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COMMUNICATIONS TO T H E
EDITOR
Vol. 86
present derivatives are under further study in these laboratories.
constants corresponding to weighted averages of the values existing in the pure solvents. During the course of an investigation of the e.s.r. (14) Publication No. 1675. spectra of m-nitrophenol negative ion produced by DEPARTMENT O F CHEMISTRY l 4 D . K . HUGGINS electrolysis in water-dimethylformamide ( D l f F ) mixUNIVERSITY OF CALIFORNIA H . D. KAESZ Los ANGELES, CALIFORNIA90024 tures we have obtained spectra which are very clearly RECEIVED APRIL 17, 1964 due to the superposition of two radical species which _________ we logically identify with two different solvates. Figure l a shows the spectrum of m-nitrophenol anion Electron Spin Resonance Spectra of Different Solvates in an approximately 507Gmixture of water and DAW. of rn-Nitrophenol Negative Ion in a Mixed Solvent The hyperfine pattern is due to a major triplet arising Sir : from the nitrogen coupling of I-&.(i gauss: this splits I t is well known that e.s.r. spectra of many organic into quartets (intensity 1 : :1:3 : 1 ) due to three almost radicals and radical ions in solution are very sensitive equivalent protons and furthermore into doublets, to solvent composition. Electron-nuclei spin-~ spin the last splitting arising from the remaining proton with the smallest coupling constant. The pattern remains practically the same in going from pure water t o pure D M F , the only feature influenced being the main nitrogen splitting which decreases smoothly from 14.6 gauss in pure water to 12.3 gauss in pure DMF. T h e proton coupling constants are not influenced much by solvent composition a t least up to almost unit D n I F mole fraction where differences are noted among the three almost equivalent bG protons. Figure l b shows the spectrum obtained from the same solution of Fig. l a at a lower temperature. The pattern of the central group is not affected but the two side groups now have a larger number of lines. T h e reconstruction of Fig. I C shows how the pattern is easily explained on the basis of the superposition of two spectra of the type of Fig. l a differing only in the major nitrogen splitting. Some of the lines of the side groups have a greater width because the overlapping is not so perfect as postulated in the reconstruction. \Ye note also that in both spectra the high field group lines are wider than the corresponding low field ones as is currently observed in many cases.3 I t is clear from this experiment that, in the case of sufficiently large differences among some coupling constants of the two alleged "solvates" RSI and RS2, it is possible to obtain conditions of sufficiently low rate of exchange among the two species such that the two spectra can be detected at the same time. Further details on this phenomenon and a comprehensive quantitative discussion will be published shortly.
-
I
(C)
Fig. I E s r first derivative spectrum of vi-nitrophenol ion in water-DhfF with electrolyte 0.1 M SEtrCIOd: a , a t room temperature; b, saine a t 0 " ; c, reconstruction of spectrum b based on superposition of the two spectra arising from two species in 1 : 1 ratio and differing only in U S
coupling constants undergo conspicuous variations with solvent and the behavior has been explained3 through the formation of "solvates" or "complexes" in which the radical is linked to one or more solvent molecules as for example in the model reaction Its1
+ s2
Its2
+ s,
where R is the radical and SI and S2 are the two solve 11t s .
The e.s.r. spectra obtained up to now in these cases always presented hyperfine patterns indicating coupling :I) E.IV S t o n e a n d A I1 M a k i . J C h r m P h v s . , 36, 1944 (1962). d ) J ( l e n d e l l . J H Freed, a n d C, K Fraenkel, i b i i i . , 37, 2832 (1962)
(3) P. B. Ayscough, F. P. Sargent, and I< Wilson, .I. ChPm. S o c , 5418 (1963).
INSTITUTE OF PHXWCAL CHEMISTRY UNIVERSITY OF PADUA PADCA,ITALY RECEIVED MARCH23, 1961
C. CORVAJA G . GIACOMETTI
Novel C-4 Modified Tetracycline Derivatives
Sir : The reaction of amphoteric tetracycline 1 with Nchlorosuccinimide to yield 1 la-chlorotetracycline-(i,12hemiketal 2 has been reported.' A less than drastic change in chlorination conditions-treatment of tetracycline hydrochloride with N-chlorosuccinimide in water--leads to the isolation of a drastically different product, 3-oxo-4dedirnethylarninotetracyclirie 4.6-hem(1) K . K . Blackwood, J. J . Beegebooni, H. H. I t e n n a r d . k l . Schach r o n Wittenau. a n d C. R . Stephens. J A m . Chrm Soc , 83, 2 7 7 3 ( 1 9 0 1 ) , 86, 3943 (1963)
COMMUNICATIONS TO THE EDITOR
July 5, 1964
2737
C, 53.8; H , 4.6; N , 9.0. Reduction of 7 with iketal 3 . 2 Anal. Found for C Z O H ~ ~ O ~ N K . O . ~ HOsN3,HzO: ZO: zinc dust in aqueous acetic acid or with sodium hydrosulC, 52.0; H , 3.8; N, 3.2; C1, 0.0; K , 8.2; Hz0, 1.7. fite yields 4-epi-4-amino-4-dedimethylaminotetracycline Absorption peaks occur a t AE~2H-o'o' 268 and 346 MeOH-0.01 N HCl 260 and 360 mk (log E 4.25 and 4.17). mp (log e 4.40 and 3.72) ; A~~:H-o.ol *'OH very unstable, (8)s Amax Anal. Found for C2oHzoOsNz.l.?j(CH3)zNCHO: C, includes Amax -370 mp (log e -4.4) ;: : : A The 5.7p. 55.8; H , 5.9,; N, 9.2. The 5a,6-anhydro derivative 9 hemiketal 3 is readily reduced to alcohol 4, by catalytic MeOH-0.01 N HCl 223, 272, and 423 mp (log €4.45,4.71, hydrogenation, sodium hydrosulfite, or zinc dust ; gave %ax A.MeOH-O.O1 N HCl and 3.93. Anal. Found for C 2 0 H l s 0 ~ N 2 ~ H(CH2)40: Cl~ 257 and 362 mp (log e 4.23 and 4.20). max C, 56.7; H , 5.1; N , 5.5; C1-, 7.1; NH2, 3.2. StereoAnal. Found for CZ0H19N09:C, 57.3; H , 4.6; N , 3.2. chemistry a t C-4a is assigned on the basis of smooth An alternative preparation of the alcohol is via catalytic conversion in acetone, propylene oxide, and methyl iodide hydrogenation of 5 3 ; AE::H-o.ol 258 and 343 mp to tetracycline methyl betaine 10.4,5 Stereochemistry (log E 4.42 and 3.68) ;: : :A 5.77 p. Anal. Found for a t C-4 is tentatively assigned on the basis of the short CzoHi60gNC1: C, 53.0; H , 3.7; N, 2.8; CI, 8.0. wave length ultraviolet maximum and by virtue of the Compound 5 is formed by analogous N-chlorosucpresence of a minor, much more antibacterial substance cinimide treatment of 2.
10
\
9
11
t
W \
//
t8
H/
*
*H *.HI
dH
OH0
0
CONHa
7
W \
OH
0
3
H /
OH H O 0
CONHz
12
.1
.1 CONHz
OH 0 5
OH 0 4
Acid degradation of the alcohol 4 yields the corre222, sponding 5a,6-anhydro derivative 6, Az::H-o.ol 262, 310, and 423 mp (log e 4.46, 4.70, 3.68, and 4.01). Anal. Found for CzoH1708N: C, 59.8; H , 4.5; N, 3.3. T h e anhydro alcohol 6 may also be obtained by the sequence 3 + 12 + 6 (anhydrous hydrogen fluoride followed by sodium hydrosulfite reduction). The 4,6-hemiketal 3 undergoes a variety of other reactions. For example, reaction with hydrazine yields the hydrazone 7, A ~ ~ ~ H - o . 'vo ' 264 and 335 mp (log E 4.16 and 4.53) ; Az::H-O.O' NaoH 261, 323, and 373 mp (log E 4.33, 4.25, and 4.29). Anal. Found for C20H19(2) For leading references concerning the conversion of tertiary amines t o aldehydes with N-bromosuccinimide and with hypochlorous acid see R. Fuller, C h e m . Rev., 63, 21 (1963), a n d A . J , Ellis a n d F. G. Soper, J . C h e m . SOC., 1750 (19541, respectively. (3) T h e 4,6-hemiketal structure for 8 is presumed on the basis of analogy t o 3.
OH OH 0
0
6
in preparations of the amine 8, which paper chromatographic studies indicate to be epimeric in nature. The 4-amino compound 8 may also be obtained by zinc reduction of the oxime 11 or by direct reductive amination of 4-oxotetracycline 3 (Hz, PtOz, MgClz, and excess NHIOH in dimethylformamide solution). Extension of the reactions described herein to other tetracyclines, to substituted hydrazines, and to other amines is in progress. (4) Under these conditions tetracycline and 4-epitetracycline yield the same product. ( 5 ) J . H. Boothe, G. E. Bonvicino, C. W. Waller, J P. Petisi, R . W . W i l kinson, and R. B. B r o x h a r d , J . A m . Chem. Soc., 8 0 , 1654 (1958).
MEDICALRESEARCH LABORATORIES ROBERTK BLACKXVOOD CHAS.PFIZER A X D Co., INC. CHARLES R . STEPHESS GROTON, CONNECTICUT RECEIVED MAP 13. 1964
