1262 COMMUNICATIONS

TO THE EDITOR Tol. i 9

methylation,s was converted into the trans product followed by crystallization from acetone-water
IV, m.p. 202-204", C, 78.9; H, 8.33, in 69%.yield. containing an equivalent of pyridine, led to 7 5 q )
Alkaline peroxide oxidation4 transformed IV into V of D-a-phenoxymethylpenicilloicacid hydrate (IV),
(R = H) which was converted with diazomethane CI~HZONZO~S.H~O; m.p. 129" dec. [Found: C,
into the ester V (R = CHa), and cyclized with 49.61; H, 5.77; N, 6.94; a Z 5 D +
94" (c, 1 in
potassium t-butoxide in benzene. The resulting methanol)]. Identity with a sample prepared by
keto ester was decarbomethoxylated with hydro- saponification of natural penicillin V5 was estab-
chloric and acetic acid to give the dl-ketone VI, lished by comparison of m.p., infrared spectra
m.p. 155.5-161.5". The infrared spectrum of this (KBr), optical rotation and mixed m.p.
material was indistinguishable from that of Treatment with N,N'-dicyclohexylcarbodiimide
authentic 3,B-hydroxy-9,1l-dehydroandrostane-17- in dioxane-water (20 min. a t 25') cyclized W a s the
one.g monopotassium salt in l(rl27, yield. By partition
(S) A t this stage t h e 3-hydroxyl group was protected a s the tetra. between methyl isobutyl ketone and pH 5.5 phos-
hydropyranyl ether (cf. ref. 3 ) . phate buffer (two funnels) the totally synthetic
(9) C. W. Shoppee, J . C k e m . SOC.,1134 (1946). crystalline potassium salt of penicillin V was iso-
DEPARTMENT OF CHEMISTRY lated. The natural and synthetic potassium salts
UNIVERSITY
OF WISCOXSIN WILLIAMS. JOHNSON were shown to be identical by microbiological as-
MADISON,WISCONSIN DUFFS. ALLEN,J R . say,6 optical rotation [synthetic, d 5 D -/- 223"
RECEIVEDFEBRUARY
1, 1957 +
(c, 0.2 in water); natural, a 2 5 ~ 223" (c, 0.2 in
THE TOTAL SYNTHESIS OF PENICILLIN V
water); reported,' Q?OD +
223" (c, 1 in water)], in-
frared spectra (KBr), m.p. 263" dec. (reported,'
Sir: 256-260" uncorr.), undepressed upon admixture.
The ability of aliphatic carbodiimides to form s
amide bonds in aqueous solution directly from the / \ (1) C6HjOCH2COC1
amine and carboxyl components under very mild HCl'HzNCH-CH C(CH3)z ( 2 ) HC1
conditions' suggested the use of these reagents for / / I >
CO XH-CHCOZH ( 3 ) CsHsN
the cyclization of a pencilloic acid to a penicillin. I
We have Drepared by total synthesis in good over- OC(CHa)3
all yield the penicilloic acid corresponding to peni- 11, D-CY
cillin V (phenoxymethylpenicillin). By use of N ,N'- S
dicyclohexylcarbodiimide cyclization was effected C6HsOCHzCOXHCH-CH/ \C( CH3)z
rapidly a t room temperature, thereby completing / / I
the first rational synthesis of a natural penicillin.2 CO NII-CHCOzH
Condensation of D-penicillamine with t-butyl I (1) KOH (one equiv.)
phthalimidomalonaldehydate afforded the t-butyl OH f
( 2 ) CJ~lli\i'. C.=NCJTI,
~-a-4-carboxy-5,5-dimethyl- a-phthalimido-2- thi- I17
azolidineacetate (I), C2d&4N2O6S, m.p. 161" dec. S
[Found: C, 57.45; H, 6.06; N, 6.83; a Z 5 ~ / \
+ 54" (c,l in acetic acid)] as described for the cor- CeHjOCHCONHCH-$If
I
CO-k--&HCO&
C(CII3)2
responding DL-a The a , or natural,
configuration of the more soluble (ethanol-water) penicillin V potassium
I was established chemically by relationship to (potassium phenoxymethylpenicillinate)
natural dimethyl D-cr-benzylpenicilloate. The less
soluble D-y-iSOmer may be isomerized in high yield The same results were obtained using IV derived
to the D-aform as in the DL-ester ~ e r i e s thus , ~ pro- from natural penicillin V. The entire series also
viding a stereochemically efficient synthesis. Hy- has been carried through starting with DL-penicil-
drazinolysis of I, followed by acidification with lamine. The crystalline DL-penicillin V potassium
hydrochloric acid, produced t-butyl ~ - a - 4 - c a r - salt showed 51.4% (514u/mg.) of the bioactivity
hoxy-5,5-dimethyl- a-amino -2-thiazolidineacetate of natural penicillin V, indicating that L-penicillin
hvdrochloride (11), Cl2H&zOnSC1, in 85% yield; V has little, if any, antibiotic activity. Cycliza-
m.p. 172" dec. [Found: C, 43.83; H, 7.18; C1, tion of the penicilloate also was effected, but in
+
10.87; C X ~ ~ D111" (c, 1 in methanol)]. lower yield, by ethoxyacetylene and a ketenimine
Phenoxyacetyl chloride and triethylamine con- (pentamethyleneketene cyclohexylimines). It is
verted I1 to a-t-butyl D-a-phenoxymethylpenicil- interesting to note that the entire reaction se-
h a t e (III), Cd&sN&S, in 75% yield; m.p. quence starting with penicillamine was conducted
120-122' dec. [Found: C, 56.85; H, 6.86; N, a t or below room temperature.
+
Ci.Ti9; a Z 5 D 67" (c, 1 in methanol)]. Cleavage We are indebted to Bristol Laboratories of
of the t-butyl ester with dry hydrogen chloride, Syracuse, N X . , for financial support, to Merck
(1) J. C. Sheehan and G. P. Hess, THISJ O U R N A L , 77, 1067 (1965).
and Co., Inc., of Rahway, N. J., for the preparation
(2) Penicillamine and 2-benzyl-4-methoxymethylene-5-(4) -oxazolone ( 6 ) Kindly furnished by Eli Lilly & Company, Indianapolis, Ind.
condense t o form trace amounts (0.03 t o 0 08% by bioassay, 0.008% ( 6 ) Synthetic potassium penicillin V had a potency of 1078 d m g . i
isolated) of penicillin G (benzylpenicillin). For a recent review of this 1Oyo (107.870 i lOYc) compared t o standard natural penicillin V in a
reaction see Karl Folkers in "Perspectives in Organic Chemistry," plate diffusion assay carried out under t h e supervision of Dr. J. Lein,
Sir Alexander Todd, Editor, Interscience Publishers, Inc., New York, Bristol Laboratories, Syracuse, N. Y .
N. Y . , 1956, p. 409. (7) E. Brand1 and H. hiargreiter, Ostew. Chenz. 2.. 65, 11 (1954).
(3) J. C. Sheehan and D. A. Johnson, THISJ O U R N A L , 76, 168 (8) Directions for t h e preparation of this ketenimine were f u r -
(1954). nished by Dr. C. L. Stevens, TVayne University. private communica-
(4) J. C. Sheehan and P. A. Cruickshank, i b i d . , 78, 3677 (1956). tion.
March 5 , 1957 COMMUNICATIONS
TO THE EDITOR 1263

of substantial quantities of certain key interme- 9 3 5.

c,
diates and to Mr. Sergey V. Chodsky for technical
assistance.
DEPARTMENTOF CHEMISTRY
MASSACHUSETTSINSTITUTE
JOHN C. SHEEHAN
OF TECHNOLOGY
a
3.3- <$34-

CAMBRIDGE
39, MASS. KENNETHR. HENERY-LOGAN 63.2-
RECEIVEDFEBRUARY11, 1957

is-
T H E SALT EFFECT I N T H E AROMATIC
NUCLEOPHILIC SUBSTITUTION REACTION' &
Sir :
The effect of added neutral salts upon the veloc-
ity of the second order of the ion-dipole aromatic
nucleophilic substitution reactions of lithium, SO-
dium and potassium methoxides with 2,4-dinitro-
chlorobenzene has been investigated a t 25". The
rates were studied in absolute methanol solvent as
a function of reactant (LiOCHs, NaOCHa, and
KOCH3) in the presence of added cations (Lif,
Na+, and K+) and added anions (C2H-02-, I-,
Br-, C104-, C1-, and NO9-). The reaction of
NaOCH3 in the presence of added LiC104.3HzO
also was studied in a 50 volume % methanol-
benzene solvent. I .9;
For reactions without added salts, the rate con-
stants (1 mole-' sec.-l) were: LiOCHI, 0.0242; 1.81
0.0 0.025 0.05 0.10 0.15 0.20
NaOCHS, 0.0262; KOCH3, 0.0278. A consistent MOLARITY OF ADDED' SALT.
pattern of salt effects is typified by the data for the
LiOCH3 reaction shown in Fig. 1. At low concen- Fig. 1.-Lithium methoxide and 2,4-dinitrochlorobenzene.
trations of added salt, each cation exhibits a.n in- sociation occurs for LiOCH, than for KOCH3 or
dividual effect, added to that of the cation intro- NaOCH3 in methanol. Potassium salts are strong
duced along with the reactant methoxide. The electrolytes in methanol with dissociation con-
anions cause an additional secondary effect. The stants of about 0.1 to 0.0Z5 It is known that
reaction rate increases for acetate > C1-, Br- > potassium salts are stronger electrolytes than are
I-, NOS- > Clod-. Salt effects are more pro- lithium salts in acetone.6 If a similar order of
nounced in solvents of lower dielectric constant. electrolyte strength holds for methanol solutions,
The observed effects cannot be correlated with then the effect of added potassium salts on the
changes in ionic strength of the reaction medium
as found by Bolto and Miller.*
LiOCH3 Li+ +
-OCH3 equilibrium would be to
supply anions which would tend to associate more
A qualitative explanation of the effect of lithium readily with Li+ so that the equilibrium would be
salts assumes the equilibrium shifted to provide a greater concentration of OCH3-.
LiOCH3 IfLi + + -0CH3 This accounts for the increase in rate of the reac-
The addition of a salt providing Li+ as a common tion. Sodium salts are not as effective as potas-
ion should shift this equilibrium to decrease the sium salts, and the anion effects are consistent with
concentration of the reactant, OCH3-. Since the those observed in the presence of Li+ alone.
effective concentration of added Li+ will depend ( 5 ) E. C. Evers and 8. 0. Knox, THIS JOURNAL, 73, 1739 (1951).
on the degree to which it remains associated with (6) J. F. Dippy, H. 0. Jenkins and J. E. Page, J. Ckem. Soc., 1368
(1939).
the added anion, the rate will differ with different
added salts. This assumes that the ion pair reacts D. REINHEIMER
JOHN
WILLIAMF. KIEFFER
a t a negligible rate compared to that for the ion. THE COLLEGE OF WOOSTER STANLEY W. FREY
A similar interpretation has been used to account ~T'OOSTER, OHIO JOHN C. COCHRAN
for the variation in rate of decarboxylation of tri- EDWARD W. BARR
chloroacetic acid.3 The observed effect of anions on 16, 1956
RECEIVEDNOVEMBER
reaction rate thus can be interpreted to suggest
that the order of attraction for lithium ions in THE EFFECT OF NITRATE ION ON T H E YIELD OF
methanol is Ac- > C1-, Br- > NO3-, I- > Clod-. HYDROGEN FROM WATER RADIOLYSIS
The fact that NaOCH3 and KOCH3 react faster sir
:
suggests that the corresponding equilibria involving Solutions of calcium nitrate have been irradiated
these methoxides is shifted more to the right, pro- in the mixed fast neutron-y-flux of the Harwell ex-
viding a greater effective concentration of OCH3-. perimental reactor BEPO a t a temperature of about
Conductivity data4 suggest that more ion as- 80'. Nitrate concentration was varied from 15.9
(1) This research supported b y the Petroleum Research F u n d of to 0.037 M . The thermal neutron dose was moni-
t h e American Chemical Society. tored using cobalt wire of high purity.l Energy
(2) B. Bolto a n d J. Miller, Ausfrolian J . Chcm., 9, 74 (1956). deposition figures were derived using the data of
(3) G.A. Hall and F. H. Verhoek, THIS JOUXNAL, 69, 613 (1947).
(4) G. E. M. Jones a n d 0. L. Hughes, J . Chcm. Soc., 1197 (1934). (1) J. Wright, t o be published.