent (diluent) is needed, then water has a lot to recommend it. This provides a golden opportunity for biocatalysis, since the replacement of classic chemical methods in organic solvents by enzymatic procedures in water at ambient temperature and pressure can provide substantial environmental and economic benefits. Similarly, there is a marked trend toward the application of organometal-lic catalysis in aqueous biphasic systems and other nonconventional media, such as fluorous biphasic, supercritical carbon dioxide and ionic liquids.10

A prime advantage of such biphasic systems is that the catalyst resides in one phase and the starting materials and products are in the second phase, thus providing for easy recovery and recycling of the catalyst by simple phase separation. A pertinent example is the aerobic oxidation of alcohols catalyzed by a water-soluble Pd-bathophenanthroline complex (Figure 9.5).11 The only solvent used is water, the oxidant is air, and the catalyst is recycled by phase separation.

The Boots Hoechst Celanese (BHC) ibuprofen process12 involves palladium-catalyzed carbonylation of a benzylic alcohol (IBPE). More recently, we performed this reaction in an aqueous biphasic system using Pd/tppts as the catalyst (Figure 9.6; tppts = triphenylphosphinetrisulfonate). This process has the advantage of easy removal of the catalyst, resulting in less contamination of the product.



Pd2+-Bathophenanthroline (L)

Figure 9.5 Aerobic oxidation of alcohols catalyzed by Pd(II)/bathophenanthroline in water.

JYJJ OH pd/tppts/H+ I /XCOOH


IBPE Ibuprofen 3-IPPA

Conversion: 83% tppts = P Selectivity to ibuprofen: 82%


Figure 9.6 Ibuprofen synthesis by Pd/tppts-catalyzed biphasic carbonylation in water.

Figure 9.6 Ibuprofen synthesis by Pd/tppts-catalyzed biphasic carbonylation in water.

60 bar

60 bar

Figure 9.7 Carbonylation of benzyl alcohol-catalyzed by tppts/Pd.

In the same way, the biphasic carbonylation of benzyl alcohol (Figure 9.7) was achieved.13 Phenylacetic acid was obtained in 77% yield, 100% selectivity, and 100% atom utilization.

Similarly, acylamino acids can be prepared with 100% atom utilization via palladium-catalyzed amidocarbonylation.14 The method was used for the synthesis of a surfactant from sarcosine (Figure 9.8).

100% atom efficient

CHo co/ch2o c11h23-v.n^.cooh

o 86% yield

Sarcoside surfactant Figure 9.8 Acylamino acids via palladium-catalyzed amidocarbonylation.


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.

Another example of the substitution of classic routes for chemical synthesis by multistep catalytic processes is the Rhodia vanillin process (Figure 9.10),8 which involves four steps, all employing a heterogeneous catalyst.

Finally, the Lonza nicotinamide process (Figure 9.11),15 involves the integration of both heterogeneous catalysis with a final step employing enzymatic catalysis.

Ni Catalyst + 2 HCN NC




Overall: ^^

^^ + 2 HCN + H20 + H2

-Caprolactam + NH3

Figure 9.9 Salt-free caprolactam process.


Figure 9.9 Salt-free caprolactam process.


Solid catalyst








La phosphate gas phase 250°C

Noble metal catalyst





Overall: C^O + H202 + CH3OH + H2CO + 1/2 02-> 0^03 + 3 H20

Figure 9.10 Rhodia vanillin process.


The key to achieving the goal of reducing the generation of environmentally unfriendly waste and the use of toxic solvents and reagents is the widespread substitution of "stoichiometric" technologies by greener, catalytic alternatives. Examples include catalytic hydrogenation, carbonylation, and oxidation. The first two involve 100% atom efficiency, while the latter is slightly less than perfect owing to the coproduction of a molecule of water. The longer-term trend is toward the use of the simplest raw materials—H2, O2, H2O, H2O2, NH3, CO, and CO2—in catalytic, low-salt processes. Similarly, the widespread substitution of classic mineral and Lewis acids by recyclable solid acids, such as zeolites and acidic clays, and the introduction of recyclable solid bases, such as hydrotalcites (anionic clays) will result in a dramatic reduction of inorganic waste.

CN CN By-product of Nylon 6,6 manuf.

Oxide cat. v\i

Whole cells Rh. rhodocrous

Whole cells Rh. rhodocrous

Figure 9.11 Lonza nicotinamide process.

A possible alternative for the use of organic solvents (many of which are on the black list), is the extensive utilization of water as a solvent. This provides a golden opportunity for biocatalysis, since the replacement of classic chemical methods in organic solvents by enzymatic procedures in water, at ambient temperature, can provide both environmental and economic benefits. Similarly, there is a marked trend toward organometallic catalysis in aqueous biphasic systems and other nonconventional media, such as fluorous biphasic, supercritical carbon dioxide, and ionic liquids.

In conclusion, the widespread application of chemo- and biocatalytic methodologies to the manufacture of fine chemicals has enormous potential for creating greener, environmentally benign processes.


2. Trost, B. M. Angew. Chem. Int. Ed., 1995, 34, 259.

3. Sheldon, R. A., Downing, R. S. Appl. Catal. A.: General, 1999, 189, 163.

4. Sheldon, R. A. Pure Appl. Chem., 2000, 72, 1233.

5. Sheldon, R. A. Chem. Ind. (London), 1997, 12, also, 1992, 903.

6. Sheldon, R. A. J. Chem. Technol. Biotechnol., 1997, 68, 381.

7. Sheldon, R. A. Chemtech, 1994, 38; also, J. Mol. Cat., 1996, 75, 107.

9. Dijksman, A.; Arends, I. W. C. E.; Sheldon, R. A. Chem. Commun., 1999, 16, 15911592.

10. For a recent review see Sheldon, R. A. Green Chem., 2005, 7, 267-278.

11. Ten Brink, G. J.; Arends, I. W. C. E.; Sheldon, R. A. Science, 2000, 287, 1636-1639.

12. Elango, V.; et al., US Patent 4, 981, 995, 1991 (to Hoechst Celanese).

13. Papadogianakis, G.; Maat, L.; Sheldon, R. A. J. Mol. Cat. A: Chem., 1997, 179, 116.

14. Beller, M.; et al. Angew. Chem., Int. Ed. Eng., 1997, 36, 1494; ibid., 1999, 38, 1454.

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