Chem. Rev. 2000, 100, 1025−1074 1025 Solvent-Free Organic Synthesis K. Tanaka† and F. Toda*,‡ Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama, Ehime 790-8577, Japan, and Department of Chemistry, Faculty of Science, Okayama University of Science, 1-1 Ridaicho, Okayama 700-0005, Japan Received June 17, 1996 Contents G. Enantioselective Photoreaction 1056 1. Enantioselective Photoreactions of Chiral 1056 I. Introduction 1025 Molecules II. Molecular Movement in the Solid State 1026 2. Enantioselective Photoreaction of Achiral 1057 III. Thermal Reaction 1028 Molecules in Chiral Inclusion Crystals A. Oxidation 1028 3. Enantioselective Photoreaction of Achiral 1066 B. Reduction 1030 Molecules in Their Chiral Crystals C. Addition Reaction 1032 V. Conclusion 1071 1. Halogenation and Hydrohalogenation 1032 VI. References 1071 2. Michael Addition and Aldol Addition 1032 D. Elimination Reaction 1034 I. Introduction E. C−C Coupling Reaction 1034 Crushed grapes give wine by fermentation, but 1. [2+2], [4+2], and [6+2] Cycloaddition 1034 dried grapes do not result in wine. Although milk Reaction turns sour and shaking of milk gives cheese, dried 2. Aldol Condensation Reaction 1036 milk can be kept unaltered. Similarly dried meat can 3. Dieckmann Condensation Reaction 1037 be stored for a long time, whereas meat soup rapidly 4. Grignard, Reformatsky, and Luche 1037 putrefies on standing. Reactions By observation of these phenomena, one can see 5. Wittig Reaction 1038 that conversion of one material into another one 6. Ylid Reaction 1038 occurs in the liquid state but not in the solid state. 7. Pinacol Coupling Reaction 1039 One of the most famous ancient philosophers in 8. Phenol Coupling Reaction 1040 Greece, Aristotle, summarized these observations by concluding “No Coopora nisi Fluida”, which means 9. Oxidative Coupling Reaction of Acetylenic 1040 Compound “No reaction occurs in the absence of solvent”. Such philosophies had a big influence on the evolution of 10. Phase Transfer Reaction 1041 the modern sciences in Europe, and this provides one 11. Addition and Coupling Reaction of 1041 historical reason most organic reactions have been [60]Fullerene studied in solution. F. Substitution Reaction 1041 Nevertheless, it is remarkable that chemists still G. Aminolysis, Hydrolysis, and 1043 carry out their reactions in solution, even when a Transesterification special reason for the use of solvent cannot be found. H. Polymerization 1044 We have found that many reactions proceed ef- I. Rearrangement and Isomerization 1044 ficiently in the solid state. Indeed, in many cases, 1. Pinacol Rearrangement 1044 solid-state organic reaction occurs more efficiently 2. Benzilic Acid Rearrangement 1045 and more selectively than does its solution counter- 3. Beckmann Rearrangement 1045 part, since molecules in a crystal are arranged tightly 4. Meyer-Schuster Rearrangement 1046 and regularly. 5. Chapman Rearrangement 1046 Furthermore, the solid-state reaction (or solvent- 6. Isomerization 1047 free reaction) has many advantages: reduced pollu- IV. Photoreaction 1047 tion, low costs, and simplicity in process and handling. These factors are especially important in industry. A. Photodimerization and Photopolymerization 1047 When greater selectivity is required in the solid- B. Photocyclization 1052 state reaction, host-guest chemistry techniques can C. Photorearrangement and Photoisomerization 1052 be applied efficaciously. Reaction in the solid state D. Photosolvolysis 1054 of the guest compound as its inclusion complex crys- E. Photodecarbonylation 1054 tal with a chiral host can give an optically active reac- F. Photoaddition Reaction between Different 1055 tion product. Various host compounds have been de- Molecules signed by us to follow this simple principle. Although both thermal and photochemical reactions can be car- † Ehime University. ried out selectively in inclusion crystals, the selectiv- ‡ Okayama University of Science. ity of the latter is usually higher than that of the for- 10.1021/cr940089p CCC: $35.00 © 2000 American Chemical Society Published on Web 02/23/2000 1026 Chemical Reviews, 2000, Vol. 100, No. 3 Tanaka and Toda esting application of chiral recognition in the solid state is resolution of a racemic guest by fractional distillation in the presence of an optically active host. When racemic guest and chirally pure host are mixed in the solid state, one enantiomer of the guest is included by the host, and then when the mixture is heated the uncomplexed guest distills at relatively low temperature. Thereafter the complexed enanti- omer is released on distillation at relatively high temperature. In this review, optical resolution by selective inclusion is not discussed. However, optical resolution by the combination of enantioselective solid-state reaction and the distillation technique is described in chapter II. In an inclusion crystal formed by a prochiral guest Koichi Tanaka received his Bachelor’s and Master’s degrees from Ehime and chiral host, molecules of the former are arranged University in 1976 and 1978, respectively, and Doctor’s degrees from Osaka University in 1983. He was appointed an Assistant Professor at in a chiral form and such chirality becomes perma- Ehime University in 1978 and worked with Professor F. Toda. He was nent on solid-state reaction. This is the basic principle promoted to Associate Professor in 1991. His research interests are in underlying enantioselective reactions in inclusion the area of design of novel host molecules, chiral recognition in host− crystals using chiral hosts. In some special cases, guest inclusion crystals, and solid-state organic reactions. prochiral molecules are arranged in a chiral form within the crystal without using any chiral source. Once again this chirality can also become permanent through solid-state photoreaction. This is absolute asymmetric synthesis and is summarized in chapter IV. Inclusion crystals are usually prepared by recrys- tallization of both components. Surprisingly, how- ever, it was discovered that movement and chiral arrangement of achiral molecules can occur by mix- ing and grinding host and guest crystals in the solid state. In other words, an optically active product results from mixing and grinding an achiral guest with a chiral host followed by irradiation. The chiral arrangement of the achiral guest resulting from mixing and grinding with a chiral host can also be Fumio Toda received his Bachelor’s, Master’s, and Doctor’s degrees from easily monitored by measurement of its CD spectrum Osaka University at Osaka City, Japan, in 1956, 1958, and 1960, in the solid state. This is described in chapter II. respectively. After staying at Osaka University for four years as an This article covers such solid-state organic reac- Instructor and in the United States for two years as a postdoctoral fellow, tions including the reactions that start with a solid, he obtained an Associate Professorship at Ehime University in 1966. He at least one solid reactant or solid catalyst, the was promoted to Full Professor in 1972. He has held the Synthetic Organic Chemistry Award in 1988, the Chemical Society of Japan Award in 1993, reactions in the inclusion crystals, and organic solvent- and the Inoue Harushige Award in 1999, and he moved to Okayama free reactions mainly since 1983 although some University of Science. His research interests are in the area of strained review articles and books on these topics have been small-ring compounds, unusual chemical bonds, host−guest inclusion already published.1 compounds, solid-state organic chemistry, and reaction control in crystals. II. Molecular Movement in the Solid State mer. However, solvent-free thermal reactions are im- portant for practical synthetic processes in industry. In 1987, it was found that inclusion complexation The occurrence of efficient solid-state reactions occurs by simple mixing and grinding of powdered shows that the molecules reacting are able to move host and guest compounds. For example, when an IR freely in the solid state. In fact, host-guest inclusion spectrum of a mixture of powdered 1,1,6,6-tetraphen- complexation can occur by simply mixing and grind- ylhexa-2,4-diyne-1,6-diol (1) (Chart 1) and an equimo- ing both crystals in the solid state. These solid-state lar amount of powdered benzophenone was measured reactions can be easily monitored by measurement as a Nujol mull, it proved to be identical to that of of IR and UV spectra in the solid state. Surprisingly, their 1:1 inclusion complex prepared normally by solid-state complexation even occurs selectively. For recrystallization of the two components from solu- example, mixing and grinding racemic guest and tion.2 This result shows that formation of the complex optically active host in the solid state gives an by solid-state reaction occurs very rapidly. Similar inclusion complex involving just one enantiomer of inclusion complexation in the solid state occurs for the guest with the host and from which the optically many other kinds of host and guest combinations. active guest can be obtained. Such efficient chiral These solid-state reactions can easily be monitored recognition has been observed in many inclusion by measurement of the IR or UV spectrum as a Nujol crystals, and efficient optical resolutions have been mull. For example, when IR spectra of a mixture of achieved by using this phenomenon. The most inter- 1 and two molar amounts of amide 2 were measured Solvent-Free Organic Synthesis Chemical Reviews, 2000, Vol. 100, No. 3 1027 Figure 1. IR spectrum of a mixture of powdered (50 µm) 1 and 2 in the solid state (measured every 10 min for 17 h). Chart 1 in Nujol every 10 min for 17 h, the νOH of 1 at 3540 cm-1 decreased and finally disappeared and a new hydrogen-bonded νOH due to a 1:2 complex (3) ap- peared at 3250 cm-1 and increased gradually. Con- -1 comitantly the νCdO of 2 at 1690 cm split into two -1 νCdO at 1680 and 1600 cm as the inclusion com- plexation proceeded (Figure 1).3 Formation of racemic 2,2′-dihydroxy-1,1′-binaphthyl (4c) by mixing and grinding of powdered (-)-(4a) and (+)-enantiomers Figure 2.