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Organic Reaction Schemes and General Reaction-Matrix Types, IV Organic Name Reactions

J a n C. J . B a r t a n d E n e a G a r a g n a n i

M ontedison R & D D ivision, “G. D onegani” Research Laboratories, Via G. Fauser 4, Novara, Ita ly

(Z. N a tu rfo rsch . 32b , 678-683 [1977 ]; received M arch 8, 1977)

R eaction-M atrices, N am e R eactions

A sample consisting of 427 one- and m ulti-step organic name reactions has been classified in term s of a previously determ ined empirical set of 43 general reaction-matrix types (R), according to procedures outlined originally by U g i et a l.14. The resulting distribution o f R-matrices is similar to the overall pattern o f other random and specialized sample analyses. The m etathesis reaction accounts for 60% o f all single-step synthetic transformations; subsets consisting o f the primary three and ten R-m atrices describe some 78% and 93% of the population, respectively. The results represent a valid experim ental basis for the mathem atical description o f the constitution o f organic chem istry.

IntroductionAction undertaken in the last decade to develop

system atic procedures for organic synthesis design has been pursued along two main courses: one centering on the use of empirical reaction libraries and the other involving algebraic models. W hereas the form er approach has led to various operational systems such as O C SS^LH A SA 2- 6, SECS7 and SYNCHEM 8, the alternative non-empirical logical m ethods still need additional development of their basic framework. In this context, it appears th a t the H e n d r i c k s o n schem e9, a system based on num erical encoding of structures and reactions th a t is specifically designed for use in synthesis-planning, is m ost advanced. I ts structure relies heavily on an extensive and critical evaluation of organic reaction types, encompassing im portan t areas of organic synthesis in a schematic fashion. No computerized version of this algebra is yet available.

In another formal approach to dynamic organic chem istry, developed by U g i et a l.10~15, some generalized structural representations of organic reaction types are introduced which allow the description of all known and unknown reactions w ithout modification of the original scheme. As known, U g i ’s non-empirical approach to system atic synthesis analysis is based on the recognition th a t

R equests for reprints should be sent to Dr. J . C. J. B a r t , M ontedison Research Laboratories “G. D one­gani” , Via G. Fauser 4, N ovara Ita ly .

all chemical reactions correspond to interconversions of isomeric ensembles of molecules (EM) within a family of isomeric ensembles of molecules (FIEM). Using B E (bond and electron) matrices Mi cor­responding to EM,-, the generation of a synthetic tree reduces to the problem of finding B E matrices Mj which are related to M* by the following equation :

M j + R = Mi

where R is the reaction-matrix, which eventually differs from a general reaction-matrix type by per­m utation of rows and columns.

As various drawbacks m ay be envisaged with such a general protocol16 and in view of the fact th a t the system had originally been designed with unsufficient recognition given to the detailed charac­teristics of chemical reactions, a ttem pts to close the gap w ith the data-base have recently led to a q ualita tiv e17-18 and qu an tita tiv e19 evaluation of general reaction-m atrix types. In particular, we have defined the boundaries of one-step heterolytic synthetic organic transform ations in term s of the U g i m atrices. The m ost surprising feature observed is the restricted variety of general reaction-m atrix ty ­pes, to tallingsom efourty-three. Thus, e.g. asm al but nevertheless representative selection of rearrange­m ent reactions, which are mainly skeleton formation reactions, could be described on the basis of some 20 reaction-m atrix ty p es17. Similarly, a rather specialized selection of 1,900 C-C bond formation

J. C. J. B art-E . Garagnani • Organic R eaction Schemes and General Reaction-M atrix Types 679

reactions20 requires about 30 general ß -m atrix ty p es19. In both cases, two such schemes (precisely the m etathesis reactions in four- and six-centered systems) stand out amongst others; on the whole, over 92% of all organic reactions are covered by ten general reaction matrices. This frequency d istribu­tion is qualitatively similar to th a t found in a more random ly chosen set of organic reactions18.

This paper examines, both qualitatively and quantitatively, the features of a representative and general population of one- and multi-step organic reactions, covering skeleton form ation reactions, reactions on the in tac t carbon skeleton, and re ­arrangem ent and cleavage reactions. As such we have chosen the classically well-known “nam e reactions“ 21-23 which, while constituting an in ­significant percentage of the general, ever-growing num ber of possible types of organic reactions, are often minor variations of particular reaction m echa­nisms, the basis of a m ost satisfying classification of the reactions of organic chemistry.

ProceduresThe reaction data-base consisted of a standard

collection of organic name reactions23, to which some other reactions of some synthetic im portance (Grob’s fragm entations, Grovenstein-Zimmerman rearrangem ent, Orton rearrangem ent, Theilacker rearrangem ent, etc.) were added, amounting finally to 427 such reactions.

Procedures for deriving ft-m atrices and general reaction-m atrix types closely follow the indications given in previous papers17-19. As the work was performed as part of a program for logical s tructure oriented com puter design of synthesis, u tm ost system atization requires consideration of the chemically significant single reaction steps. There­fore, m ultistep reactions were described as linear combinations of the previously defined 43 ^ -m a trix types corresponding to one-step synthetic tra n s ­formations. Some 37 complex organic name reactions were om itted from further processing because of substantial divergence in the literature concerning the reaction course or simply because no reasonable reaction path could be advanced; six typically homolytic reactions (Baudisch reaction, Gomberg- Bachm ann-Hey reaction, Gomberg free radical reaction, McLafferty rearrangem ent, Reed reaction and Schmidlin ketene synthesis) were also discarded. Reactions involving compounds for which more than

one mesomeric structure m ay be w ritten, such as the 1,3-dipolar reactan ts (nitril oxydes, nitrones, nitriles-imines, azomethins-imines, nitriles-ylures, azides, ketocarbenes, etc.) are obviously not de­scribed by a unique reaction-m atrix type. In the quan tita tive analysis these cases were recorded by double entries.

Results and DiscussionThe classification of the 427 one- and m ultistep

organic nam e reactions according to their general reaction-m atrix types is summarized in Tables I - I I I and Fig. 1, following the nom enclature of refs. 17~19. Tables I - I I I list reactions which transform starting products into the desired end-products by essentially one synthetic transform ation; m ultistep reactions are norm ally no t explicitly m entioned in the Tables bu t are accounted for in the quantita tive analysis, following up the ir decomposition into single step reaction sequences.

i 50

0 1 10 5 21 22 17 15 9 18 27 40 37 11 19 24 26 43 2 31 12 0 7 41 42 3 23 29 6 4 13 20 25 28

Synthetic transformation reference number

Fig. 1. D istribution o f 940 single-step synthetic trans­form ations in a sam ple of 427 single- and m ulti-step organic reactions according to general reaction-matrix types. For synthetic transformation reference numbers

cf. Tables I - I I I and r e fs .17- 19.

I t tu rns ou t th a t the previously defined set of 43 ^ -m a trix types adequately describes all 940 single-step synthetic transform ations which consti­tu te the data-base, w ithout the need for introducing other reaction-m atrices. We notice th a t ten schemes (R 14, 1116, &30, !R32-36, &38, R39) are not represented in our present data-set; apart from R 14 and R 16 these differ from those absent in a population studied before19 and thus constitute

680 J. C. J. B art-E . Garagnani • Organic R eaction Schemes and General Reaction-M atrix Types

Table I. General reaction-matrix types o f synthetic transformations o f organic name reactions.

R 1 A -B + C -D -> A-C + B -D1. Acetoacetic ester condensation2. Adkins reduction3. Akabori amino acid reaction through reduction4. Aldol condensation5. Amadori rearrangement6. Baker-Venkataraman transformation7. Bamberger triazine synthesis8. Bardhan-Sengupta phenanthrene synthesis9. Bechamp reaction

10. Benzoin condensation11. Blanc reaction12. Bodroux-Chichibabin aldehyde synthesis13. Von Braun cyanogen bromide reaction14. Bucherer reaction15. Chapman rearrangement16. Claisen condensation17. Claisen rearrangement w ithout allyl reversal18. Claisen-Schmidt condensation (2* R l )19. Creighton process20. Crum Brown-Gilson rule21. Dakin reaction22. Darzens procedure23. Darzens synthesis of tetralin derivatives24. Dem janov rearrangement25. D-Hom o rearrangement of steroids26. Dieckmann reaction27. Dimroth rearrangement28. Elirlich-Sachs reaction (2* R l)29. E ltekoff reaction30. Em m ert reaction31. Favorskii-Babayan synthesis32. Finkelstein substitutions33. Fischer-Hepp rearrangement34. Fischer-Speier esterification m ethod35. Friedel-Crafts reaction36. Fries rearrangement37. Grignard reaction38. Gryszkiewicz-Trochimowski and McCombie

m ethod39. Hayashi rearrangement40. Helferich m ethod41. Henkel reaction42. H enry reaction; K am let reaction43. Herzig-Meyer alkimide group determ ination44. Hofmann-Löffler reaction

(Löffler-Freytag reaction)45 . Hofmann-Martius rearrangement46. Jourdan-Ullm ann-G oldbeig synthesis47. Koenigs-Knorr synthesis48. Leuckart amide synthesis49. Meyer and Hartmann reaction50. Meyer reaction51. Meyer synthesis52. M eyer-Schuster rearrangement (2* R l )53. Michael condensation54. M ichaelis-Arbuzov reaction55. Milas hydroxylation o f olefins56. Orton rearrangement57. Paterno-Büchi reaction58. Pelouze synthesis59. Perkin reaction60. R eilly-H ickinbottom rearrangement61. Riemschneider thiocarbam ate synthesis62. R osenm und-Von Braun synthesis63. Rosenmund reaction

Table I continued64. Rosenmund reduction65. R ow e rearrangement66. R upe reaction (3* R l)67. R uzicka large ring synthesis68. Salol reaction69. Saytzeff elimination70. Scholl reaction71. Sem idine rearrangement72. Sm iles rearrangement73. Stuffer disulfone hydrolysis74. Strecker sulfite alkylation75. Theilacker rearrangement76. Thorpe reactions77. Tishchenko reaction78. Truce-Smiles rearrangement79. Tscherniac-Einhorn reaction80. Tyrer sulfonation process81. U ltee cyanohydrin m ethod82. Vilsmeier-Haack reaction83. Wagner-Meerwein rearrangement84. W allach rearrangement85. W enker ring closure (overall)86. W essely-Moser rearrangement87. W idm an-Stoerm er synthesis88. W illiam son synthesis89. W ittig rearrangement90. W ohl-Ziegler reaction91. Zerevitinov reaction92. Zimmermann reaction93. Zincke nitration

Table II. General reaction-matrix types o f synthetic transformations o f organic name reactions.

R 2 A -B + C -D + E -F -> A-C + D -E + B -F1. A lly lie rearrangement2. Benzidine rearrangement3. B enzilic acid rearrangement4. B lanc reaction5. B ogert synthesis6. Cannizzaro reaction7. Claisen rearrangement with ally] reversal8. Cope rearrangement9. D iels-Alder reaction (alder-rickert, 2* R 2)

10. Favorskii rearrangement11. F enton reaction12. Gabriel ethylenim ine method13. Grob’s fragmentation o f /3-halocinnamic acids14. H am m ick picolinic acid decarboxylation15. Hunsdiecker reaction (Borodine reaction)16. Janovsky reaction17. L etts nitrile synthesis18. Lobry deBruyn-vanEkenstein transformation19. N am etkin rearrangement20. N e f synthesis21. N enitzescu reductive acylation22. Oppenauer oxidation23. Perkin rearrangement24. (Retro)pinacol rearrangement25. R everdin reaction26. Serini reaction27. Tiffeneau-Demjanov ring expansion28. W agner-Jauregg reaction (2* R 2)29. W estphalen-Lettre rearrangement30. W urtz-Fittig reaction (2* R 2)31. W urtz reaction32. Ziegler cyclization

J. C. J. B art-E . Garagnani • Organic R eaction Schem es and General Reaction-M atrix Types 681

Table III . General reaction-matrix types o f synthetic transformations o f organic name reactions.

R 4 A -B + C — D -E -F A -D -B + C = EIF

1. Neber rearrangement

R 5 A -B + :C -D -> A -C -B + D:1. Buchner-Curtius-Schlotterbeck reaction*2. Curtius rearrangement**3. Gattermann-Koch reaction4. Schmidt rearrangement5. W olff rearrangement**

R 6 A -B -C -D -E -> A -C -E + B = D1. Beckmann rearrangement (eventually 2* R 1)

R 7 A -B + C -D -E -* A -D -B + C -E1. Baeyer-Villiger oxidation2. Elbs persulfate oxidation3. Fritsch-Buttenberg-W iechell rearrangement4. Hofmann rearrangement**5. Lossen rearrangement**6. Prileschajew reaction7. Stieglitz rearrangement

R 8 A -B + C -D + E : -* A-C + D -E + B:1. Bart reaction2. Cope elim ination reaction3. Emde degradation4. Meerwein arvlation5. Sandmeyer reaction (Gattermann reaction)6. Somm elet rearrangement7. Grob’s fragm entation of N -substituted

a-am ino-oximes

RIO A -B -C + D = E -> A -D -C + B = E1. Claisen-Schmidt condensation (overall)2. Ehrlich-Sachs reaction (overall)3. Etard reaction4. Kucherov reaction5. Meyer-Schuster rearrangement (overall)6. R iley oxidation7. Stobbe condensation (overall)

R 12 A: + B-C -* A -C + B:1. Chichibabin reaction***2. Craig method***3. Grovenstein-Zimmerman rearrangement4. ter Meer reaction***5. Meisenheimer rearrangement6. Menschutkin reaction7. Stevens rearrangement

R 13 A -B -C + D -E + F: A -D + C -E + :B F1. Weerman degradation

R 15 A -B + C -D + : E -F A -E -D + B -C + F:1. Hydroform ylation reaction (oxo process)2. Pechmann pyrazole synthesis3. Pummerer reaction4. Sarett oxidation

R 17 A -B + C -D + E -F + G -H ->A -D + B -H + C -E + F -G

1. Glaser coupling2. Kolbe electrolytic synthesis3. Meerwein-Ponndorf-Verley reduction4. Zincke-Suhl reaction

Table III continued

R 18 A -B + C -D + E -F -G A -G + B -E + D -F -C1. D ienol-Benzene rearrangement2. D ienone-Phenol rearrangement

R 19 A -B + C -D -E + F -G -H ->A -H + B -E + F-C + G = D

1. Gabriel-Colman rearrangement

R 20 A + B -C -D -> A-C + B -D1. Wallach degradation of a,a'-dihaloketones

R 22 A -B -C A-C + B:1. Adkins decarboxylation2. Marckwald asym metric synthesis

R 27 A: + B -C + D -E + F -G ->B -A -G + C -D + E -F

1. Malaprade reaction

R 28 A -B + C -D + E -F + G: ->A -F + B -D + E -G + C:

1. Perkow reaction

R 31 A = B + C -D + E -F -> C -A -E + D -B -F1. B etti reaction2. Bischler-Napieralski reaction3. Blanc (chloromethylation) reaction4. Bosch-Meiser urea process5. Clemmensen reduction6. Ferrario reaction7. Mannich reaction8. Meldrum condensation9. Mignonac reaction

10. P ictet-H ubert reaction (Morgan-Walls reaction)

11. Quelet reaction

R 40 A -B -C + D -E + F -G + H -I A -G + C -D + E -F + H -B -I

I. Semmler-W olff reaction (overall)

R 41 A -B -C + D -E -F B = E + A -F + C-D1. M cFadyen-Stevens reaction

* May also be described as R 3 7 18.** Only the essential rearrangement step, not the

overall process.*** P seu d o-R l.

random fluctuations due to the size and nature of the data-base.

I t is of interest to notice the great variety of reaction types and mechanisms which coalesce into the same general R-m atrix. In particular, the m ost common schemes, I I I and H2, which are essentially m etathesis reactions in four- and six-centered systems, comprise reactions involving skeletal for­m ation and cleavage, rearrangem ents and functional group intercon version, both in saturated and unsaturated systems, and mechanistically vary from electrophilic or nucleophilic to “no-mecha­nism ” .

682 J . C. J. B art-E . Garagnani • Organic Reaction Schem es and General Reaction-M atrix Types

Although the data-base considered here differs considerably from a more specialized se t19 and may be considered to arise from random sampling, the distribution of the reaction-matrices amongst the 940 single-step transform ations (Fig. 1) is very similar to the previously defined distribution of th a t more specialized sample (cf. Fig. 1 in ref. 19). In term s of the to tal num ber of reactions examined, f t 1 accounts for over 60% and ft 2 and ft 10 for 9.6 and 9.0%, resp . These figures differ slightly from previous findings in the data-base of C-C bond-forming re­ac tions19- 20: f t l , 51.4% ; f t2 , 19.5%; I I 10, 2.8%. Particu lary noteworthy is the considerable increase of f t 10, a scheme which typically describes conden­sation reactions. This finding may be rationalized on the basis of the nature of the data-bases used for the quantita tive analysis. f t 10-type C = C bond- forming reactions19-20, being mainly condensations of carbonyl compounds writh reactive methylene groups (e.g. Claisen-Schmidt, Knoevenagel, Rap- Stoermer and Stobbe condensations, Pschorr reac­tion, etc.), are typically less numerous than C = X (X = heteroatom , normally N or O) bond-forming reactions such as the condensation of carbonyl compounds and ammonia, amines or hydrazine (e.g. Combes and Riehm quinoline syntheses, Forster - Decker method, Pictet-Spengler isoquinoline and Conrad-Limpach syntheses, etc.), the hydrolysis of anils (e.g. Sonn-Müller method, Sandmeyer isatin synthesis, etc.) or the condensation of compounds containing active methylene groups with nitroso compounds or nitrous acid (e.g. Ehrlich-Sachs reac­tion, G utknecht pyrazine synthesis). Although we realize th a t an alkaline condensation of aldehydes with amines (Schiff reaction) may involve two s tep s:

R

IT

R'NH2 R\ / 0 H - H 20 R\ c = o ------- v XX ------ ► ;C=NR'

W N H R ' IT

in a f t 1 + f t 1 sequence, the description of the reaction as f t 10 is m aintained deliberately in view of the particular synthetic value of condensation reactions for the synthetic chem ist24. In a sample of 80 organic name reactions containing ft 10 type transform ations, we have accordingly observed a ratio of C = X / C = C bond formations of about two, thus explaining adequately the observed discrepancy in f t 10 frequency in the special set of ref. 19 and in the more general data-base of the present paper.

As to the percental variations of R l and ft 2, we notice th a t the distribution of the reported 190 single-step organic nam e reactions (Tables I—III) is even closer to th a t found in M athieu’s sam ple19-20, nam ely w ith R l and f t 2 accounting for 49.4 and 16.8%, respectively.

W hereas the prim ary three electron-flow schemes ( f t l , 112 a n d ftlO ) account for the m ajority (78.7%) of the fundam ental transform ations, the first ten m atrices even describe 93.3% of the reaction steps (cf. 92.2 % 19) : R l , 60.1% ; R2, 9.6% ; f t 10, 9.0% ; ft31 , 3.6% ; f t5 and R 12, 2.2% ; R21, 1.9% ; R8 and ft22 , 1.6% ; R 7, 1.5%. The la tte r set differs from the corresponding one in ref. 19 only with regard to f t 5, f t 7 and f t 22, which a t th a t occasion ranked lower than f t 3, f t 9 and ft 15. All other reaction-m atrices score (considerably) less than 1 % of the to ta l num ber of reactions.

Conclusions

Our efforts have been directed towards analyzing chemical reaction schemes for use in a logical structure oriented algorithm based on mathem atical structures.

In spite of the diversity of reaction mechanism and scope, 427 organic name reactions could be classified by means of a set of 33 general reaction m atrix types. Results conform to previous analyses perform ed by the authors and confirm th a t the m ajority of synthetic organic transform ations is comprised in a very restricted set of such electron- flow schemes. Summarizing our results (refs.17-19 and present paper), we claim th a t a t most some 40 to 50 reaction schemes are essentially sufficient to cover all or almost all basic organic reaction sequen­ces ; am ongst these, the docum entation of four sche­mes (ft4 , f t 6, f t 13 and f t 16) is no t sufficient to w arran t further consideration, two others are doubt­ful (ft 20 and f t 40), whereas a conspicuous number of m atrices (ft 14, f t 24, ft26, ft27 , R29, ft30, ft32-36 , ft38 , ft43) each account for not much more th an about l°/oo of the reactions in the da ta ­bases examined, which all together contained up to alm ost 3,000 reactions.

W hile the results obtained in this series of papers are of general interest, they are not unexpected25. I t is more im portant to emphasize th a t the imple­m entation of U g i’s algebraic model of chemistry with empirical reaction docum entation can signifi­

J. C. J . B art-E . Garagnani • Organic R eaction Schem es and General Reaction-M atrix Types 683

cantly improve performance in organic synthesis design, assures optimum use of existing compilations of organic reaction schemes and does not restrict the innovative properties of the system, a feature

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