Albert E. Z u n e and Ulrich Hollstein The University of New Mexlco
Albuquerque, New Mexico 87106
The Use of Networks in Organic Synthesis
The synthesis of organic compounds presents problems to the beginning student in organic chemistry which to him seem unsurmountahle. He is learning a myriad of new compounds, physical concepts, reactions, their scope, .mechanistic pathways, and many other aspects, but when i t comes to even a simple two step synthesis, he is usually a t a loss. Without considerable exercise the student usually remains incapable of carrying out the typical analytical thought process which is required to solve a synthetic problem. In the years we have taught organic chemistry we have become aware of these difficulties and of several ways to solve them. We consider the synthesis of comnound Z from a eiven startinz- material A as the ulannine of a voyage, say by bus, from city A to city Z. One needs a map and a bus schedule. The best route will be determined by the shortest path, the quickest path, or a minimum number of transfers. Obviously, the plan does not start a t A only, but the possibilities of several intermediate stations and their connections are considered as well. T h e concept is easily translated into organic synthesis terms, in particular the well known trick to "work from
both sides." One can ask and the student can usually, after consulting his notes, easily answer the following questions 1) Where can I go fmm compound A, i.e., what are the chemical properties of the functional groups in A? 2) Where can I go from these products of A, say BI,Ba, B3,etc.? from the products fmm the B compounds, say 3) Where can
C1,C2, Ca,etc.? This process can he depicted as a fanning out from A, with possible overlap or crossing of the diverging lines. The diagram may he called a "synthesis tree" (Fig. 1). At the same time one can ask 1) How can I go to Z, i.e., what are the possible immediate precursors of Z or what are the modes of formation of the functional
groups in Z? 2) what are the pssible immediate precursors of the precursors of Z.. sav . Y,. - . Yv-.. Yn-.. etc.? 3) What are the immediate precursors of the precursors of the Y compounds, say XX,XZ,X8, etc.?
.
Aromatic Grouo Interconversions ~~
CHs 01
H H
NO,
NH?
SOsH
OH
HNOs I+H2S041
via NO,
450.
via NH.
via NH.
NeNH2 + NHs
X
F:via NH.
CI: viaNH.0~ C b + FsCl. Br: via NH20r
ifummgl
m
SH
RIalkyll
RX
+ AIXa
viaS01H
via SOsH
60 + FeBr. I: v i a N H 2 0 r
X
Mg. H z 0
ICI
viaNH~
O H (heal1
via NH,
viaCOOH or
RCOCH. (via ArCHfOR)
NOI
via NHm
NHx
HNO*.HsPOz or
HNOI. NaBH,
SOaH
HzO/H2S04
Hz,
via NH,
,,NO2,
Raney Ni
C
BF4
C"S12 CuBo
cuztl
via OH
CF>COOOH
via NHz
via NH.
via NHz
viaNHz
via SH
HNO.. He0
via X
HNOn,KSH
KOH 3WC
via OH
PC!..
or
CHaCOOOH or HNOZ. C u d N O d z vie OH
A
via OH
Zn + HCI
.
Zn. 5W.
via NH?
0,
IEtOl"POC1,Li NHj 1ig I d 19)) via COOH
via COOH
via COOH
via COOH
via S0.H
visS0.H
via COOH
via COOH
via COOH
HNOa
vieSOaH
visSOaH
viaCOOH
visCOOH
07
KMnOa or
viaCOOH
vie COOH
via COOH
naCOOH
HlOl viaCOOH
via COOH
01
via CH2NH,, CH2X or via CHZX
CHO COOH
A or A
or
via NHa
via NHI
+ cao
via CONHz + NaOBr (Hofmsnnl
via NHI
visCOOH
via COOH
via NHI
via CHnOH,
+ LAH
+ nucleoaoume
+ TsCl,
via NHx
07
via NH. or
viaCOOH
via COOH
via COOH
via COOH or peracid (Baeyer Villige.)
0
via COOH
viaCOOH
I1
C-H
16
/ Journal of Chemical Education
via COOH
via COOH
viaCOOH
via COOH
via COR via COOH or
viaCOOH
NHINH~,O H (W. K.1
or
Zn CHCI(Clemm.1
NH2NHz, O H I W . K.1 or Zn HCIIClemm.1
+
viaCOOH
This process is depicted as a set of converging lines, some of which may overlap or cross. By continuing this process a path P between, e.g., Ca and Xs will become apparent or, if the process has been carried to an extreme, an identity, e.g., Cz XI will have been established. The number of organic reactions that the beginning organic student is trying to memorize is overwhelming. Yet, any one of these reactions may be needed and must be kept a t one's fingertips in constructing the synthesis tree. This task, which initially often discourages the student, seems to require years of experience and practice. In such a study rationalizations and mechanistic insight is helpful, but any mnemonic device is a we)come extra tool. We have experienced that the students' memory is aided by the study of networks depicting possible routes between common functional groups attached to a constant (e.g., alkyl) group. Such a diagram is often easily imprinted in the visual memory. In the interconversion of functional groups it is helpful to identify families of functions and to show their interrelations in a network. We have done this for three families
--
by taking data from several undergraduate textbooks (14). Diagrams of the type shown in Figure 1 are involved in computer planned synthesis (5-7). Figures 2 and 3, the table, and a system for deriving synthetic pathways to polysubstituted benzenes from mono- and disubstituted ones (8) provide essentially the information necessary to build specific tree diagrams. Alkane, alkene, alkyne, olkyl halide, alcohol, amine, aldehyde, ketone and corboxylic acid (Fig. 21. These compounds are interre-
lated by simple electrophilic additions, eliminations, nucleaphilic substitutions, oxidations, and reductions. The diagram shows,
Figure 1. Construction of a "synthesis tree."
CN
via CHs or via X
via NHI
M,. CO.
0
0
C-R
C-H
11
COOH
RCOCl + AlCla
11
CO + HCl
or
MF. RCHO.
ME H L O ,
IRCOhO + AlClr
oildatlon
HCN + ZnCh
via NHn
via NH,
via NHl
via NH,
HNOz, Cu!CNh
viax
via X
viax
KOH, KCN.
via OH
viaOH
via OH
or via NHI via NHs
via NH2
via NHz
via NHz
5W-C
or via CN
+ AICls + HCI
or
Figure 2. Interrelation between aliphatic functional groups (excluding the carboxyi family.) a, Arrows arriving at or departing from t h e outside of the box refer to the general functional group. b, R does not necessarily contain the same number of carbons. R,OH
I via COOH
KMnO. or
via COOH
COCI, R k d
**a
1
Clr + h " ~ H10
croa
or
via SOaH
via SOsH
via SOaH
H,O, H'
+Grignard
via CHINH1.
via COOH.
c1aiSen
via SOaH
or H20.
OH-
via amide P203, A or SOCll,d
viaC00R
COCI, R&d
"is COC1,
via COOR. Claisen
LiAlltBuhH
or
KMDO. 07
Br2 +
CHZOH
or via COOH
+
viaCOOH
OH-
!o"ly on
via COOH
acetyl)
NaOH ~Cannirzam) or
KMnO,
via COOH
Figure 3. The carboxylic acid family. a, Transesterification with R 2 0 H , H+ gives RCOORI. b. If R f R I two additional anhydrides RCOOCOR and R,COOCORl areformed. Volume 51, Number 7, January 1974
/
17
clearly the key positions of alkyl halides and alcohols. The unique position of the Grignard complex is also apparent: it can only he made fmm the halide hut it can serve in numerous (seven in this diagram) reactions. CO1, nitrile, or the This family is related via the Grignard aldehyde with the next family. Carboxylic acid and deriuatiues (Fig. 3). Here we place the parent carboxylic acid in the center of a square, the comers of which are occupied by the four carboxylic acid derivatives: acyl ehloride, ester, amide, and anhydride. The amide carries a branch to the nitrile. Arrows indicate the possible interconversions and required reagents and catalysts. All reactions are nueleophilic displacements at the carbonyl function. The network shows clearly the unique position of the aeyl chloride, to which only one arrow points, and the somewhat lesser unique position of the anhydride (2 arrows). Both compounds can be used to prepare any of the other three and are "acylating agents" par excellence. A third family of compounds, unrelated to the previous, is the group of Aromatic compounds. The tahle represents the interrelationship of monosubstituted aromatic compounds. The reactions here comprise common aromatic electmphilic substitutions as well as aromatic nueleophilie substitutions, elimination/addition (via heuzyne) .and typical aliphatic sidechain intereonversions. I t can easily he seen that one can go from any functional group to any other functional group, including hydrogen, at the same position on the benzene ring, although the conversion sometimes requires several steps. Three examples will illustrate the use of the diagram. (1) To go from aniline to phenol: Look up NH2 in the left margin and proceed to the column under the heading OH. The entry indicates the use of nitrous acid (giving the diazonium ion) followed by decomposition with water. .(2) To go from a phenolic group to an amino group: This difficult step has recently become accessible with the new reagent 4-chloro-2-phenylquinazoline (9). (3) To go from cyano to halogeno: The entry "via C O O H indi-
+
18
/
Journal of Chemical Education
-
COOH (acid or alkaline cates that one must f m t look up CN hydmlysis). From carboryl to halogeno requires "via NHz" and one Looks up how to go from carboxyl to amino. The Hofmann hypohromite reaction is suggested. Finally, the conversion of amino. to halogeno is accomplished directly by a Sandmeyer type reaction. The tahle reveals some unique patterns. Certain groups can only be converted into any other group via the same intermediate, e.g., -(CO)R or -(CO)H via -COOH, or -NO2 via NH2. The synthetic importance of the aromatic NHz group as precursor of the diazonium ion is likewise apparent from the table. W e have found these charts helpful i n guiding t h e stud e n t throueh a svnthesis. T h e networks are limited to t h e most common interconversions and n o a t t e m p t is made t o exhaust all oossibilities. Also.. mour, - . transformations comprise only one aspect of organic synthesis. They m u s t be used in conjunction with construction of t h e carbon skeleton, a n d a knowledge of carbon-carhon bond formations, including ring formations, is required a s additional skill.
Literature Cited 11) Morrison. R. T.. and Bayd. T. N.. "Oraanie Chemistw," 2nd Ed.. Allyn and earnn,'~mton.M-., 1966. (2) Roberts. J. 0..and csacrio, M. C.. "B8.i~F?incir.lm of o m n i e Chemistw." W. A. Benjakin. & Co.. New York, 1965. (31 Handrickson, 3. B., Cram. D. J., and Hammond. G. 8.. "Organic Chemistry," 3rd F A McGraw-Hi... NeuYark. 19l0. Allinger. N . L., Caw. M. P.. & Jongh, D. C.. Johnson. C. R., -1, N . A., and Stevens, C.L.,"OrganicChemisfry," Worth.NcwYork. 1971. (51 Isenhow. T. L.. m d Jws, P. C.. "Intmdudion to Computer Raglamming fm Chcmiafa,"AUynandBaeon.Boatrm. Msa*.. 1972. D. 253. (6) Ugi. I., and Gillcnpie. P.. Angem. Chem, i n t e m t . Ed*. 10.915 (19711. (71 Cony, E. J.. Quart. Real.. 455 (19721. (81 Hendriekson, J.B..JAmer Chrm. Sac., OS,6&17andW(19711. (91 Sohomer, R.A,. andBeatty. H. R..J Or& Chem., 57.1681 (19721. (10) Goldkamp,A.H.efal.. J. Med. Chem.. S.UPJ(19651. ~
