Robert D. Stolow and Leo J. J o n c a s Tufls University Medford. MA 02155
Computer-Assisted Teaching of Organic Synthesis
During the past decade, several groups of researchers have been de;elop& computer programs t o assist chemists in planning organic syntheses ( 1 4 ) . The degree of sophistication demonsirated by some of these approaches is quite remarkable and, in limited applications, these computer programs have been used to assist research chemists in analyzing synthetic problems. These programs generally use a data base which includes a laree number of svntheticallv useful reactions plus important generalizations concerning the scope and limitations of each reaction. Used oro~erlv.this wealth of information could prove extremely ;al;ahle'for educational purposes. Accordingly, we have taken advantage of the exteniive data base an%-highly-developed sophist&ation of the LHASA computer . program in the teaching of organic syn. thesis. T h e LHASA program (1,2), developed a t Harvard University by a group of researchers headed by Professor E. J. Corey, can he used to generate a number of alternative pathways for consideration in planning the synthesis of a desired organic compound. The program is interactive, featuring s i m ~ l eranhical e communication between user and comouter. ~ o ; k i & 6ackwards from the target structure (the desired oreanic compound). LHASA disdavs each step as it is aener&d and g i k the user three options: to work backward'oue more step, to generate an alternative for the current step, or to quit.' LHASA can accept target structures containing up to 64 bonds and up to 64 atoms chosen from among ten atom types (C, H, N, 0,P, S, F, Cl, Br, I). This capacity far exceeds our needs. One application of the LHASA program in teaching synthesis to undergraduate organic chemistry students has been renorted hv Orf (5). He concluded that "the notential of LHASA as un interactiveand productive teachit~gcuol in orranic svnthesis" had heen successiullv demonstrated. Startine. from this point, and working in cooperation with members of the LHASA erouo a t Harvard. we have developed a new verspecifically designed for use by Students in the sion O~LHASA second half of the Tufts elementary. organic chemistry . course.
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Planning a Synthesis a computer to analyze a 'ynthetic problem requires a general set of rules2 The development of such rules is, in itself, a major accomplishment of the LHASA project since these rules provide a "deeper comprehension of the strategies, principles, and elements of chemical synthesis. . . and new and more powerful methods of teaching chemical synthesis and solving synthetic problems" (1).We have incorporated some of these ideas into the Tuftsorganic istry course. Before being introduced to the computer program, the students are taught the basic principles of r e t r o w t h e t i c analysis. They start with the molecule they want to make (the TARGET molecule) and work backwards one step a t a time 868 / Journal of Chemical Education
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3
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Figure 1. An exampie of a subgoal reaction (2 I), reduction of a double bond. which sets upa reaction of maiw symhetic i m w a n c e (3 4- 2). a DieisAider reaction.
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until the starting materials (PRECURSOR structures) are readily availahie c~~mpounds. It is useful t u distinguish be1wet.n rewtions of maim synthetic irnnortancr and "suh~.oal"reactions.' ln F ~ L ' I 1. I ~tor P example,'the Diels-Alder s t G is a reaction of majorUsynthetic im~ortancehecause the orecursor structures (3 and 4) are simpler, smaller moleculks than structure 2. o n the other hand. the retrosvnthetic step from 1to 2 is called a SUBGOAL becake by itseli it has not simplified the molecule; the carbon skeleton is unchanged. and an additional functional arouu. (a carbon-carbon do;hle bond) has been introduced. Nevertheless it is an important step because it generates structure 2 which can hec~~istructed b;, the ~ ) i e ~ s - ~ ireaction der shr,un in Figure 1. When rrasoning l~arkwnnls,the iturlenr needs ru consider carefully the manipulation of functionality (introduction or interconversion of functional groups) in order to set uo thenossihilitv of disconnectine the molecule into simpier pieces. A number of imoortant factors affecting" the choice of a synthetic strategy which were exemplified in an earlier version of LHASA have been outlined and discussed hv Orf ( 5 ) .Additional concepts considered in our course incllded choice of reagents and reaction conditions which give high yields hut minimize interference by other functionality in the molecule, the arrangement of individual steps in a sequence designed to minimize functional group interference, and the use of protecting groups where necessary (6).
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The Program When a student runs the program, the first thing that appears on the screen is the SKETCHPAD display (Fig. 2) which is used to draw or modify the target structure. The words and Presented at the 178th American Chemical Society Meeting, Washington, D.C., September 10,1979.
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LHASA does not proceed in the forward direction from a specific starting compound to a target molecule. ? Streitwieser and Heathcock have included this analytical approach in the chapter on organic synthesis in their text (6). ~h~~ emphasize construction of the proper carbon skeleton, placement of functional groups, and control of stereochemistry. 3Pine, Hendrickson, Cram, and Hammond have treated this subject in the chapter on organic synthesis in their text (7). They distinguish between "construction"reactionsand "functionalalteration" reactions.
STORE H E L P SCAN T R E E DRAW D E L E T E W I P E
PROCESS SKETCH2
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Figure 2. Sketchpad display after target structure has been drawn. 8 Figure 5. Three alternative routes tor synthesis of t.2dimethylbutyl hew1 ether
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cnen nr/ra 60 RATING
PRDCESS
PROCESS
Figure 3. "Functional group recognition" portion of perception dialog. Student responses are underlined.
295 REDUCTIVE lVllNATlDN
Figure 6. Display ota successful reaction,The student has selected the reaction conditions "NH3 then NaCNBH3."
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Which reaction do you w i s h to use?
Figure 4. Reaction selection display. Stvdent has painted to the phrase "PRIM AMINE." The program responds by listing all the reactions it can use to produce primary arnines.
symbols above and below the large box are "buttons" which can be activated graphically hy the student in order to perform the specified f u n ~ t i o nAfter . ~ pointing to the word "DRAW", the student can create a line drawing of the target molecule directly on the graphic terminal screen, or indirectly hy use of a drawing tablet, in virtually the same way as it would he drawn on paper. The students seem to enjoy this procedure and, after drawing one or two simple structures, they are usually comfortable with the graphic terminal. After drawing and storing a target structure, the student points to the word "PROCESS". 'l'he llrst phase of processing is perception, the recognition by the pn,gram uf all pertinent structural featllrl~iin the e, mdecule. I t no crrtrrs are drtrctrd in the s t r ~ ~ t t u rI.HASA initiates a rliillog to te>t the student's perceptiw~111 some I)IIS~C strurt~lralfr:ltures s w h ns lunrti,rnal gruup types, bridgehead atom.;, and f'usion h n d s . I.H,\SA will refer t ~ the r loration o i a particular it~nrtioniilgroup in the m~,leculei~nda ~ kthe student to name i t I Fig. 31.Any correct answer typed by t he student will be accepted, even for positions that are ambiguous (for example, a vinyl halide is recognized as both a halide and an alkene). hut in such cases LHASA names all the functional group types it finds a t that position. The dialog can he modified to include rines. " stereochemistry, and other significant structural features.
Alter the perwption dialc,:, the pmxrani indicates that it oro~lu V C I I wish is ready to do rhr~nistrv . In" a k i w "Which . dcr . to process?". The name of each kind of functional group mesent in the tareet molecule (if it is one of the 64 tvues explicitly recognize; by the program) is then displaied. The student points to a functional group name, such as PRIM AMINF: in Figure 4, and a list appears on the screen containing all the reactions that the program can use to produce that group. The student selects a reaction from the list. LHASA then evaluates the feasibility of producing the current tnreet via the reanested reaction hv comnutineu a RATING which weighs the effects various structural features in the molecule are likelv to have on the course of the reaction (3). Among the factors considered are steric hindrance, relative stahilitv of comoetine reaction intermediates. and uresence of othe; functionalitithat is sensitive to the reaction conditions (8). Ratings can he used to compare different routes to the samr tilrget,Hs 111 the Williamson Ahers\ntheses in I.'igurt, .-B. In this ~.x:nni)le, the route via the unhranrhed ~,rimar\.halide (7) was &en a higher rating than the routevia the secondary halide (10) because a lower yield was expected as a result of the greater difficulty of performing an S N dis~ placement a t a secondary carbon having a beta branch. Successful reactions are displayed as shown in Figure 6. Contrary to normal convention, the starting materials (precursors) are on the right and the product (target) is on the left, reminding the student to work hackwards. Once a reaction is displayed, the program initiates a dialog with the student about reagents and reaction conditions. In order to make better use of this feature, we have expanded the number of reagents recognized by the program from 60 to 138 (see the Appendix). When the student points to the word "RE-
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W i t h our Tektmnix graphics terminals, thumb wheels on the keyboard are used to position a crosshair cursor on the screen. Striking a keyboard character while the crosshair is on the screen causes the coordinates of the crasshair to he transmitted to the computer. Thus, the student can "point to" any place on the screen. Volume 57, Number 12, December 1980 / 869
SKETCH
I . Figure 7.Thee altwnative Grignard syntheses of 2.4dimethyl-3ethyW-hexanol (121.
Subtracted 1 5 because aton 1 vss stereocenter. Subtracted 20 because radical not berter on arm 2 than atom 3 .
Figure 8. An exampleaf a reaction considered impractical by LHASA because of a combination of undersirable structural features. The subtractions brought the rating below its "cutoff value" so no successful reaction was displayed.
AGENTS" on the display, the program responds with "Select reaction conditions from the list" and then displays a list of possible reaction conditions from which the student selects a set. There are many situations where different reagents would give the same result, for example, conversion of an imine to an amine by catalytic hydrogenation or by metal hvdride reduction. However, if other functional groups are piesent in the molecule, care in choosing reage& &ay be crucial to the success of the reaction. For the reductive amination in Figure 6, it is necessary to use a reagent which does not reduce the carhon-carbon double bond. Therefore, the conditions "NH3 followed by NaCNBH3" get a high rating. The conditions "NH3 followed by H21Pd" get a lower rating because of the sensitivity of the carhon-carbon double bond to catalytic hydrogenation. If the student had selected this latter set of reagents, the computer would draw a box around the carhon-carbon double hond in the precursor to indicate that it mav he an interfering functional -mouv. . Finallv, ratings are displnyrd ior d l the, sets o i reartion nmditions. A i t c r h k i n g a t I he reagent infixmationand the rating, the to check for alternative pr&urstudent can asik the sors that could produce the current target via the requested reaction. LHASA will then display another precursor, if there is one. This procedure can be repeated in order to show all possible precursors. For example, for the target tertiary alcohol (12) in Figure 7, there are three different pairs of precursors. each oair consistine of an alkvl halide and a ketone. that c < ~ lyield d the target via a Grigniird reaction. Note that t h e rcwtim disr)lav shows the nlkvl hnlide and the krtme: the intermediate sieps in the ~ r i ~ n a reaction rd are not shown. However, the reagent information shows the student the three indi\,iduill s t e p ;hat omatinlre t h e Crignnrd reaction: preparation u t the Grirnard reagent from the alksl halide, addition to the carbonyl group, andproton transfer: Analogously, the alkoxide anions derived from alcohols 6 and 11 are not displayed for the Williamson ether syntheses shown in Figure 5.
Not all reactions selected hv the student will be successful. Absence of a key structural feature in the target molecule can make a particular reaction inapplicable. For example, an attempt to use the Diels-Alder reaction to make a target molecule lacking a carhon-carbon double hond in a six-membered ring would fail. Even when all required key structural features are present in the target molecule, a single undesirable 870 / Journal of Chemical Education
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PROCESS
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Figure 9. The synthesis TREE generated by students during their first h
