Professor of Chemistry Emeritus
Harvard University, PhD
My major focus over many years at Brandeis has been to examine the logic of organic chemistry, principally in two main areas:
A) Organic Synthesis Design. Long a major activity of organic chemistry, synthesis is remarkable in having had so little close examination of how to proceed to design the best route, i.e., the sequence of chemical reactions from chosen starting materials which will afford the desired product compound. It is easily shown that there are literally millions of different routes possible, from different available starting materials, for the synthesis of any substance of interest, but there has traditionally been no clear protocol to follow to design the best one before going into the laboratory to try it.
We have been engaged for some years in creating a logic for synthesis design, which has hitherto been only an art in the midst of the otherwise systematic science of organic chemistry. This has led to the creation of the computer program SynGen which embodies logical principles to provide the optimal synthetic sequences for any desired target molecule, and has had considerable success. The SynGen output route for synthesizing lysergic acid is shown below.
The present program serves to derive both the shortest and cheapest routes to any single input target molecule. Since pharmaceutical research is often aimed at designing a group of molecules that might fit closely to some receptor site, either to activate or deactivate it, we now need to rebuild SynGen to take in all of these molecules together and quickly determine which will be easiest to synthesize in order to test the hypothetical fit.
B) Classification of Organic Reactions For two centuries organic reactions have been identified by the name(s) of the chemist(s) who discovered/developed them, but this has never been a general or rigorous basis for reaction classification. We have developed a new system of “reaction signatures” that defines any reaction by the net overall change in the bonds between the reactant(s) and the product(s). The signature of any reaction is derived automatically from their structures and has the form of a linear letter string, unique for each reaction change and suited to organize a reaction database for reliable searching.
The program merges the reactant and product states to locate the reaction center, those atoms that change their bonding. The bond changes at each reacting atom form naturally a linear sequence of alternating bonds broken and made at each atom, which is then described with a unique reaction signature.
Hendrickson, J.B. Hussoin, Md.S. 1987. Seeking the Ideal Dehydrating Agent. J. Org. Chem. 52: 4137.
Hendrickson, J.B. 1990. Organic Synthesis in the Age of Computers. Angew. Chem. Intl. Ed. 29: 1286.
Hendrickson, J.B. 1992. Descriptions of Reactions: their logic and applications. Rec. Trav. Chim. Pays-Bas 111: 323.
Hendrickson, J.B., Sander, T. 1995. COGNOS: A Beilstein-type System for Organizing Organic Reactions. Eur. J. Chem. 1: 449.
Hendrickson, J.B. 1997. Teaching Alternative Syntheses: The Syngen Program," p. 214-231 in "Green Chemistry," ed. P. T. Anastas and T. C. Williamson, ACS Symposium Series #626.
Hendrickson, J. B. 2010. Systematic Signatures for Organic Reactions. J. Chem. Inf. & Model. xxxx.