reaction planning: computer-aided reaction design

Tetrahedron Computer Methodology Vol. 1, No. 1, pp. 15 to 25, 1988 0898-5529/88 $3.00+.00 Printed in Great Britain. Pergamon Press plc

REACTION PLANNING: Computer-Aided Reaction Design

Rainer Herges

Institut fuer Organische Chemie der Universitaet Erlangen-Nuernberg Henkestr. 42, 8520 Erlangen, West Germany

Received: 7April 1988; Revised: 7May 1988; Accepted: 7May 1988

Keywords: IGOR; Reaction design; Pericyclic reactions; Reaction hierarchy

Abstract: A new concept for the search for unprecedented chemical reactions is presented. With the aid of the expert system IGOR 1 - 4 the complete set of pericyclic reaction schemes (up to 8 reacting atoms) has been generated. The result looks like a "periodic table" of conceivable reactions. Most of them are known. Some "rows" contain unknown reactions. They can be predicted. Some of these predicted reactions have been successfully performed in the laboratory. 1, 2, 4 In this article the "design" of two of these new reactions aimed at the syntheses of given classes of compounds is described. They both have been verified experimentally.

INTRODUCTION

The two major fields in synthetic organic chemistry are:

, planning and performing an intricate natural product synthesis, "SYNTHESIS PLANNING" o development of new reactions and methods for the synthesis of certain classes of compounds,

"REACTION PLANNING".

Computer aided-synthesis planning 5 can now look back on a tradition of more than 20 years. Computer programs are routinely used for the solution of intriguing synthetic problems in industry. The development of new chemical reactions and methods in the past however was mainly driven by "chemical intuition" rather than by formal algorithms. Surely most of the known "name" reactions have been discovered by plain luck. It has been the geniu s of the discoverers to notice that they found something worth investigating further iv detail. The "synthon approach" and "umpolung" were the first systematic and deductive principles for the "design of reactions". Even though those principles have been proven to be powerful as guidelines they can only be applied to known reactions (e.g., nucleophilic substitution). The target in "Reaction Planning"~ however, is an unprecedented reaction which is to be searched for and "designed", for the synthesis of a desired class of compounds (e.g., Michael reaction for 1,5-difunctionalised compounds, or Diels--Aidc~ reaction for 6-membered rings).

The first attempts using a more rigorous treatment on the basis of graph theory were published by A. T. Balaban in 1967. 6 He evaluated the set of pericyclic "cyclomerizations", analogous to the Diels-Alder reaction. Six years later R. V. Stevens and T. F. Brownscombe developed a "reaction generating" computer

15

16 R. HERGES

program based on graph theoretical algorithms, but no applications were published. 6b The first reaction predicted by an expert type computer program (IGOR) which could successfully be

performed in the laboratory was published in 1985 (Fig. 1): 1, 2, 4 the thermal decomposition of alpha-formyl-

i•0 ~ ~ 0

H 0 0

Fig. 1. The first reaction predicted by an expert computer program and then performed in the laboratory.

oxy ketones, a new exponent of the known class of retro-ene reactions (another well-known example is the ester pyrolysis). Computer-aided Reaction Planning is still in its infancy but reactions with a higher "degree of novelty" have recently been performed in our laboratory.

THE HIERARCHICAL MODEL OF CHEMICAL REACTIONS

To use graph theory in order to search for new chemical reactions, one needs a graph theoretical representation of chemical reactions. A chemical reaction should be represented by a single graph. The Ugi-Dugundji model 7 complies with this precondition and is used for the internal representation of reactions in IGOR. Reactants and products are represented by their connectivity matrix and the reaction by subtracting the two matrices mathematically (see Fig. 2). The resulting "reaction matrix" represents the changes in bond

5 5 5

3 , ~ .~1 3 1 3 1 .-

2 2 2

1 2 3 4 5 6 1 2 3 4 5 6 6 1 2 3 4 5 6 I0-I ~ 0 1 0 0 0 1 1 0 2 0 0 0 0 0 0 0 1 ~ 2 0 1 0 0 0 2 - 1 0 1 0 0 0 2 1 0 2 0 0 0

0 1 0 1 0 0 + 3 0 1 0 - 1 0 0 = 3 0 2 0 0 0 0 0 0 1 0 1 0 4 1 0 0 - 1 0 1 0 4 0 0 0 0 2 0 0 0 0 1 0 2 5 0 0 0 1 0 - 1 5 0 0 0 2 0 1 0 0 0 0 2 0 6 1 0 0 0 - 1 0 0 0 0 1 0

educt reaction-matrix product

Fig. 2. The Ugi-Dugundji model is used to represent reactions internally.

order during the reaction. Dashed lines indicate a decrease of bond order by one, solid lines an increase by one. A reaction thus can be separated into a "R-matrix" representing the changes during the reaction, and an invariant "sigma-frame" (Fig. 3).

In the case of concerted reactions, the R-matrix represents the topology of the transition state. By varying the sigma-frame (without changing the R-matrix) reactions belonging to the given transition state can be generated. The basic principle is exemplified in Fig. 4.. If we start with the ene-reaction and add, on both sides, an additional bond we can "generate" the 1,5-sigmatropic shift, Diels-Alder and Cope-rearrangement. Since we perform the operation on the reactant and the product side, the R-matrix remains constant (i.e., the reactions belong to the 6-electron 6-center pericyclic reactions). The algorithm implemented in IGOR is more sophisticated since one has to consider symmetry in order to avoid multiply generated reactions.

Computer-aided reaction design 17

C /

R-matrix

-

\

V ~-frame

Fig. 3. Dashed lines indicate a decrease of bond order by one, solid lines an increase by one.

L3-( ene-reaction

" f I 'L3- ( 1,5-sigmatropic Diels-Alder Cope-rearr.

Fig. 4. Varying the a-frame (without changing the R-matrix) generates reactions with the same transition state.

Another factor restricting the number of generated reactions is the valency of carbon° The next step in our reaction generating procedure is to introduce hetero atoms into the reaction centers.

Consequently we call this level the "level of hetero reactions" (e.g., hetero Diels-Alder reaction). The last step, generating the level of specific reactions is introducing substituents. Fig. 5 shows the hierarchical scheme of reaction generating. The reaction generating procedure is the reverse process of classification of chemical reactions, Since any reaction can be classified by our hierarchical procedure we can in principle generate any organic reaction. Thus our model complies with two important conditions:

• it is formal enough to supply the basis for computer handling. • it is close enough to the traditional view to allow the evaluation of the computer output using the

plentiful empirical chemical knowledge.

Another advantage of the hierarchical scheme is that it allows one to define a "degree of s mfila,-',~y" between reactions. This is important to retrieve the most suitable reaction out of a reaction data base if the searched reaction is not accurately known.

18 R. HERGES

1 C L A S S I F I C A T I O N

¢"~""" I reaction category ~,,,, . (6-center pericyclic)

~ basic reaction G ~ E (3,3-sigmatropic) N E R A O ~ ~ O ~ hetero reaction T / - -~ (oxy Cope rearrangement) I O N

~ -~ ~ ~p~ci~iCnr~eaCli:~gement)

Fig. 5. The hierarchical scheme of reaction generation and classification.

REACTION CATEGORIES

Just as molecules can be classified into acyclic, cyclic and polycyclic, so too can organic reactions be divided into acyclic, cyclic and polycyclic reactions according to the "electron flow" defined by the reaction matrix, as illustrated in Fig. 6. The most important and populated reaction category is the class of linear reactions. Mechanisms are usually interpreted in terms of a linear sequence of electron pushing arrows. A nucleophile attacks a substrate at the most electrophilic site, which in turn gives way to "electron pushing" resulting in the transfer of electrons to a deficient center or to a leaving group (via cleavage of the bond to the leaving group). There are two reasons for suggesting that linear reactions are not the most suitable class in which to search for new reactions: a) because of the "linear mode of chemical thinking" most of the linear reactions are already known (or tried) and b) the linear topology restricts the combinatorial number of conceivable solutions. Fig, 7 shows the four "basic reactions" of the four-electron three-center category of linear reactions.

In our model, cyclic reactions, assuming that they are concerted, are equivalent to the class of pericyclic reactions. Using IGOR we generated the complete set of pericyclic reactions from three up to eight reacting atoms. Fig. 8 shows part of the "periodic table" of pericyclic reactions. Most reactions are already known, but some rows contain unknown reactions. Hence, it follows that the classification into cycloaddition, sigmatropic, electrocyclic, cheleotropic reaction and group transfer according to Woodward and Hoffmann 8 is not complete and not unequivocal. Especially among reaction categories with an odd number of reaction centers there are many unknown examples. They can be predicted.

The reactions are generated purely on the basis of graph theoretical considerations. For the design of reactions their "chemical plausibility" has to be checked first, prior to the next step of reaction generation (introducing hetero atoms). This level of abstraction is too high to apply sophisticated methods such as quantum mechanical calculations to evaluate basic reactions. Instead, empirical rules, and the constraints of


z\ _ '~ -"~ Z / C H + C = C - O:::Q

! o o - - o Ol

Z~. z / C H - - C - - C - C - - O

l inear topology

.© cyclic topology

Fig. 6. Reactions can be classified by "electron flow" as defined by the reaction matrix.

o t ~ o ~ o o ~" nucleophilic substitution

o ~ ~ o o o elimination

o / ~ o ~ o, o ~ " nucleophilic addition

0 ~ ~ 0 ,~ ~ resonance

Fig. 7. The four linear "basic reactions" of the four-electron three-center category are shown. Atom types are generalized.

the problem to be solved are used to prune the number of conceivable solutions. At the level of hetero reactions we can apply energy estimations based on bond energies, and at the level of specific reactions, the time consuming ab initio or semi-empirical calculations. The most promising candidates are then tried in the laboratory.

Moving down the hierarchy of abstraction (from the reaction category to the specific reaction) and using selection criteria of increasing sophistication on a decreasing number of candidates (reactions) is obviously the optimum way to save time and expenses. The general procedure can be depicted as shown in Scheme 1.

Formally our approach corresponds to what is called by scientists "strong interference ... a scientific method which should lead to a particularly fast proceeding." 9

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I N e x t

L e v e 1

DEFINITION OF THE PROBLEM (and the scope of search) Wanted: e.g., reactions for the synthesis of strongly electrophilic isonitriles

I SOLUTION BY COMPUTER

Generation of the complete combinatorial set of conceivable solutions to the given problem

I PLAUSIBILITY CHECK

Use empirical rules and crude energy estimations first and quantum mechanical calculations with selected candidates on the level of specific reactions.

I LABORATORY

Trial of the best candidates

Scheme 1. A procedure for reaction design.

THE SEARCH FOR A NEW RETRO-ENE REACTION

A theoretically "planned" reaction which has been successfully carried out in our laboratory should serve as an example. It is the first reaction predicted by an artificial intelligence type computer program which could be experimentally verified.

In the first step we generated the complete set of the 6-center 6-electron basic reactions shown in Fig. 9. Basic reaction 6 is known as the general scheme of the retro-ene reaction. Introducing hetero elements into the reaction center of this basic reaction is the next step of our reaction generating procedure. In order to increase the "plausibility" and to limit the number of the generated reactions we set the following restrictions. The group which is to be transferred should be a hydrogen atom since a 1,5-hydrogen shift is a suprafacially allowed process. Rearrangements of atoms other than hydrogen by the 1,5-shift are known, but are much less common. 10 We chose oxygen as the sp2-center to which the hydrogen is transferred during the reaction. All other centers were allowed to be either oxygen or carbon. Using these restrictions we generated eight hetero reactions (13-20) illustrated in Fig. 10.

Reaction 16 corresponds to the well known ester pyrolysis. All other reactions are unknown. In order to favor the elimination process further we substituted the reaction center in such a way that carbon dioxide would be eliminated. Carbon dioxide is a small and stable molecule and thus should favor the elimination process. Fig. 11 shows the four specific reactions (21-24) generated.

Three of them are known. Reaction 21 is known as the decarboxylation of g-ketoacids, reaction 22 as the decarboxylation of a mixed anhydride of a carboxylic acid with carbonic acid and reaction 23, the decarboxylation of peroxyester, is reported in the literature. 11 Reaction 24 is new according to a careful search of the literature. The starting compounds, the alpha-formyloxy ketones, can be easily prepared by esterification of an acyloin with formic acid. The pyrolysis was carried out in the gas phase at 350 ° C (reaction time 0.5 s). The yields are almost quantitative. The new reaction could be useful for the synthesis of macrocyclic ketones, which are prepared by acyloin condensation and subsequent reduction of the acyloin to the ketone. Our method could provide a way to reduce acytoins chemoselectively to the corresponding ketones without affecting other reducible groups such as hydroxy groups. Macrocyclic ketones are importar~ in perfumery (e.g., muscone and synthetic analogs). The next section describes a second example of reaction design that has been persued in our laboratories.

22 R. HERGES

CJJ--'O

'O--"C o(.i "C © .© ,,ll" (

J

Fig. 9. The complete set of six-center six-electron basic reactions was generated.

THE SEARCH FOR A SYNTHESIS OF STRONGLY ELECTROPHILIC ISONITRILES

Isonitriles with strong electron withdrawing groups are both of theoretical and synthetic interest. They are predicted to exhibit carbene like properties and should differ in their reactivity from normal isonitriles. All attempts in the past however to synthesize strongly electrophilic isonitriles have failed. The most common implications are isomerization to the corresponding nitriles or reaction with nucleophilic solvents. Since pericyclic reactions are usually solvent independent we chose this class of reactions as the source of our new reaction. Pericyclic reactions with 4n+2 electrons are generally thermally allowed and those with 4n electrons are photochemically allowed (exceptions are m6bius aromatic systems). In view of the thermal lability of our target compounds and in order to be able to work at low temperatures we selected the photochemically allowed reactions, i.e., the 3-, 4-, 7- and 8-center pericyclic reactions. Another constraint helped us prune the number of reaction categories to be considered: during the reaction a formal lone pair must be generated (at the isonitrile carbon atom). Only the 3- and 7-center reactions comply with this restriction. We considered the 7-center reactions to be too large a system to provide an elegant synthesis and confined the search to the 3-center pericyclic reactions. This reaction category consists of five basic reactions (see Fig. 12). Only two of them comply with an isonitrile substructure. In the last step of our reaction generating procedure we introduce the suitable elements and substituents to get three conceivable "specific reactions" for an isonitrile synthesis. One of them is identical with the most common isonitrile synthesis by alpha-elimination. Fig. 12 shows the hierarchical reaction generating procedure used to search for our new


13 O.. H 0 H" 0 O-. H

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( ) - - - " o. II °o ---.. 0 0 H 0

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Fig. 10. Expansion of basic reaction 6 with the constraint that an H-atom must be transferred to an sp2-oxygen atom gave eight hetero reactions.

21 ~ . ~ O ~ O. I,,- I ~ O O

23 ( O r~ 0 O .O O. O O O.

H H H O H O

22 o o

O O

O .O O O O O,.H H "H H O

Fig. 11. Substitutions were made so CO 2 would be a product.

isonitrile synthesis. Since the reactants could be easily prepared, we chose the elimination reaction of cyclopropenone imine

for out first trial in the laboratory. N-benzolsulfonyldiphenylcyclopropenone imine was irradiated at -80 ° C with a low pressure mercury lamp. As predicted by quantum mechanical calculations, the strongly electrophilic isonitrile reacted like a carbene and inserted into the C-H bond of the alpha-hydrogen of the solvent (THF). Trapping experiments with electron rich alkenes are planned.

CONCLUSION

Many attempts have been made in the past to develop formal approaches and computer algorithms tbr Synthesis Planning, with the result that some of the programs are now frequently used as tools in organic synthesis (mainly in industry). As in many fields of "artificial intelligence" the necessity to convert intuitive knowledge and heuristics into formal algorithms (which can be programmed on a computer) have led to a better understanding of the corresponding field of research. In synthesis planning these "didactical side effects" can be expressed in terms such as: strategic bond, synthon, FGI (Functional Group Interconversion),

24 R. HERGES

l" "I I"'I \--A , , , , , . .

PERICYCLIC REACTIONS

/

LONE PAIR GENERATED

l.-~-.\ o i

THERMALLY ALLOWED

" N j 1 ~ N'

/ k

¥

A~f_.

BASIC REACTIONS

NEW METHOD

COMPLIANCE WITH ISOCYANIDE SUBSTRUCTURE

Fig. 12. Scheme for synthesis of strongly electrophilic isonitriles, Z-N=CI.


N ~ TS

¢,o o

Ao

hv

0

N ~-Ts

II C

o ~ C N + TsH

Fig. 13. The elimination reaction of cyclopropenone imine was tried in the laboratory.

etc. We believe that computer-aided "reaction planning" will have a similar impact on the other important field of synthetic chemistry, namely the development of new reactions and methods.

REFERENCES

1. Bauer, J.; Herges, R.; Fontain, E.; Ugi, I. "IGOR and Computer Assisted Innovation in Chemistry". Chimia 1985, 39, 43.

2. Herges, R. Computergestiitzte, deduktive Suche nach neuen Reaktionen und deren experimentelle Realisierung, Ph.D. Dissertation, Technische Universit~it, MiJnchen 1985.

3. Bauer, J. Die Erzeugung prgizedenzloser Reaktionen auf der Grundlage der Algebra der BE- und R-Matrizen, Ph.D. Dissertation, Technische Universit~it, MiJnchen 1981.

4. Herges, R. "Reaction Planning," Proceedings of the Conference Chemical Structures: international Language of Chemistry, in press.

5. Winter, J. H. Chemische Syntheseplanung; Springer Verlag: Heidelberg; 1982; pp. 154-197, loc. cir. 6. a) Balaban, A. T. "Reactions with 6-Membered Transition States". Rev. Roum. Chim. 1967, 12, 875. b)

Brownscombe, T. F. "A Computer-Assisted Derivation of Possible Unimolecular Pericyclic Reactions". Diss. Abstr. Int. B. 1973, 34 (3), 1035. Similar approaches have been made later by other authors: c) Hendrickson, J. B. "Multilicity of Thermal Pericyclic Reactions". Angew. Chem. 1974, 86, 71. d) Arens, J. F. "A formalism for the classification and design of organic reactions III. The class of (+_)nC reactions". RecI. Trav. Chim. Pays-Bas 1979, 98, 471. e) Zefirov, N. S.; Tratch, S. S. "Systematization of Tautomeric Processes and Formal-logical Approach to the Search for New Topological and Reaction Types of Tautomerism". Chemica Scripta 1980, 15, 4.

7. a) Dugundji, J.; Ugi, "An Algebraic Model of Constitutional Chemistry as a Basis for Chemical Computer Programs". I. Top. Curr. Chem. 1973, 39, 19. b) Ugi, I.; Bauer, J.; Brandt, J.; Friedrich, J.; Gasteiger, J.; Jochum, C.; Schubert, W. "New Fields of Application for Computers in Chemistry". Angew. Chem. 1979, 91, 99, loc. cit.

8. Woodward, R. B.; Hoffmann, R. "The Conservation of Orbital Symmetry". Angew. Chem. Int. Ed 1970, 8, 781.

9. Platt, J. R. Science 1964, 146, 347. 10. See, e.g., Berson, J. A.; WiUcott III, M. R. J. Am. Chem. Soc. 1965, 87, 2751. 11. Kharasch, M. S.; Kuderna, J.; Nudenberg, W. "Reactions of Atoms and Free Radicals m Solution.

XXXVI. Formation of Optically Active Esters in the Decomposition of Optically Active Diacyl Peroxides in Solution". J. Org. Chem. 1954, 19, 1283.

reaction planning: computer-aided reaction design

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