Bull. Hist. Chem. 22 (1998) 2 WHEN PIPERIDINE WAS A STRUCTURAL PROBLEM Edr W. Wrnhff, Unvrt f Wtrn Ontr In 80 At fnn n ndn pblhd h b ph lltr n r (5). Sn pprn r nl dvlpd thd fr drdn n, hh t th xtnt f 0% n ppprrn fr vr h ltr t ll xhtv thltn, nldn r (6, nd l xtrtbl b lhl, t ntn f t ptntl n lld (. Wthn rdl vlbl t th hl nt r n 82 At Chr n r n r Erp. In ft, pprn b f th nnd th ltn f n ld b, rtl ntrt n nntn th rl pprdn, C5H 11 , fr pppr (2. pltn n th ntr f plnt l Whn rn trtrl thr n l: Wr th rl tn f trdd n 88, th ntttn f p n th rbn pnd, r, prdn b prbl hh t b hd td, dd th bln d t hv bn tlr—d fr t th l f d [hr nn n fnn n prdr. Whl t rn rdl tthd t 2] (,8? n hrd t blv tht h In rnt th th lttr v, pl ll ld hv ffrd df hdr Wrth t nn n llb flt, t nt ntl bt 88 tht rtn th rdrh hldr t th trtr f pprdn tb br fnd n 84 tht pprn lhd. Irnll, lthh t fnn plt b ll nt n d nd hlf h vntll ppld th xhtv ld b hh th dntfd nln thltn prdr t pprdn, h nbl t n [nn n 826 (] ll n th b f C, nd trprt rrtl th r f th rtn bfr Albrt t nl f th hlrpltnt (0. tr n 84 dnbr xplnd t n 88. h prbbl rn Wrth hnd h nd ( nd ddd tht th fr th lp ll thr r pt f th rl ld b ft bttr th prprt f th r p htr f pprdn r fr th ltrtr, hh ln [n nn t b ] rntl dvrd n 846 ntbl fr th t pprh tn t ht (2, . Oddl nh, Wrth d n ntn f ndrd proof of structure. th bln pnt f h b vn thh th rprtd Piperidine became available early in the develop- tphr bln pnt fr nln [82°C (4] nd ment of organic chemistry, at a t hn f ld pln [°C (2] dffrd dl h pprntl hd rn b r known, because it happened to be a nt dtrnd th rtl phl prprt component of the crystalline alkaloid piperine, It th pttv dntftn pln tht C17H19NO3, which had been isolated as early as 1820- ld th rnh ht At Chr t rpt 21 from pepper (Piper nigrum) b n Chrtn Or Wrth ltn. Chr hd t td n Cpnhn (, 4, h td th n, nd prn f pln th nln, prhp th th f dtrnn th b fr thr r. tll 30 Bull. Hist. Chem. 22 (1998) rivatives. He further surmised that the two alkyl groups attached to the nitrogen atom might be ethyl and ally!. Beyond this in 1853 there was not much more that could be done in investigating piperidine. Hofmann at this time the Professor of Chemis- try at the new Royal College of Chemistry in London. Cahours and Hofmann were already known to each other from having corresponded regularly about chemical matters of common interest (19). On a visit to Paris in 1850 Hofmann took the opportunity to become person- ally acquainted with Cahours (19); the two chemists hit it off well and became good friends. When Cahours visited London for several weeks in 1855 to learn about the state of chemistry there, he stayed with Hofmann, and they began joint investigations which resulted in publications on two topics, neither of which involved nitrogen chemistry (19, 20). They must have discussed piperidine during their time together in London or else in letters, but it was too early for collaboration on a struc- ture for this alkaloid fragment. However, after the struc- tural theory of 1858 had been introduced, the question At—h Chr 8-8 of the structure of the simple piperidine molecule must surely have entered both their minds. Rather puzzlingly, tion of a mixture of piperine, water, and potassium/cal- Cahours never published on piperidine again, even cium hydroxide, followed by addition of more potas- though he did work on the structure of nicotine in 1879- sium hydroxide to the distillate, caused the separation 83. Nor did Hofmann take up the problem until much of an oily base which Cahours distilled twice to obtain a later. Cyclic structures were unknown at this time, and colorless basic liquid of strong ammoniacal odor and perhaps Cahours and Hofmann, considering only acy- constant boiling point 106°C (15). Although he did not l arrangements, regarded the question of which simple say so, it was presumably this boiling point, much lower alkyl groups were attached to the secondary nitrogen than that of either aniline or picoline, which first indi- atom as being relatively unimportant. cated to Cahours that he actually had a different base; During the period from 1857 to 1878 several chem- he named the new compound piperidine because of its ists worked on piperine, but they were more interested source (16). in the non—basic part from its hydrolytic cleavage (21). Analysis of the free base and eleven of its crystal- Wertheim continued studying piperidine, and in 1863 line derivatives fixed the formula as C 5H N [in Cahours' he investigated the nitrosation reaction and its reversal H11terms C10H11Az] Az] which was confirmed by two vapor but got no further before his early death in 1864 (22). density determinations, altogether a very thorough piece In 1871 Karl Kraut in Hannover made several salts from of work for the time (15). Cahours made no mention of the adduct of piperidine and chloroacetic acid but did the fact that his analysis of the chloroplatinate of the not comment on the structure of the base (2. Evnt base from piperine differed appreciably from Wertheim's ll vdn f ntrt on Hofmann's part came analysis of [presumably] the same derivative, but he did from a paper appearing in 1871, the first paper of the state that piperidine differs completely in composition twenty one-year old graduate student Julius Brühl, pub- and properties from picoline with which Wertheim had lished from Hofmann's Berlin laboratory (24). In it confused it (17). It is surprising to the modern reader Brühl pointed out that the constitution of piperidine was that no melting points are reported in either Cahours' or still not known, and he prepared some salts in the hope Wertheim's papers; melting points had not yet come into of transforming piperidine into a member of a known general use as criteria of identity or purity (18). Rely- group of compounds, but without success. By now a ing on Hofmann's work on amines, Cahours concluded cyclic structure was beginning to be considered because that piperidine was an imide base [= secondary amine] Brühl remarked on the likelihood that piperidine was since it formed mono- methyl, ethyl, and [iso]amyl de- formed from the entry of a bivalent C51-1 0 group into Bull. Hist. Chem. 22 (1998) 31 ammonia (25). Finally in 1879, Hofmann published his group when dimethylpiperidinium hydroxide was dis- first work on the structure of piperidine (26). tilled. When he found by analysis that no alkyl group Although by 1870 five— and six—membered rings had been lost, and the product, C 7 H 15 N, named were becoming generally accepted [.. benzene (1865), dimethylpiperidine by him, formally contained two pyridine (1869-70), pyrrole (1870)], Hofmann pointed methyl groups added to piperidine, he was puzzled by out that current chemical thinking still supposed that this apparent violation of his own rules for decomposi- piperidine C5H 10NH contained two alkyl groups, one tion of quaternary ammonium salts: It was not possible being unsaturated, such as ethyl and ally' or methyl and to add two methyl groups to the secondary nitrogen atom crotonyl, a view unchanged since Cahours' statement in of piperidine and still have a tertiary amine. As a way 1853 (15). He did not employ his exhaustive methyla- out of this quandary, Hofmann was initially inclined to tion method at first but instead tried to remove one of think "dimethylpiperidine" might be a the [supposed] alkyl groups by the well-known proce- dimethylangelylamine [angelyl = CH 3—CH=C(CH 3)— dure of heating with the strongest hydrochloric acid for CH2—]. Although this idea was close to the truth, he days in a sealed tube, even up to 300°C, but no alkyl rejected it on the basis of the following experiment: halide was split off (26). Nor did dry distillation of the When the dry hydrochloride salt of "dimethylpiperidine" hydrochloride salt give an alkyl halide. Reaction of pi- was heated, methyl chloride was evolved. The residue peridine with bromine in a sealed tube at 200-220°C from this pyrolysis on treatment with alkali yielded a afforded a crystalline product of dehydrogenation, C5H3NOBr2, soluble in hot hydrochloric acid and in so- dium hydroxide solution, which Hofmann was tempted to consider a pyridine derivative. However, because he was unable to obtain the same crystalline product from the reaction of bromine with pyridine [instead a dibromopyridine, m.p. 109-110°C, now known to be the 3,5-dibromo—isomer, was isolated], he did not insist on the crystalline product being a pyridine compound (26). Hofmann was not the only chemist concerned with the structure of piperidine.