Organic Reaction Schemes and General Reaction-Matrix Types, II Basic Types of Synthetic Transformations J a n C. J. Bart and Enea Garagnani Montedison S. p. A., Istituto Ricerche “G. Donegani”, Via del Lavoro 4, Novara, Italy (Z. Naturforsch. 32 b, 455-464 [1977]; received August 31, 1976) Reaction-Matrices, Synthesis-Planning Organic synthetic transformations are described in terms of a set of 43 distinct general reaction-matrix types, of which ten account for rearrangement reactions only. The schemes identified conform partially to the semi-empirical rules governing synthetic transformations, as previously defined by Ugi et a l . 30. 1. Introduction general schemes by considering basic types of Chemistry is concerned both with the understand­ synthetic transformations, such as: modification ing of the statical properties of chemical compounds of side chains (lengthening, shortening, branching), and their dynamical interconversions, i.e. reactions ring synthesis and ring reactions (cleavage, contrac­ (redistributions of electron-density). In recent years tion, expansion), introduction and modification of attempts have been made to treat some of the most functional groups (removal, inter con version), etc. important aspects of statical and dynamical Thus the fundamental reactions in organic chem­ chemistry more systematically. In this respect we istry, as acid-base reactions, electrophilic and mention combinatorial studies of chemical graphs1, nucleophilic substitution and addition reactions, computer-oriented representations and methods for eliminations and insertion reactions were considered. computer handling of chemical structure informa­ Molecular rearrangement reactions were already tion2, the introduction of logical structures in dealt with in a previous paper31. chemistry3, applications of artificial intelligence in mass spectrometry4, molecular structure elucida­ 2. Procedures tion5 and organic synthesis6. In particular the latter The reactions that will be discussed have one problem has attracted much attention, namely feature in common. Electrons are transferred in through the computational procedures of C o r e y pairs during the processes of bond formation and et al .7-14 and others15-19. Due to a satisfactory breakage, and thus only polar or heterolytic knowledge of many organic chemical phenomena, it reactions are considered. The reaction scheme takes is now possible, mechanistically speaking, to recog­ into account the behaviour of the participating nize broad classes of reactions. Recent work on atoms without, however, furnishing a picture of the synthesis-planning has shown the need for a participating species at the more crucial instants different kind of rationalization of organic reaction during the course of the reaction. Thus, in fact, it schemes, namely in terms of net structural changes. records the situation before the reacting species Procedures based on various algebraic models of approach each other and after the products have constitutional chemistry are under development20-30. emerged. We therefore also consider reactions which In the practical application of general reaction involve overall transfers of electrons in pairs, even matrices to synthesis planning25-31 the use of a though the reaction mechanism involves homolytic restricted optimum set of algebraic expressions of steps. A classification according to mechanism is structural changes is required. Our research efforts not necessary for the purpose of definition of an are therefore directed towards deriving such a set of optimum set of general R-matrices of overall organic reactions. Requests for reprints should be sent to Dr. J. C. J. When possible then, we shall adhere to current B a r t , Montedison Research Laboratories “G. Done­ gani”, Via del Lavoro 4, Novara, Italy. usage and base our primary classification of syn­ 456 J. C. J. Bart-E. Garagnani • Organic Reaction Schemes and General Reaction-Matrix Types thetic reactions on the overall change that occurs. Ar-H + S 03 ^ ArSOsH (ft 21, 1) Obviously, complex multistep reactions give rise to Other reactions, such as the Friedel-Crafts more specific R-matrices, which eventually are linear alkylation or acylation of an aromatic ring in the combinations of more general R-matrices corres­ presence of such catalysts as AICI 3, BF3, SnCl4 or I 2, ponding to basic reactions. Whenever such evidence wThich occur with skeletal rearrangement, are ft 2 type: is available, the overall R-matrix is not further considered for inclusion in the optimum set. Rather, Me I PhH such more specific R-matrices are useful for classifi­ Me-C-CH2C1: A1C13------- cation and codification of organic reactions for re­ I Me trieval purposes, as will be illustrated in a next Ph Me paper32. The general desirability of generating precursors Me-C - CH2 + HC1: A1C13 (R 2, 1) I (intermediates) of established chemical stability and Me the necessity of adherence to ensembles of molecules, In case of nucleophilic aromatic substitutions a make it desirable to express a process as: greater variety of reaction schemes occurs as in a (C6H 5)2CH-OH + HC1 -> (C6H 5)2CH-C1 + H 20 number of substitutions the introduced group does not take the place of the expelled group, but a as a R 1-reaction31, even though the carbon-to- hydrogen shift is involved, e.g. in substitutions oxygen bond is broken first: involving elimination (benzyne mechanism), as in case of replacement of halogen by an amino-group (C6H 5)2CH-OH + H+ ^ (C6H 5)2CH+ + H 20 by the action of metal amides on aromatic halides: The latter process, which may be considered as an electrophilic substitution by hydrogen for the benz- hydryl group on oxygen, is schematically represented as A—B+C^A—C+B (Rll) (fl8, 5) This kind of subclassification will be introduced Table I. Synthetic transformations of the type only where mechanistic differences have bearings on A-B + C-D -> A-C + B-D. the product distribution. R 1 3. Results and Discussion 1 Electrophilic and nucleophilic substitution reactions. The results of the classification of the more 2 Esterification and ester saponification. fundamental types of organic reactions in terms of 3 Formation and hydrolysis of carboxylamides. 4 C l a i s e n condensation. !R-matrices or electron-flow schemes, are summa­ 5 D i e c k m a n n r e a c tio n . rized in Tables I and II. 6 Cleavage of /S-diketones. 7 Halogenation of ketones. In accordance with previous findings31, !R1 8 Aldol condensation and related reactions. appears to account for the majority of organic 9 Cyanohydrin formation. reactions. In particular, with the restrictions 10 P e r k i n r e a c t io n . indicated above, electrophilic substitutions (e.g. 11 M i c h a e l reaction. aromatic substitution reactions, including alkyla- 12 Benzoin condensation. 13 Addition reactions (of halogens, hydrogen tions, acylations, nitrations, sulfonations, halogena- halides, hypohalous acids; hydration). tions, diazonium coupling reactions, etc.) are often 14 Formation of azomethines, oximes, arylhydra- !R 1 type, e.g. zones, semicarbazones. CISOaH + CH 3C-NH-C 6H 5 ~> 15 Additions of olefins to give four-membered rings. II 16 Addition reactions of organolithium compounds. 0 17 Addition reactions of G r i g n a r d reagents. 29CH3C-NH-C 6H 4-SO 3H + HCl (R 1, 1) 18 Friedel-Crafts acylation (without decarbonyla- II tion). 0 19 Beta-elimination reactions. 2 0 Intramolecular (cis) eliminations ( C h t j g a e v and RC1:AICI3 + C6H 6 -> C o p e reactions). c 6h 5-r + H+ + AlCU- (ftl, 1) 2 1 Intramolecular displacement by oxygen in halo- although other schemes may arise, as in case of carboxylic acids. sulfonation: 2 2 Tautomerizations. J. C. J. Bart-E. Garagnani • Organic Reaction Schemes and General Reaction-Matrix Types 457 Table II. General reaction-matrix types of synthetic Table II (continued). transformations. R22 A-B-C * A-C + B: R2 A-B + C-D + E-F > A-C + D-E + B-F 1. CO2, CO, SO2 and N = N heterolysis 1. Friedel-C rafts alkylation (with skeletal (decarboxylation, etc.). rearrangement). 2. Internal nucleophilic substitutions without 2. 1,4 Additions to conjugated polyolefins. allylic rearrangement (Si^i). 3. 1,4 Tele-eliminations. 3. a-Elimination reactions of alkyl halides and 4. Telesubstitutions. related compounds. 5. D i e l s -A l d e r reactions. R23 A-B A + B: 6. Neighbouring-group partecipation in electrophilic addition reactions. 1. Nucleophilic aliphatic substitutions (SnI)- 2. Dissociation reactions. 7. G r o b ’s fragmentation of /3-halocinnamic 3. Pyrolysis of diazoalkanes or ketenes. acids. R24 A + B: A-B R3 A-B + C-D A + B-C + D: 1. Electron pair transfers ( L e w i s acid-base 1. Metal hydride addition. system ). 2 . H o e s c h reaction (form ation of im inochloride). 2. Formation of amino oxides, sulfoxides, sulfones. R7 A-B + C-D-E A-D-B + C-E 3. Addition of dichlorocarbenes. 1. Insertion reactions (e.g. Baeyer-V illiger oxidation of ketones). R25 A + B-C + D: * A-B + C-D 2. Neighbouring group partecipation in E 1-type 1. H o e s c h reaction. elimination reactions. R 2 6 A-B + C-D + E-F A + B-C + D-E + F: 3. Epoxidation ( cis addition to C = C bond). 1. Heterolytic addition of hydrogen to R8 A-B + C-D + E: » A-C + D-E + B: conjugated olefinic carbonyl compounds. 1. Addition of 1,3 dipoles to give five-membered R i t t e r reaction (first step). rings. R 27 + B -C + D -E + F -G -> 2. E2 type olefin elimination reactions. A-G + C-D + E-F 3. Sn 2' reactions in allylic systems. 4. Copulation reactions. 1,4 Tele-eliminations. Staedel-Rügheim er pyrazine synthesis 5 . Benzyne formation. (last step). 6. S a n d m e y e r reaction.