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Newer Synthetic Methods
CHAPTER 2
Newer Synthetic Methods
Introduction Waste prevention and environmental protection are major requirements in an overcrowded world of increasing demands. Synthetic chemistry continues to develop various techniques for obtaining better products with less damaging environmental impacts. The control of reactivity and selectivity is always the central subject in the development of a new methodology of organic synthesis. Novel, highly selective reagents appear every month. New reactions or modifications of old reactions have been devised to meet the ever-increasing demands of selectivity in modern synthesis. Periodic review articles and books appear in the literature on these newer reagents. The scope of this chapter is to focus on newer techniques (experimental) for improving the yield and reducing the duration of the reactions and also to discuss the need for a good synthetic design. In other words, newer methods of kinetic activation, which minimize the energy input by optimizing reaction conditions, will be discussed along with the need for an elegant synthetic design. In most reactions, the reaction vessel provides three components (as shown in Fig. 2.1): • solvent, • reagent/catalyst, • energy input.
28 Green Chemistry and Processes Energy input
PRODUCTS
REACTANTS
Reagent
Solvent
Figure 2.1. Components of chemical reaction.
Hence, efforts to green chemical reactions focus predominantly on "greening" these three components. By "greening," we mean to • Use benign solvents or completely dispense with the solvent. • Use alternate, more efficient and effective reagents/catalysts. • Optimize the reaction conditions by using cost-effective, ecofriendly alternative processes. The role of alternate reagents, solvents, and catalysts in greening chemical reactions is discussed in other chapters. In this chapter we shall see newer methods of kinetic activation of molecules in chemical reactions. Pressure and temperature are important parameters in reaction processes in chemical systems. However, it is a less well-known fact that other than thermally initiated reactions can also lead to sustainable results. The basic requirement is to capture the energy required by a reaction. The energy required for synthesis as well as that required for cooling are of interest here. In order to minimize energy and control reactions with a view to green chemistry, attempts are being made to make the energy input in chemical systems as efficient as possible. Approaches are being taken and possibilities investigated to use until now scarcely used forms of energy, so-called nonclassical energy forms, in order to optimize the duration and product yield and avoid undesired side products. Teams working in this area are also interested in the energetic aspects of the preparation of starting substances and
Newer Synthetic Methods 29 products and the conditioning of reaction systems (e.g., surface activation, emulsification, homogenization, degassing, etc.). We now have six well-documented methods of activating molecules in chemical reactions, which can be grouped as follows: the classical methods, including • thermal, • photochemical, • electrochemical, and the nonclassical methods, which include • sonication, • mechanical, • microwave. Each of these methods has its advantages and niche areas of applications, alongside its inherent limitations. A comparative study of these techniques is given in Table 2.1. What do we mean by classical and nonclassical energy forms? In classical processes, energy is added to the system by heat transfer; by electromagnetic radiation in the ultraviolet (UV), visible, or infrared (IR)range; or in the form of electrical energy. On the other hand, microwave radiation, ultrasound, and the direct application of mechanical energy are among the nonclassical forms. Sonochemical Processes
Ultrasound, an efficient and virtually innocuous means of activation in synthetic chemistry, has been employed for decades with varied success. Not only can this high-energy input enhance mechanical effects in heterogeneous processes, but it is also known to induce new reactions, leading to the formation of unexpected chemical species. What makes sonochemistry unique is the remarkable phenomenon of cavitation, currently the subject of intense research, which has already yielded thought-provoking results. The majority of today's practitioners accept a rationale based on "hotspot" interpretation, provided this expression is not taken literally, but rather as "a high-energy state in a small volume." One should also recall that only a small part (10-3) of the acoustic energy absorbed by the system is used to produce a chemical activity (Margulis and Mal'tsev, 1968). High-power, low-frequency
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Newer Synthetic Methods
31
(16-100 Hz)waves are often associated with better mechanical treatment and less importantly with chemical effects. With highfrequency ultrasound, the chemistry produced displays characteristics similar to high-energy radiation (more radicals are created). One of the most striking features in sonochemistry is that there is often an optimum value for the reaction temperature. In contrast to classical chemistry, most of the time it is not necessary to go to higher temperatures to accelerate a process. Each solvent has a unique fingerprint. Sonochemistry in heterogeneous systems is the result of a combination of chemical and mechanical effects of cavitation, and it is very difficult to ascribe sonochemistry to any single global origin, other than the overriding source of activity, namely, cavitation. The real benefit of using ultrasound lies in its unique selectivity and reactivity enhancement. The heterogeneity of the reaction phase would be particularly significant. In fact, heterogeneous reactions are those in which ultrasound is likely to play the most important role by selective accelerations between potentially competitive pathways. Apart from the use of ultrasound in enhancing the reactivity in organic reactions, ultrasound has varied uses in industry, such as welding, cutting, emulsification, solvent degassing, powder dispersion, cell disruption, and atomization. It was reported that the sonochemical decomposition of volatile organometallic precursors was shown to produce nanostructured materials in various forms with high catalytic activities. This has proved extremely useful in the synthesis of a wide range of nanostructured inorganic materials, including high surface area transition metals, alloys, carbides, oxides, and sulfides, as well as colloids of nanometer cluster. Ultrasound is known to enhance the reaction rate, thus minimizing the duration of a reaction. A large number of published examples, which highlight this observation, are shown in Appendix 2.1. Apart from this, it is known to induce specific reactivity, known as "sonochemical switching." Ando et al. (1984)reported that benzyl bromide, on treatment with alumina impregnated with potassium cyanide, yielded benzyl cyanide on sonication, while, without sonication, on heating the reaction mixture yielded diphenylmethanes (see Fig. 2.2). This work was the first experimental evidence that ultrasonic irradiation induces a particular
32 Green Chemistry and Processes CN
r
KCN
/~
na, sonication
~
, heat KCN
Ph H2 C /
\Ph Figure 2.2. Sonochemical switching. reactivity. Further studies on sonochemical induction indicated that • Reactions activated by sonication are those that proceed via a r a d i c a l or radical ion intermediate (electron transfer). • I o n i c r e a c t i o n s (polar) mostly remain unaffected. U s e of M i c r o w a v e s for S y n t h e s i s
In synthetic chemistry, 1986 was an important year for the use of microwave devices. Since that year, countless syntheses initiated by microwaves have been carried out on a laboratory scale. The result is often a drastic reduction in the reaction time with comparable product yields, if microwaves are used instead of classical methods of energy input. Unwanted side reactions can often be suppressed and solvents dispensed with. Numerous reactions, such as esterifications, Diels Alder reactions, hydrolyses, or the production of inorganic pigments, have been investigated in recent years. Reactions listed in Appendix 2.2 illustrate nicely the advantages of this nonclassical means of energy input. Apart from the obvious advantages of the use of microwaves in chemical syntheses, microwave technologies are being tested as energy- and cost-saving alternatives. Hopes are high, for example, in the field of green extraction of pollutants from contaminated soil, or for the improvement of the breakdown of biomass waste by fermentation as part of green biorefinery.
Newer Synthetic Methods
33
Electro-Organic Methods Over the past 25 to 30 years, the use of electrochemistry as a synthetic tool in organic chemistry has increased remarkably. According to Pletcher and Walsh (1993), more than 100 electro-organic synthetic processes have been piloted at levels ranging from a few tons up to 10s tons. Such examples include reductive dimerization of acrylonitrile, hydrogenation of heterocycles, pinacolization, reduction of nitro aromatics, the Kolbe reaction, Simons fluorination, methoxylation, epoxidation of olefins, oxidation of aromatic hydrocarbons, etc. Many excellent reviews and publications highlight the synthetic utility of electro-organic methods (Lund and Baizer, 1991). These cover a broad spectrum of applications of electrochemical methods in organic synthesis, including their use in the pharmaceutical industry. Mild reaction conditions, ease of control of solvent and counter-ions, high yields, high selectivities, as well as the use of readily available equipment, simply designed cells, and regular organic glassware make the electrochemical syntheses very competitive to the conventional methods in organic synthesis. The use of sacrificial anodes is an effective way for the preparation of metallo-organic compounds by cathodic generation of organic anions and anodic generation of metal cations. This approach was very successful for synthesis of the organosilicon compounds (Fry and Touster, 1989). A large variety of fluorinated organosilicon compounds can be synthesized using a sacrificial A1 anode and a stainless steel cathode under very mild conditions and in good yields (Bordeau et al., 1997). Discoveries of new types of electro-organic reactions based on coupling and substitution reactions, cyclization and elimination reactions, electrochemically promoted rearrangements, recent advances in selective electrochemical fluorination, electrochemical versions of the classical synthetic reactions, and successful use of these reactions in multistep targeted synthesis allow the synthetic chemist to consider electrochemical methods as one of the powerful tools of organic synthesis.
Elegant and Cost-Effective Synthetic Design The heart of synthesis is in the design of the synthetic scheme for the given target molecule. All the technological advances (discussed above) can only supplement the synthetic scheme. Innovation, elegance, and brevity in the synthetic design are essential
34 Green Chemistry and Processes CH3~N
CH3N •N
CH3 NN
O o/CH3
H
H/ N ~ O O
Atropine (1)
Tropinone (2)
Cocaine (3)
Figure 2.3. Structures of atropine, tropinone, and cocaine.
primary requisites to green chemical processes. A classic example to highlight the importance of the synthetic scheme can be understood by analyzing the two divergent synthetic schemes developed for the synthesis of tropinone, a precursor of an alkaloid atropine, a close analogue of the well-known local anesthetic "cocaine" (see Fig. 2.3). Richard Willst~itter achieved the first synthesis of tropinone in 1901 (see Fig. 2.4). At that time, structure determination was not always equivocal, and final proof could only be established by unambiguous synthesis of the compound with the suspected structure followed by comparison with an authentic sample of the natural product. Thus, synthesis was often a matter of utilitarian necessity rather than the creative, elegant art form illustrated by the work of many of the great synthetic chemists such as Woodward and Corey. Willst~itter's preparation of tropinone is a competent but long synthesis that demonstrates one of the fundamental difficulties involved in the preparation of complex organic molecules. Although the individual steps in the synthesis generally give good to excellent yields, there are many steps, which means that the overall yield becomes diminishingly small, of the order of 1%. As a result, the early steps in the synthesis have to be carried out on inconveniently large quantities of material and, despite this, usually have to be repeated several times in order to obtain sufficient material to carry out the later stages on an acceptable scale. In 1917, Robinson approached the synthesis in a totally radical way. Tropinone was obtained by condensation of succinaldehyde with acetone and methylamine in aqueous solution (see Fig. 2.5). An improvement
Newer Synthetic Methods 35
[~
NH2OH ~ ~
O
HON
Na/EtOH
~.C)
(,) Me, (ii)"AgOH"
l
N(CH3)2 ~~
~)HBr [ ~ (ii) Me2NH
~: Br2 ~ quinoline
~)Me, (ii)"AgOH"
(i) Br2 (ii) Me2NH
C~
_~,0.3,~
I Na/EtOH NMe2
NMe2 Br2
warm ]/.NMe~ (i)NaOH (ii) CI e
Br Br
Br 130°C
O
rO3
.
Figure 2.4. Willst~tter's synthesis of tropinone.
followed with the replacement of acetone by a salt (calcium)of acetone dicarboxylic acid. The initial product was a salt of tropinone dicarboxylic acid, and this loses two molecules of carbon dioxide with the formation of tropinone when the solution was acidified and heated. In fact, we can view this synthesis of tropinone as one of the earliest examples of multicomponent reactions (MCR). MCRs are convergent reactions in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product. In an MCR, a product is assembled according to a cascade of elementary chemical
36
Green Chemistry and Processes
dislocation 0
"2
~
CHO +
H2NMe
+
~---0
CHO
COOCHO
(/
.:
CHO
q,
.......",,
CO0-
Figure 2.5. Robinson's synthesis of tropinone.
H ~,
H
R'
a'
R2N
Figure 2.6. Multicomponent reaction.
reactions. Thus, there is a network of reaction equilibria, which all finally flow into an irreversible step, yielding the product. Carbonyl compounds played a crucial role in the early discovery of multicomponent reactions. Some of the first multicomponent reactions to be reported function through derivation of carbonyl compounds into more reactive intermediates, which can react further with a nucleophile. One example is the Mannich reaction (see Fig. 2.6). Some of the well-known (or "name")MCRs are listed in Table 2.2. In the more specific applications to the drug discovery process, MCRs offer many advantages over traditional approaches. Thus, the chemistry development time, which can typically take up to 6 months for a linear six-step synthesis, is considerably shortened. With only a limited number of chemists and technicians, more scaffold synthesis programs can be achieved within a shorter time. With one-pot reactions, each synthesis procedure (weighing of reagents, addition of reagents, reaction/time control) and work-up procedure (quenching, extraction, distillation, chromatography,
Newer Synthetic Methods
37
TABLE 2.2 Common Multicomponent Reactions Name of the Reaction
Reactants/ Components
Predominant Product
Mannich
Carbonyl compounds + amines Carbonyl compounds + esters + amines Carbonyl compounds + cyanides + ammonium salts Carbonyl compounds + cyanides + sulphur Carbonyl compounds + active methylenes + amines Carbonyl compounds + amines + phosphates Carbonyl compounds + HCN + mineral acid Carbonyl compounds + sulphur + amines Carbonyl compounds + carboxylic acid + isocyanide Carbonyl compounds + amines + isocyanides
Ketoamines
Biginelli Bucherer-Bergs
Gewald Hantzschdihydropyridine synthesis Kabachnik-Fields Strecker Kindler thioamide synthesis Passerini Ugi
Diazine derivatives Imidazolium derivatives Thiophene derivatives Dihydropyridine derivatives Aminophosphates Amino acids Thioamide Amino esters Keto amines
weighing, analysis)needs to be performed only once, in contrast to multistep syntheses.
Conclusions The various reaction types most c o m m o n l y used in synthesis can have different degrees of impact on h u m a n health and the environment. Addition reactions, for example, completely incorporate the starting materials into the final product and, therefore, do not produce waste that needs to be treated, disposed of, or otherwise dealt with. Substitution reactions, on the other hand, necessarily generate stoichiometric quantities of substances as byproducts and
38 Green Chemistry and Processes waste. Elimination reactions do not require input of materials during the course of the reaction other than the initial input of a starting material, but they do generate stoichiometric quantities of substances that are not part of the final target molecule. As such, elimination reactions are among the least atom-economical transformations. For any synthetic transformation, it is important to evaluate the hazardous properties of all substances necessarily being generated from the transformation, just as it is important to evaluate the hazardous properties of all starting materials and reagents that are added in a synthetic transformation. The atom-economy of various reaction types is shown in Fig. 2.7. The most atom-economy-suited reactions are condensations, multicomponent reactions, and rearrangements. Hence, where possible, these reaction types should be adopted, in order to ensure
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~
80
c--
70
.c_
6o
• CONDENSATIONS
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•MCR
=o ca
40
III III
~•
3o
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• REARRANGEMENTS
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I
• SUBSTITUTIONS • OXIDATIONS • FRAGMENTATIONS
~
10
n
0,111111111
n • REDUCTIONS
Reaction class
Figure 2.7. Atom-economy of various reaction types.
Newer Synthetic Methods
39
efficient synthesis. The challenges for designing a synthetic route can therefore be listed as • • • • •
• • • • • • •
Minimize overall number of steps. Maximize yield per step. Maximize atom-economy per step. Use stoichiometric conditions. In multistep syntheses, perform the following: Maximize frequency of condensations, MCRs, rearrangements, C-C and non-C-C bond-forming reactions. Minimize frequency of substitutions (protecting group strategies) and redox reactions. If forced to use oxidations, opt for hydrogen peroxide as oxidant. If forced to use reductions, opt for hydrogen as reductant. Devise electrochemical transformations. Devise catalytic methods where catalysts are recycled and reused. Devise regio-/stereoselective synthetic strategies. Opt for solventless reactions, recycle solvents, or use benign solvents (ionic liquids). Minimize energy demands: heating, cooling, reactions under pressure.
Thus, a judicious use of suitable synthetic transformations coupled with an energy-efficient kinetic activation is the way to eco-friendly and cost-effective chemical synthesis.
References Ando T., Shinjiro S., Takehiko K., Junko I. (nde Yamawaki), and Terukiyo H., J. Chem. Soc., Chem. Commun., 10: 439-440, 1984. Bordeau, M., Biran, C., Serein-Spirau, F., Leger-Lambert, M.-P., Deffieux, D., and Dunogues, J., The Electrochemical Society Meeting Abstracts, 97(1): 1167, 1997. Fry, A. J. and Touster, J., J. Org. Chem. 54: 4829, 1989. Lund, H. and Baizer, M. M., Organic Electrochemistry, Marcel Dekker, New York, 1991. Margulis, M. A. and Mal'tsev, A. N., Russ. J. Phy. Chem. 42: 751-757, 1968. Pletcher, D. and Walsh, F. C., Industrial Electrochemistry, 3rd ed., Blackie Academic & Professional, London, 1993.
40
Green Chemistry and Processes
A p p e n d i x 2.1 C o m p a r i s o n of Thermal Vs. Ultrasound A s s i s t e d Reactions (shown above and b e l o w the arrow) C6H5COOAg, NEt3,CH3OH, )))), lmin, r.t. C15H31-CH2COOCH3
1. C15H31-COCHN2 90% silent, > 1h, 180°C, 81%
Pd(PPh3)4, NEt3, CH3CN, C6H6, 50°C, 76% ,rits( )))), 6h24h, 71%) 80°C,
"/ ~
"'.COOMe
~OOMe
~ ~ P ~ O "Et
PhCH3' ))))' 80°C'90man >90% Ira,
+
I-['~ \ O - E t
N
N
3-thienyl ~ ~ CH3
--
O
~O--Et ONEt
H/ Thermal reaction exhibits an induction period of c a . 1 h, then proceeds to give 50% of the adduct after 2 h. Cr(CO)5 4.
0
Me + n_C3H7
H 2. CAN
,.._
75%, ""(~, CH3CN,24 h,45°C,69%) O
RMgX, THF, 25°C, )))), 1.5h O
(stirred: "slow", 61% ) R= (CH2)2-C(OCH2CH20)-CH2CH3
)))), neat, lh, 99% 65°C, neat, 5h, 99%
Reactions:
ID, f \ ' - ~ ~/'.~.. " ~ R OCH3 OIH'
Newer Synthetic Methods
HN
OH
Ac
Hg(CN)2, CH3CN, )))) r.t., 25 min
O
+
HN
41
OR
,,.._ ,...-
r
62% (silent, 28%)
LAc R = 1~ - D- Gal(OAc) 4
60% HNO 3, stirring, r.t., 12 h
n-C7H15-CH2ONO 2
,,..-
100%
8. n - C 7 H 1 5 - C H 2 O H ~
60% HNO 3, )))), r.t., 20 min
n-C7H15-COOH
100%
OMe(or Allyl) O 9. Me/
~
k
~
~
_1_ Me
10.
Ph N
O~ ~
OMe | 1.EtOH,ZnBr2, )))), r.t. ~1~ ,, 2. Oxidation
28%,100%Regioselect e
~,~ ~ v
[ R
Ph N
Ph N + AcO" f
/ cH3
ac(~ Conditions Stirring, 50°C, 1h )))), 50°C, lh )))), 50°C, l h, radical scavanger
0 38 38
I R
/OAc
1-Octene + N C ~ C O N H
2
Ph N
/OAc
+
0 12 12
~OAc
5 3 3
Mn(OAc) 3, Cu(OAc)2, AcOH, )))), r.t., 3h
l l.
jAllyl(or OMe)
"Ii
.,,~
in AcOH, Reflux, Yield 6% "U Regioselectivity 7:3 Me l~le
+ Pb(Oac)4 AcOH, 50°C
,~
ID~
'~ONH2
73% (Stirring, r.t., 4h, 30%) C5HI1
Na2S203, NaHCO 3, )))), CH3CN, H20, 1-2h, r.t. 12.
+ Rf-I Q
• TBAHS, Et20, H20, 4h, r.t., 45 - 72%
RI ~
17
OH 13.
C H. 3 ( C H 2 ) 4 7 ~ ~ ~ . ~ C H 2 ) 7 C O O M
e A orB
CH3(CH2)4,,~ "~ r " ~~ ' - "~0
"(~CH2)7COOMe
42
Green Chemistry and Processes
References o
o
o
,
o
,
o
o
.
10.
11. 12. 13. 14. 15. 16. 17. 18. 19.
Winum, J. Y., Kamal, M., Leydet, A., Roque, J. P., and Montero, J. L. Tetrahedron Lett., 37: 1781-1782, 1996; Rehorek, D. and Janzen, E. G., J. Prakt. Chem. 326: 935-940, 1984. O'Connor, B., Zhang, Y., Negishi, E., Luo, F. T., and Cheng, J. W., Tetrahedron Lett., 29: 3903-3906, 1984; Cheng, J. and Luo, F., Bull. Inst. Chem. Acad. Sin., 36: 9-15, 1989. Hubert, C., Oussaid, B., Etemad, G., Koenig, M., and Garrigues, B., Synthesis, 51-55, 1994; Hubert, C., Munopz, A., Garrigues, B., and Luvhe, J. L., J. Org. Chem., 60: 1488-1490, 1995. Harrity, J. P. A., Kerr, W. J., and Middlemiss, D., Tetrahedron, 49: 55655576, 1993. Uyehara, T., Yamada, J., Furuta, T., and Kato, T., Chem. Lett., 609612, 1986. Smith, K. and Pelter, A., in Comprehensive Organic Synthesis, Trost, B. M., ed.; Pergamon Press, Oxford, Vol. 8 (Fleming, I., vol. ed.), pp. 703-731, 1991. Brown, H. C. and Racherla, U. S., Tetrahedron Lett., 26: 2187-2190, 1985. Polidori, A., Pucci, B., Maurizis, J. C., and Pavia, A. A., New J. Chem., 18: 839-848, 1994. Einhorn, C., Einhorn, J., Dickens, M. J., and Luche, J. L., Tetrahedron Lett., 31: 4129-4130, 1990. Zhang, Z., Flachsmann, F., Moghaddam, F. M., and Ruedi, P., Tetrahedron Lett., 35: 2153-2156, 1994. Ando, T., Bauchat, P., Foucaud, A., Fujita, M., Kimura, T., and Sohmiya, H., Tetrahedron Lett., 32: 6379-6382, 1991; Ando, T., Fujita, M., Bauchat, P., Foucaud, A., Sohmiya, H., and Kimura, T., Ultrasonics Sonochemistry, 1: $33-$35, 1994. Bosman, C., D'Annibale, A., Resta, S., and Trogolo, C., Tetrahedron, 50: 13847-13856, 1994. Rong, G. and Keese, R., Tetrahedron Lett., 31: 5615-5616, 1990. Lie Ken Jie, M. S. F. and Lam, C. K., Ultrasonics Sonochemistry, 2: S 11S14, 1995. Fuentes, A., Marinas, J. M., and Sinisterra, J. V., Tetrahedron Lett., 28: 4541-4544, 1987. Silveira, C. C., Perin, G., and Braga, A. L., J. Chem. Res., 492--493, 1994. Moon, S., Duchin, L., and Cooney, J. V., Tetrahedron Lett., 39173920, 1979. Grigon-Dubois, M., Diaba, F., and Grellier-Marly, M. C., Synthesis, 800-804, 1994. Silveira, C. C., Braga, A. L., and Fiorin, G. L., Synth. Commun., 24: 2075-2080, 1994. Ezquerra, J. and Alvarez-Builla, J., J. Heterocyclic Chem., 25: 917925, 1988; Alvarez-Builla, J., Galvez, E., Cuadro, A. M., Florencio, F., and Garcia Blanco, S., J. Heterocyclic Chem., 24: 917-926, 1987.
Newer Synthetic Methods
43
20. Davidson, R. S., Patel, A. M., Safdar, A., and Thornthwaite, D., Tetrahedron Lett., 24: 5907-5910, 1983. 21. Mason, T. J., Lorimer, J. P., Paniwnik, L., Harris, A. R., Wright, P. W., Bram, G., Loupy, A., Ferradou, G., and Sansoulet, J., Synth. Commun., 20: 3411-3420, 1990; Mason, T. J., Lorimer, J. P., Turner, A. T., and Harris, A. R., J. Chem. Res., 80-81, 1988; Davidson, R. S., Safdar, A., Spencer, J. D., and Robinson, B., Ultrasonics, 25: 35-39, 1987. 22. Preston Reeves, W. and McClusky, J. V., Tetrahedron Lett., 24: 15851588, 1983. 23. Ando, T., Kawate, T., Ishihara, J., and Hanafusa, T., Chem. Lett., 725-728, 1984. 24. Singh, A. K., Synth. Commun., 20: 3547-3551, 1990. 25. Casiraghi, G., Cornia, M., Rassu, G., Zetta, L., Fava, G. G., and Belicchi, M. F., Carbohydr. Res., 191: 243-251, 1989. 26. Han, B. H. and Boudjouk, P., Tetrahedron Lett., 23: 1643-1646, 1982. 27. Kumar, D., Singh, O. V., Prakash, O., and Singh, S. P., Synth. Commun., 24: 2637-2644, 1994. 28. Yamawaki, J., Sumi, S., Ando, T., and Hanafusa, T., Chem. Lett., 379-380, 1983. 29. Adams, L. L. and Luzzio, F. A., J. Org. Chem., 54: 5387-5390, 1989. 30. Morey, J. and Saa, J. M., Tetrahedron, 49:105-112, 1993. 31. Farooq, O., Farnia, S. M. F., Stephenson, M., and Olah, G. A., J. Org. Chem., 53: 2840-2843, 1988. 32. Harrowven, D. C. and Dainty, R. F., Tetrahedron Lett., 37: 76597660, 1996. 33. Lickiss, P. D. and Lucas, R., Polyhedron, 15: 1975-1979, 1996. 34. Petrier, C. and Luche, J. L., Tetrahedron Lett., 28: 2347-2352, 1987. 35. Lillwitz, L. D. and Karachewski, A. M., U.S. Patent 5198594, Chem. Abstr., 119: 72339r, 1993.
44
Green Chemistry and Processes
Appendix 2.2 Comparison of Thermal Vs. Microwave-Assisted Reactions COOH
0020 H3
H2SO4
(MW, 1 min) (thermal, 80 min)
HBr (MW, 5 min ) (thermal, 72 hours)
[KC1], 1100°C ,
CoCO 3
+
A1203
~
CoA1204
4- C O 2
(MW, 4 min) (thermal, more)
R1
O II
H
NaBH4 R2
R 1
(thermal, 5 days)
a: R 1 = R 2 =
Ph
b. R 1 = trans-PhCH=CH ; R 2 = Ph c. R 1 = 2 naphthyl ; R 2 = Me d. R 1 = P h C H 2 ; R 2 = Ph e. R 1 = P h C H ( O H ) ; R 2 = Ph OH
O NaBH 4 R
~
C-R 1 M W 30 sec
a. R = M e ; R I = H b. R =C1 ; R 1 = H c. R = N O 2 ; R 1 = H d.R=Rl=Me
H
Newer Synthetic Methods
45
NaBH 4 R
R--k
C-R l (MW, 30 sec )
a: b: c: d:
/F"--",
e: R = H , R I=Me f: R = H , Rl=Ph g: R =OCH 3 , RI=CH(OH)C6H4OCH3 P
R = M e , R I=H R=C1 , Rl =H R = N O 2 , RI=H R =RI=Me
h: R = H , R l =CH(OH)Ph
HCHO
~
R-CHO
R-CH2OH
NaOH, (MW, 25sec)
a:R= b: R= c: R= d: R= e: R= f: R=
Ph 4-C6H4 4- MeOC6H4 4- Me2NC6H4 4- MeC6H 4 4- O z N C 6 H 6
g" R h" R= i" R= j" R= k" R=
3-O2NC6H4 2-O2NC6H4 PhCH=CH 2-furyl 2-thienyl
Ba(OH)2.8H20 R-CHO
+
R-CH2OH +
( CH20)n
R-COOH
MW
RCHO
+ (CH20)n
Ba(OH)2.8 H20
RCH2OH
(MW, -- 1min)
a: R = P h b: R = 4 - C 1 C 6 H 4 c: R = 4 - B r C 6 H 4 d: R = 4 - F C 6 H 4
e: R = 2 - F C 6 H 4 f: R = 2 - H O C 6 H 4 g" R = 4 - M e C 6 H 4 h: R = P h C H = C H
+ RCOOH
46
Green Chemistry and Processes
NaHePO2 / FeSO4. 7 H20
R1
y
NH2
(MW, 50 sec) R R
R,RI= H, Me, OH, CONH 2, Ph, COOH, CN, NH 2 O R1-S-R 2
II
(CH3)3COOH
R1-S-R 2
SILICA GELL (thermal, >48hrs) a: RI=R2= n-Bu b: Rl=Ph, R2=CH2Ph c: RI=R2=Ph
10.
20% NaIO4- silica
R1-S-R 2
r
R1-S-R 2
(MW, stipulated time) a: RI=PhCH2 , R2=Ph b: Rl=R2=PhCH2 c: RI=R2=Ph d: Rl=Ph, R2=Me e: RI=R2=Bu
11.
PhCHO
ZnC12
+
R
A, lOOOC (specified time)
R=CN, CONH2, COOEt
Ph X H
/CN R
Newer Synthetic Methods
12.
~
PhCHO
CN
LiC1
R
(MW, given time)
47
Ph H
R
R=CN, COOEt Ar 13. N ArCHO
600 alumina
+
Ar
A
(thermal, 4 hrs)
Ph
14. PhCHO (MW, 10 min)
Ph
P h
N
Ph
15
O
O Ph
Ph MnO 2 or BaMnO 4 r
OH
thermal, 2 hrs
O
48
Green Chemistry and Processes
16 O
O Ph
Ph
Fe(NO3)3.9H20 MW, 0.5-1 min
OH
O
17 H
NH4+MeCO2-1~._ thermal, 24 hrs
HO
COOH 18 H
CLAY, MW 2 sec
HO
COOH
19.
NaOH
RICHO
+
~'-
R2CH2 P+ Ph 3
R1CH=CH R 2
thermal
RI=Fc
R2= C6H5,Fc
X= C1, I, Br
20. MW R1N
0
+
Ph3P=CHCOOEt
R1 ~
R:/ Rl=R2=Ph R1=Ph, R2=Me
~
CHCOOEt
Newer Synthetic Methods
49
21.
R
H2NY, Si Gel
)
R,~
NaOH
H
NY
H/
Y=PhNH
R=Ph 22
R
)
o
.R~
H2NY, MW
~Y
( 15 sec)
H
Y=OH
R=4-FC6H4, 4-C1C6H4
23. HONH2, HC1;
CaO
thermal, few minutes
R)
NOH
~)
NOH
R I=R2= -(CH2)5-, -(CH2)6
24. RI
silica gel, MW, 2min
R?
98% pure RI= Ph, R2= H, Me
25.
O R3SH, CdI2
R2
MW, 75sec RI=Ph, R2=H, R3=-(CH2)3-
R3S~ R1
SR3 R2
50
Green Chemistry and Processes
26.
O
R3SH,LiOSO2
R2
thermal, 90-110°C
R3S~ R1
SR3 R2
RI=C6H5,R2=H,R3=-(CH2)3-
References
,
3. .
o
.
7. 8. .
10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
Emelingmeier, A., R6mpp Lexikon Chemie, Mikrowelle, Version 1.3, Georg Thieme Verlag, Stuttgart/New York, 1997. Mingos, M. P. and Baghurst, D. R., Chem. Soc. Rev., 20: 1, 1991. Brockhaus, F. A., ABC Physik, Auflage, Brockhaus-Verlag, Leipzig, 586, 1989. Kingston, H. M. and Haswell, S. J. (Hrsg.), Microwave-Enhanced Chemistry, American Chemical Society, Washington, DC, 1997. Toda, F., Kiyoshige, K., and Yagi, M., Angew. Chem. Int. Ed. Engl., 28: 320, 1989. Varma, R. S. and Naicker, K. P., Org. Lett., l: 189, 1999. Varma, R. S. and Saini, R. K., Tetrahedron Lett., 38: 4337, 1997. Thakuria, J. A., Baruah, M., and Sandhu, J. S., Chem. Lett., 995, 1999. Varma, R. S., Naicker, K. P., and Liesen, P. J., Tetrahedron Lett., 39: 843 7, 1998. Meshram, H. M., Ganesh, Y. S. S., Sekhar, K. C., and Yadav, J. S., Syn. Lett., 993, 2000. Kropp, P. J., Breton, G. W., Fields, J. D., Tung, J. C., and Loomir, B. R., J. Am. Chem. Soc., 122: 4280, 2000. Varma, R. S., Meshram, H. M., and Saini, R. K., Tetrahedron Lett., 38: 6525, 1997. Rao, P. S. and Venkatratnam, R. V., Tetrahedron Lett., 32: 5821, 1999. Sabitha, G., Reddy, B. V. S., Satheesh, R. S., and Yadav, J. S., Chem. Lett., 773, 1998. Gross, Z., Galili, N., Simkhovich, L., Saltsman, I., Botoshansky, M., Blaser, D., Boese, R., and Goldberg, I., Org. Lett., 1: 599, 1999. Firouzabani, H., Karimi, B., and Abbasi, M., J. Chem. Soc., 236, 1999. Warner, M. G., Succaw, G. L., and Hutchison, J. E., Green Chem., 3: 267, 1999. Scott, J. L. and Ratoson, C. L., Green Chem., 2: 245, 2000. Bandgar, B. P., Uppalla, L. S., and Kurule, D. S., Green Chem., 1: 243, 1999.
Newer Synthetic Methods
51
20. Liu, W., Xu, Q., Ma, Y., Liang, Y., Dong, N., and Guan, D., J. Organomet. Chem., 625: 128, 2001. 21. Spinella, A., Fortunati, T., and Soriente, A., Synlett., 93, 1997. 22. Hajipour, A. R., Mohammadpoor-Baltork, I., and Bigdeli, M., J. Chem. Res., 570, 1999. 23. Bandger, B. P., Sadavarte, V. S., Uppalla, L. S., and Govande, R., Monatsh. Chem., 132: 143, 2001. 24. Shaghi, H. and Sarvani, M. N., J. Chem. Res., 24, 2000. 25. Hajipour, A. R., Mallakpour, S. E., and Imanzadeh, G., J. Chem. Res., 228, 1999. 26. Firouzabani, H., Karimi, B., and Eslami, S., Tetrahedron Lett., 40: 4055, 1999. 27. Laskar, D. D., Prajapati, D., and Sandhu, J. S., J. Chem. Res., 331, 2001.
Newer Synthetic Methods
Introduction Waste prevention and environmental protection are major requirements in an overcrowded world of increasing demands. Synthetic chemistry continues to develop various techniques for obtaining better products with less damaging environmental impacts. The control of reactivity and selectivity is always the central subject in the development of a new methodology of organic synthesis. Novel, highly selective reagents appear every month. New reactions or modifications of old reactions have been devised to meet the ever-increasing demands of selectivity in modern synthesis. Periodic review articles and books appear in the literature on these newer reagents. The scope of this chapter is to focus on newer techniques (experimental) for improving the yield and reducing the duration of the reactions and also to discuss the need for a good synthetic design. In other words, newer methods of kinetic activation, which minimize the energy input by optimizing reaction conditions, will be discussed along with the need for an elegant synthetic design. In most reactions, the reaction vessel provides three components (as shown in Fig. 2.1): • solvent, • reagent/catalyst, • energy input.
28 Green Chemistry and Processes Energy input
PRODUCTS
REACTANTS
Reagent
Solvent
Figure 2.1. Components of chemical reaction.
Hence, efforts to green chemical reactions focus predominantly on "greening" these three components. By "greening," we mean to • Use benign solvents or completely dispense with the solvent. • Use alternate, more efficient and effective reagents/catalysts. • Optimize the reaction conditions by using cost-effective, ecofriendly alternative processes. The role of alternate reagents, solvents, and catalysts in greening chemical reactions is discussed in other chapters. In this chapter we shall see newer methods of kinetic activation of molecules in chemical reactions. Pressure and temperature are important parameters in reaction processes in chemical systems. However, it is a less well-known fact that other than thermally initiated reactions can also lead to sustainable results. The basic requirement is to capture the energy required by a reaction. The energy required for synthesis as well as that required for cooling are of interest here. In order to minimize energy and control reactions with a view to green chemistry, attempts are being made to make the energy input in chemical systems as efficient as possible. Approaches are being taken and possibilities investigated to use until now scarcely used forms of energy, so-called nonclassical energy forms, in order to optimize the duration and product yield and avoid undesired side products. Teams working in this area are also interested in the energetic aspects of the preparation of starting substances and
Newer Synthetic Methods 29 products and the conditioning of reaction systems (e.g., surface activation, emulsification, homogenization, degassing, etc.). We now have six well-documented methods of activating molecules in chemical reactions, which can be grouped as follows: the classical methods, including • thermal, • photochemical, • electrochemical, and the nonclassical methods, which include • sonication, • mechanical, • microwave. Each of these methods has its advantages and niche areas of applications, alongside its inherent limitations. A comparative study of these techniques is given in Table 2.1. What do we mean by classical and nonclassical energy forms? In classical processes, energy is added to the system by heat transfer; by electromagnetic radiation in the ultraviolet (UV), visible, or infrared (IR)range; or in the form of electrical energy. On the other hand, microwave radiation, ultrasound, and the direct application of mechanical energy are among the nonclassical forms. Sonochemical Processes
Ultrasound, an efficient and virtually innocuous means of activation in synthetic chemistry, has been employed for decades with varied success. Not only can this high-energy input enhance mechanical effects in heterogeneous processes, but it is also known to induce new reactions, leading to the formation of unexpected chemical species. What makes sonochemistry unique is the remarkable phenomenon of cavitation, currently the subject of intense research, which has already yielded thought-provoking results. The majority of today's practitioners accept a rationale based on "hotspot" interpretation, provided this expression is not taken literally, but rather as "a high-energy state in a small volume." One should also recall that only a small part (10-3) of the acoustic energy absorbed by the system is used to produce a chemical activity (Margulis and Mal'tsev, 1968). High-power, low-frequency
~D ~d °1,,~
~d
~
z
z
~
~:
z 4~
0 "'~
~ ~
~ ~ "-4 "'4
~
ka
¢/3
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0
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O
~
4-~
"~
0
~
,-~
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0
t~
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oo
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.,~
~ ~
~,
~> ,~
0 0
"~
~
~
0
Z
0
o
~o
D ©
~ "~
~
~
~
-,-~
~
.,-~
0
z
~
z
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0
0
©
~
z
~
°~-'t 4-~
<
° ~,,,{
.~
M
~
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~
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0 0
Z
©
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o
m
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•
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4~
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E
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,-a o~
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o
Newer Synthetic Methods
31
(16-100 Hz)waves are often associated with better mechanical treatment and less importantly with chemical effects. With highfrequency ultrasound, the chemistry produced displays characteristics similar to high-energy radiation (more radicals are created). One of the most striking features in sonochemistry is that there is often an optimum value for the reaction temperature. In contrast to classical chemistry, most of the time it is not necessary to go to higher temperatures to accelerate a process. Each solvent has a unique fingerprint. Sonochemistry in heterogeneous systems is the result of a combination of chemical and mechanical effects of cavitation, and it is very difficult to ascribe sonochemistry to any single global origin, other than the overriding source of activity, namely, cavitation. The real benefit of using ultrasound lies in its unique selectivity and reactivity enhancement. The heterogeneity of the reaction phase would be particularly significant. In fact, heterogeneous reactions are those in which ultrasound is likely to play the most important role by selective accelerations between potentially competitive pathways. Apart from the use of ultrasound in enhancing the reactivity in organic reactions, ultrasound has varied uses in industry, such as welding, cutting, emulsification, solvent degassing, powder dispersion, cell disruption, and atomization. It was reported that the sonochemical decomposition of volatile organometallic precursors was shown to produce nanostructured materials in various forms with high catalytic activities. This has proved extremely useful in the synthesis of a wide range of nanostructured inorganic materials, including high surface area transition metals, alloys, carbides, oxides, and sulfides, as well as colloids of nanometer cluster. Ultrasound is known to enhance the reaction rate, thus minimizing the duration of a reaction. A large number of published examples, which highlight this observation, are shown in Appendix 2.1. Apart from this, it is known to induce specific reactivity, known as "sonochemical switching." Ando et al. (1984)reported that benzyl bromide, on treatment with alumina impregnated with potassium cyanide, yielded benzyl cyanide on sonication, while, without sonication, on heating the reaction mixture yielded diphenylmethanes (see Fig. 2.2). This work was the first experimental evidence that ultrasonic irradiation induces a particular
32 Green Chemistry and Processes CN
r
KCN
/~
na, sonication
~
, heat KCN
Ph H2 C /
\Ph Figure 2.2. Sonochemical switching. reactivity. Further studies on sonochemical induction indicated that • Reactions activated by sonication are those that proceed via a r a d i c a l or radical ion intermediate (electron transfer). • I o n i c r e a c t i o n s (polar) mostly remain unaffected. U s e of M i c r o w a v e s for S y n t h e s i s
In synthetic chemistry, 1986 was an important year for the use of microwave devices. Since that year, countless syntheses initiated by microwaves have been carried out on a laboratory scale. The result is often a drastic reduction in the reaction time with comparable product yields, if microwaves are used instead of classical methods of energy input. Unwanted side reactions can often be suppressed and solvents dispensed with. Numerous reactions, such as esterifications, Diels Alder reactions, hydrolyses, or the production of inorganic pigments, have been investigated in recent years. Reactions listed in Appendix 2.2 illustrate nicely the advantages of this nonclassical means of energy input. Apart from the obvious advantages of the use of microwaves in chemical syntheses, microwave technologies are being tested as energy- and cost-saving alternatives. Hopes are high, for example, in the field of green extraction of pollutants from contaminated soil, or for the improvement of the breakdown of biomass waste by fermentation as part of green biorefinery.
Newer Synthetic Methods
33
Electro-Organic Methods Over the past 25 to 30 years, the use of electrochemistry as a synthetic tool in organic chemistry has increased remarkably. According to Pletcher and Walsh (1993), more than 100 electro-organic synthetic processes have been piloted at levels ranging from a few tons up to 10s tons. Such examples include reductive dimerization of acrylonitrile, hydrogenation of heterocycles, pinacolization, reduction of nitro aromatics, the Kolbe reaction, Simons fluorination, methoxylation, epoxidation of olefins, oxidation of aromatic hydrocarbons, etc. Many excellent reviews and publications highlight the synthetic utility of electro-organic methods (Lund and Baizer, 1991). These cover a broad spectrum of applications of electrochemical methods in organic synthesis, including their use in the pharmaceutical industry. Mild reaction conditions, ease of control of solvent and counter-ions, high yields, high selectivities, as well as the use of readily available equipment, simply designed cells, and regular organic glassware make the electrochemical syntheses very competitive to the conventional methods in organic synthesis. The use of sacrificial anodes is an effective way for the preparation of metallo-organic compounds by cathodic generation of organic anions and anodic generation of metal cations. This approach was very successful for synthesis of the organosilicon compounds (Fry and Touster, 1989). A large variety of fluorinated organosilicon compounds can be synthesized using a sacrificial A1 anode and a stainless steel cathode under very mild conditions and in good yields (Bordeau et al., 1997). Discoveries of new types of electro-organic reactions based on coupling and substitution reactions, cyclization and elimination reactions, electrochemically promoted rearrangements, recent advances in selective electrochemical fluorination, electrochemical versions of the classical synthetic reactions, and successful use of these reactions in multistep targeted synthesis allow the synthetic chemist to consider electrochemical methods as one of the powerful tools of organic synthesis.
Elegant and Cost-Effective Synthetic Design The heart of synthesis is in the design of the synthetic scheme for the given target molecule. All the technological advances (discussed above) can only supplement the synthetic scheme. Innovation, elegance, and brevity in the synthetic design are essential
34 Green Chemistry and Processes CH3~N
CH3N •N
CH3 NN
O o/CH3
H
H/ N ~ O O
Atropine (1)
Tropinone (2)
Cocaine (3)
Figure 2.3. Structures of atropine, tropinone, and cocaine.
primary requisites to green chemical processes. A classic example to highlight the importance of the synthetic scheme can be understood by analyzing the two divergent synthetic schemes developed for the synthesis of tropinone, a precursor of an alkaloid atropine, a close analogue of the well-known local anesthetic "cocaine" (see Fig. 2.3). Richard Willst~itter achieved the first synthesis of tropinone in 1901 (see Fig. 2.4). At that time, structure determination was not always equivocal, and final proof could only be established by unambiguous synthesis of the compound with the suspected structure followed by comparison with an authentic sample of the natural product. Thus, synthesis was often a matter of utilitarian necessity rather than the creative, elegant art form illustrated by the work of many of the great synthetic chemists such as Woodward and Corey. Willst~itter's preparation of tropinone is a competent but long synthesis that demonstrates one of the fundamental difficulties involved in the preparation of complex organic molecules. Although the individual steps in the synthesis generally give good to excellent yields, there are many steps, which means that the overall yield becomes diminishingly small, of the order of 1%. As a result, the early steps in the synthesis have to be carried out on inconveniently large quantities of material and, despite this, usually have to be repeated several times in order to obtain sufficient material to carry out the later stages on an acceptable scale. In 1917, Robinson approached the synthesis in a totally radical way. Tropinone was obtained by condensation of succinaldehyde with acetone and methylamine in aqueous solution (see Fig. 2.5). An improvement
Newer Synthetic Methods 35
[~
NH2OH ~ ~
O
HON
Na/EtOH
~.C)
(,) Me, (ii)"AgOH"
l
N(CH3)2 ~~
~)HBr [ ~ (ii) Me2NH
~: Br2 ~ quinoline
~)Me, (ii)"AgOH"
(i) Br2 (ii) Me2NH
C~
_~,0.3,~
I Na/EtOH NMe2
NMe2 Br2
warm ]/.NMe~ (i)NaOH (ii) CI e
Br Br
Br 130°C
O
rO3
.
Figure 2.4. Willst~tter's synthesis of tropinone.
followed with the replacement of acetone by a salt (calcium)of acetone dicarboxylic acid. The initial product was a salt of tropinone dicarboxylic acid, and this loses two molecules of carbon dioxide with the formation of tropinone when the solution was acidified and heated. In fact, we can view this synthesis of tropinone as one of the earliest examples of multicomponent reactions (MCR). MCRs are convergent reactions in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product. In an MCR, a product is assembled according to a cascade of elementary chemical
36
Green Chemistry and Processes
dislocation 0
"2
~
CHO +
H2NMe
+
~---0
CHO
COOCHO
(/
.:
CHO
q,
.......",,
CO0-
Figure 2.5. Robinson's synthesis of tropinone.
H ~,
H
R'
a'
R2N
Figure 2.6. Multicomponent reaction.
reactions. Thus, there is a network of reaction equilibria, which all finally flow into an irreversible step, yielding the product. Carbonyl compounds played a crucial role in the early discovery of multicomponent reactions. Some of the first multicomponent reactions to be reported function through derivation of carbonyl compounds into more reactive intermediates, which can react further with a nucleophile. One example is the Mannich reaction (see Fig. 2.6). Some of the well-known (or "name")MCRs are listed in Table 2.2. In the more specific applications to the drug discovery process, MCRs offer many advantages over traditional approaches. Thus, the chemistry development time, which can typically take up to 6 months for a linear six-step synthesis, is considerably shortened. With only a limited number of chemists and technicians, more scaffold synthesis programs can be achieved within a shorter time. With one-pot reactions, each synthesis procedure (weighing of reagents, addition of reagents, reaction/time control) and work-up procedure (quenching, extraction, distillation, chromatography,
Newer Synthetic Methods
37
TABLE 2.2 Common Multicomponent Reactions Name of the Reaction
Reactants/ Components
Predominant Product
Mannich
Carbonyl compounds + amines Carbonyl compounds + esters + amines Carbonyl compounds + cyanides + ammonium salts Carbonyl compounds + cyanides + sulphur Carbonyl compounds + active methylenes + amines Carbonyl compounds + amines + phosphates Carbonyl compounds + HCN + mineral acid Carbonyl compounds + sulphur + amines Carbonyl compounds + carboxylic acid + isocyanide Carbonyl compounds + amines + isocyanides
Ketoamines
Biginelli Bucherer-Bergs
Gewald Hantzschdihydropyridine synthesis Kabachnik-Fields Strecker Kindler thioamide synthesis Passerini Ugi
Diazine derivatives Imidazolium derivatives Thiophene derivatives Dihydropyridine derivatives Aminophosphates Amino acids Thioamide Amino esters Keto amines
weighing, analysis)needs to be performed only once, in contrast to multistep syntheses.
Conclusions The various reaction types most c o m m o n l y used in synthesis can have different degrees of impact on h u m a n health and the environment. Addition reactions, for example, completely incorporate the starting materials into the final product and, therefore, do not produce waste that needs to be treated, disposed of, or otherwise dealt with. Substitution reactions, on the other hand, necessarily generate stoichiometric quantities of substances as byproducts and
38 Green Chemistry and Processes waste. Elimination reactions do not require input of materials during the course of the reaction other than the initial input of a starting material, but they do generate stoichiometric quantities of substances that are not part of the final target molecule. As such, elimination reactions are among the least atom-economical transformations. For any synthetic transformation, it is important to evaluate the hazardous properties of all substances necessarily being generated from the transformation, just as it is important to evaluate the hazardous properties of all starting materials and reagents that are added in a synthetic transformation. The atom-economy of various reaction types is shown in Fig. 2.7. The most atom-economy-suited reactions are condensations, multicomponent reactions, and rearrangements. Hence, where possible, these reaction types should be adopted, in order to ensure
100 ,
ooiI
~
80
c--
70
.c_
6o
• CONDENSATIONS
I
•MCR
=o ca
40
III III
~•
3o
I / / / / /
• REARRANGEMENTS
lI
• NON C-C FORMING RXNS • C-C FORMING RXNS
I
• SUBSTITUTIONS • OXIDATIONS • FRAGMENTATIONS
~
10
n
0,111111111
n • REDUCTIONS
Reaction class
Figure 2.7. Atom-economy of various reaction types.
Newer Synthetic Methods
39
efficient synthesis. The challenges for designing a synthetic route can therefore be listed as • • • • •
• • • • • • •
Minimize overall number of steps. Maximize yield per step. Maximize atom-economy per step. Use stoichiometric conditions. In multistep syntheses, perform the following: Maximize frequency of condensations, MCRs, rearrangements, C-C and non-C-C bond-forming reactions. Minimize frequency of substitutions (protecting group strategies) and redox reactions. If forced to use oxidations, opt for hydrogen peroxide as oxidant. If forced to use reductions, opt for hydrogen as reductant. Devise electrochemical transformations. Devise catalytic methods where catalysts are recycled and reused. Devise regio-/stereoselective synthetic strategies. Opt for solventless reactions, recycle solvents, or use benign solvents (ionic liquids). Minimize energy demands: heating, cooling, reactions under pressure.
Thus, a judicious use of suitable synthetic transformations coupled with an energy-efficient kinetic activation is the way to eco-friendly and cost-effective chemical synthesis.
References Ando T., Shinjiro S., Takehiko K., Junko I. (nde Yamawaki), and Terukiyo H., J. Chem. Soc., Chem. Commun., 10: 439-440, 1984. Bordeau, M., Biran, C., Serein-Spirau, F., Leger-Lambert, M.-P., Deffieux, D., and Dunogues, J., The Electrochemical Society Meeting Abstracts, 97(1): 1167, 1997. Fry, A. J. and Touster, J., J. Org. Chem. 54: 4829, 1989. Lund, H. and Baizer, M. M., Organic Electrochemistry, Marcel Dekker, New York, 1991. Margulis, M. A. and Mal'tsev, A. N., Russ. J. Phy. Chem. 42: 751-757, 1968. Pletcher, D. and Walsh, F. C., Industrial Electrochemistry, 3rd ed., Blackie Academic & Professional, London, 1993.
40
Green Chemistry and Processes
A p p e n d i x 2.1 C o m p a r i s o n of Thermal Vs. Ultrasound A s s i s t e d Reactions (shown above and b e l o w the arrow) C6H5COOAg, NEt3,CH3OH, )))), lmin, r.t. C15H31-CH2COOCH3
1. C15H31-COCHN2 90% silent, > 1h, 180°C, 81%
Pd(PPh3)4, NEt3, CH3CN, C6H6, 50°C, 76% ,rits( )))), 6h24h, 71%) 80°C,
"/ ~
"'.COOMe
~OOMe
~ ~ P ~ O "Et
PhCH3' ))))' 80°C'90man >90% Ira,
+
I-['~ \ O - E t
N
N
3-thienyl ~ ~ CH3
--
O
~O--Et ONEt
H/ Thermal reaction exhibits an induction period of c a . 1 h, then proceeds to give 50% of the adduct after 2 h. Cr(CO)5 4.
0
Me + n_C3H7
H 2. CAN
,.._
75%, ""(~, CH3CN,24 h,45°C,69%) O
RMgX, THF, 25°C, )))), 1.5h O
(stirred: "slow", 61% ) R= (CH2)2-C(OCH2CH20)-CH2CH3
)))), neat, lh, 99% 65°C, neat, 5h, 99%
Reactions:
ID, f \ ' - ~ ~/'.~.. " ~ R OCH3 OIH'
Newer Synthetic Methods
HN
OH
Ac
Hg(CN)2, CH3CN, )))) r.t., 25 min
O
+
HN
41
OR
,,.._ ,...-
r
62% (silent, 28%)
LAc R = 1~ - D- Gal(OAc) 4
60% HNO 3, stirring, r.t., 12 h
n-C7H15-CH2ONO 2
,,..-
100%
8. n - C 7 H 1 5 - C H 2 O H ~
60% HNO 3, )))), r.t., 20 min
n-C7H15-COOH
100%
OMe(or Allyl) O 9. Me/
~
k
~
~
_1_ Me
10.
Ph N
O~ ~
OMe | 1.EtOH,ZnBr2, )))), r.t. ~1~ ,, 2. Oxidation
28%,100%Regioselect e
~,~ ~ v
[ R
Ph N
Ph N + AcO" f
/ cH3
ac(~ Conditions Stirring, 50°C, 1h )))), 50°C, lh )))), 50°C, l h, radical scavanger
0 38 38
I R
/OAc
1-Octene + N C ~ C O N H
2
Ph N
/OAc
+
0 12 12
~OAc
5 3 3
Mn(OAc) 3, Cu(OAc)2, AcOH, )))), r.t., 3h
l l.
jAllyl(or OMe)
"Ii
.,,~
in AcOH, Reflux, Yield 6% "U Regioselectivity 7:3 Me l~le
+ Pb(Oac)4 AcOH, 50°C
,~
ID~
'~ONH2
73% (Stirring, r.t., 4h, 30%) C5HI1
Na2S203, NaHCO 3, )))), CH3CN, H20, 1-2h, r.t. 12.
+ Rf-I Q
• TBAHS, Et20, H20, 4h, r.t., 45 - 72%
RI ~
17
OH 13.
C H. 3 ( C H 2 ) 4 7 ~ ~ ~ . ~ C H 2 ) 7 C O O M
e A orB
CH3(CH2)4,,~ "~ r " ~~ ' - "~0
"(~CH2)7COOMe
42
Green Chemistry and Processes
References o
o
o
,
o
,
o
o
.
10.
11. 12. 13. 14. 15. 16. 17. 18. 19.
Winum, J. Y., Kamal, M., Leydet, A., Roque, J. P., and Montero, J. L. Tetrahedron Lett., 37: 1781-1782, 1996; Rehorek, D. and Janzen, E. G., J. Prakt. Chem. 326: 935-940, 1984. O'Connor, B., Zhang, Y., Negishi, E., Luo, F. T., and Cheng, J. W., Tetrahedron Lett., 29: 3903-3906, 1984; Cheng, J. and Luo, F., Bull. Inst. Chem. Acad. Sin., 36: 9-15, 1989. Hubert, C., Oussaid, B., Etemad, G., Koenig, M., and Garrigues, B., Synthesis, 51-55, 1994; Hubert, C., Munopz, A., Garrigues, B., and Luvhe, J. L., J. Org. Chem., 60: 1488-1490, 1995. Harrity, J. P. A., Kerr, W. J., and Middlemiss, D., Tetrahedron, 49: 55655576, 1993. Uyehara, T., Yamada, J., Furuta, T., and Kato, T., Chem. Lett., 609612, 1986. Smith, K. and Pelter, A., in Comprehensive Organic Synthesis, Trost, B. M., ed.; Pergamon Press, Oxford, Vol. 8 (Fleming, I., vol. ed.), pp. 703-731, 1991. Brown, H. C. and Racherla, U. S., Tetrahedron Lett., 26: 2187-2190, 1985. Polidori, A., Pucci, B., Maurizis, J. C., and Pavia, A. A., New J. Chem., 18: 839-848, 1994. Einhorn, C., Einhorn, J., Dickens, M. J., and Luche, J. L., Tetrahedron Lett., 31: 4129-4130, 1990. Zhang, Z., Flachsmann, F., Moghaddam, F. M., and Ruedi, P., Tetrahedron Lett., 35: 2153-2156, 1994. Ando, T., Bauchat, P., Foucaud, A., Fujita, M., Kimura, T., and Sohmiya, H., Tetrahedron Lett., 32: 6379-6382, 1991; Ando, T., Fujita, M., Bauchat, P., Foucaud, A., Sohmiya, H., and Kimura, T., Ultrasonics Sonochemistry, 1: $33-$35, 1994. Bosman, C., D'Annibale, A., Resta, S., and Trogolo, C., Tetrahedron, 50: 13847-13856, 1994. Rong, G. and Keese, R., Tetrahedron Lett., 31: 5615-5616, 1990. Lie Ken Jie, M. S. F. and Lam, C. K., Ultrasonics Sonochemistry, 2: S 11S14, 1995. Fuentes, A., Marinas, J. M., and Sinisterra, J. V., Tetrahedron Lett., 28: 4541-4544, 1987. Silveira, C. C., Perin, G., and Braga, A. L., J. Chem. Res., 492--493, 1994. Moon, S., Duchin, L., and Cooney, J. V., Tetrahedron Lett., 39173920, 1979. Grigon-Dubois, M., Diaba, F., and Grellier-Marly, M. C., Synthesis, 800-804, 1994. Silveira, C. C., Braga, A. L., and Fiorin, G. L., Synth. Commun., 24: 2075-2080, 1994. Ezquerra, J. and Alvarez-Builla, J., J. Heterocyclic Chem., 25: 917925, 1988; Alvarez-Builla, J., Galvez, E., Cuadro, A. M., Florencio, F., and Garcia Blanco, S., J. Heterocyclic Chem., 24: 917-926, 1987.
Newer Synthetic Methods
43
20. Davidson, R. S., Patel, A. M., Safdar, A., and Thornthwaite, D., Tetrahedron Lett., 24: 5907-5910, 1983. 21. Mason, T. J., Lorimer, J. P., Paniwnik, L., Harris, A. R., Wright, P. W., Bram, G., Loupy, A., Ferradou, G., and Sansoulet, J., Synth. Commun., 20: 3411-3420, 1990; Mason, T. J., Lorimer, J. P., Turner, A. T., and Harris, A. R., J. Chem. Res., 80-81, 1988; Davidson, R. S., Safdar, A., Spencer, J. D., and Robinson, B., Ultrasonics, 25: 35-39, 1987. 22. Preston Reeves, W. and McClusky, J. V., Tetrahedron Lett., 24: 15851588, 1983. 23. Ando, T., Kawate, T., Ishihara, J., and Hanafusa, T., Chem. Lett., 725-728, 1984. 24. Singh, A. K., Synth. Commun., 20: 3547-3551, 1990. 25. Casiraghi, G., Cornia, M., Rassu, G., Zetta, L., Fava, G. G., and Belicchi, M. F., Carbohydr. Res., 191: 243-251, 1989. 26. Han, B. H. and Boudjouk, P., Tetrahedron Lett., 23: 1643-1646, 1982. 27. Kumar, D., Singh, O. V., Prakash, O., and Singh, S. P., Synth. Commun., 24: 2637-2644, 1994. 28. Yamawaki, J., Sumi, S., Ando, T., and Hanafusa, T., Chem. Lett., 379-380, 1983. 29. Adams, L. L. and Luzzio, F. A., J. Org. Chem., 54: 5387-5390, 1989. 30. Morey, J. and Saa, J. M., Tetrahedron, 49:105-112, 1993. 31. Farooq, O., Farnia, S. M. F., Stephenson, M., and Olah, G. A., J. Org. Chem., 53: 2840-2843, 1988. 32. Harrowven, D. C. and Dainty, R. F., Tetrahedron Lett., 37: 76597660, 1996. 33. Lickiss, P. D. and Lucas, R., Polyhedron, 15: 1975-1979, 1996. 34. Petrier, C. and Luche, J. L., Tetrahedron Lett., 28: 2347-2352, 1987. 35. Lillwitz, L. D. and Karachewski, A. M., U.S. Patent 5198594, Chem. Abstr., 119: 72339r, 1993.
44
Green Chemistry and Processes
Appendix 2.2 Comparison of Thermal Vs. Microwave-Assisted Reactions COOH
0020 H3
H2SO4
(MW, 1 min) (thermal, 80 min)
HBr (MW, 5 min ) (thermal, 72 hours)
[KC1], 1100°C ,
CoCO 3
+
A1203
~
CoA1204
4- C O 2
(MW, 4 min) (thermal, more)
R1
O II
H
NaBH4 R2
R 1
(thermal, 5 days)
a: R 1 = R 2 =
Ph
b. R 1 = trans-PhCH=CH ; R 2 = Ph c. R 1 = 2 naphthyl ; R 2 = Me d. R 1 = P h C H 2 ; R 2 = Ph e. R 1 = P h C H ( O H ) ; R 2 = Ph OH
O NaBH 4 R
~
C-R 1 M W 30 sec
a. R = M e ; R I = H b. R =C1 ; R 1 = H c. R = N O 2 ; R 1 = H d.R=Rl=Me
H
Newer Synthetic Methods
45
NaBH 4 R
R--k
C-R l (MW, 30 sec )
a: b: c: d:
/F"--",
e: R = H , R I=Me f: R = H , Rl=Ph g: R =OCH 3 , RI=CH(OH)C6H4OCH3 P
R = M e , R I=H R=C1 , Rl =H R = N O 2 , RI=H R =RI=Me
h: R = H , R l =CH(OH)Ph
HCHO
~
R-CHO
R-CH2OH
NaOH, (MW, 25sec)
a:R= b: R= c: R= d: R= e: R= f: R=
Ph 4-C6H4 4- MeOC6H4 4- Me2NC6H4 4- MeC6H 4 4- O z N C 6 H 6
g" R h" R= i" R= j" R= k" R=
3-O2NC6H4 2-O2NC6H4 PhCH=CH 2-furyl 2-thienyl
Ba(OH)2.8H20 R-CHO
+
R-CH2OH +
( CH20)n
R-COOH
MW
RCHO
+ (CH20)n
Ba(OH)2.8 H20
RCH2OH
(MW, -- 1min)
a: R = P h b: R = 4 - C 1 C 6 H 4 c: R = 4 - B r C 6 H 4 d: R = 4 - F C 6 H 4
e: R = 2 - F C 6 H 4 f: R = 2 - H O C 6 H 4 g" R = 4 - M e C 6 H 4 h: R = P h C H = C H
+ RCOOH
46
Green Chemistry and Processes
NaHePO2 / FeSO4. 7 H20
R1
y
NH2
(MW, 50 sec) R R
R,RI= H, Me, OH, CONH 2, Ph, COOH, CN, NH 2 O R1-S-R 2
II
(CH3)3COOH
R1-S-R 2
SILICA GELL (thermal, >48hrs) a: RI=R2= n-Bu b: Rl=Ph, R2=CH2Ph c: RI=R2=Ph
10.
20% NaIO4- silica
R1-S-R 2
r
R1-S-R 2
(MW, stipulated time) a: RI=PhCH2 , R2=Ph b: Rl=R2=PhCH2 c: RI=R2=Ph d: Rl=Ph, R2=Me e: RI=R2=Bu
11.
PhCHO
ZnC12
+
R
A, lOOOC (specified time)
R=CN, CONH2, COOEt
Ph X H
/CN R
Newer Synthetic Methods
12.
~
PhCHO
CN
LiC1
R
(MW, given time)
47
Ph H
R
R=CN, COOEt Ar 13. N ArCHO
600 alumina
+
Ar
A
(thermal, 4 hrs)
Ph
14. PhCHO (MW, 10 min)
Ph
P h
N
Ph
15
O
O Ph
Ph MnO 2 or BaMnO 4 r
OH
thermal, 2 hrs
O
48
Green Chemistry and Processes
16 O
O Ph
Ph
Fe(NO3)3.9H20 MW, 0.5-1 min
OH
O
17 H
NH4+MeCO2-1~._ thermal, 24 hrs
HO
COOH 18 H
CLAY, MW 2 sec
HO
COOH
19.
NaOH
RICHO
+
~'-
R2CH2 P+ Ph 3
R1CH=CH R 2
thermal
RI=Fc
R2= C6H5,Fc
X= C1, I, Br
20. MW R1N
0
+
Ph3P=CHCOOEt
R1 ~
R:/ Rl=R2=Ph R1=Ph, R2=Me
~
CHCOOEt
Newer Synthetic Methods
49
21.
R
H2NY, Si Gel
)
R,~
NaOH
H
NY
H/
Y=PhNH
R=Ph 22
R
)
o
.R~
H2NY, MW
~Y
( 15 sec)
H
Y=OH
R=4-FC6H4, 4-C1C6H4
23. HONH2, HC1;
CaO
thermal, few minutes
R)
NOH
~)
NOH
R I=R2= -(CH2)5-, -(CH2)6
24. RI
silica gel, MW, 2min
R?
98% pure RI= Ph, R2= H, Me
25.
O R3SH, CdI2
R2
MW, 75sec RI=Ph, R2=H, R3=-(CH2)3-
R3S~ R1
SR3 R2
50
Green Chemistry and Processes
26.
O
R3SH,LiOSO2
R2
thermal, 90-110°C
R3S~ R1
SR3 R2
RI=C6H5,R2=H,R3=-(CH2)3-
References
,
3. .
o
.
7. 8. .
10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
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Newer Synthetic Methods
51
20. Liu, W., Xu, Q., Ma, Y., Liang, Y., Dong, N., and Guan, D., J. Organomet. Chem., 625: 128, 2001. 21. Spinella, A., Fortunati, T., and Soriente, A., Synlett., 93, 1997. 22. Hajipour, A. R., Mohammadpoor-Baltork, I., and Bigdeli, M., J. Chem. Res., 570, 1999. 23. Bandger, B. P., Sadavarte, V. S., Uppalla, L. S., and Govande, R., Monatsh. Chem., 132: 143, 2001. 24. Shaghi, H. and Sarvani, M. N., J. Chem. Res., 24, 2000. 25. Hajipour, A. R., Mallakpour, S. E., and Imanzadeh, G., J. Chem. Res., 228, 1999. 26. Firouzabani, H., Karimi, B., and Eslami, S., Tetrahedron Lett., 40: 4055, 1999. 27. Laskar, D. D., Prajapati, D., and Sandhu, J. S., J. Chem. Res., 331, 2001.