The relative basicities of oxygen versus nitrogen in amides is a problem which has not been satisfactorily resolved. However, it might be anticipated from considerations of resonance and structural parameters that in strongly acidic solutions the proton will attach to oxygen rather than to nitrogen, to give [structure] I rather than [structure] II. 



It is generally recognized that amides are monoprotonated in 100 per cent sulfuric acid. For example, O'Brien and Niemann [1] reported i-factors of 2.0, 2.7, 2.0, 2.9, and 1.9 for benzamide, glycinamide, trichloroacetamide, benzoylglycinamide, and phthalimide, respectively, in this solvent. Similarly, in this study we have found the i-factors of N,N-dimethylformamide, N,N-dimethylacetamide, and acetamide to be 2.1, 2.1, and 2.0, respectively. Thus the problem is to locate the locus of protonation in singly protonated primary, secondary, and tertiary amides

Fraenkel, Gideon

Niemann, Carl

English

Caltech Authors - Main

CHEMISTRY: FRAENKEL AND NIEMANN
TABLE 7
CRITICAL VOLUMES (CC.)
n = 6 (Walter) Observed
Neon 43.48 49.0 41.74
Argon 77.69 78.7 75.26
Krypton 88.32 81.0
Xenon 113.52 112.0 113.8
The critical properties above were calculated algebraically in the usual way,
using
(A\ 8P\ (b2p
VVT 0V=T0V2T
The method of significant structures thus leads to a simple and surprisingly success-
ful reduced equation of state for normal liquids. The deviations from experiment,
particularly in the pressure, are such as would arise from insufficient account of
clusters of molecules in the saturated vapor. Such clusters are known to exist.
Extension of our partition function to abnormal liquids and to metals and molten
salts are in progress along lines that have previously been found successful, using
the Walter-Eyring partition function.
The authors wish to express appreciation to the National Science Foundation
and one of them (N. H.) to the Research Corporation for their generous support.
1 R. H. Ewell and H. Eyring, J. Chem. Phys., 5, 726, 1937.
2 Ralph Livingston, private communication.
8 J. Walter and H. Eyring, J. Chem. Phys., 9, 393, 1941.
4H. Eyring, J. Walter, and A. E. Stearn, in Surface Chemistry, (Washington, D. C.: American
Association for the Advancement of Science, 1943), No. 21, p. 88.
THE MODE OF PROTONATION OF AMIDES
BY GIDEON FRAENKEL AND CARL NIEMANN
GATES AND CRELLIN LABORATORIES OF CHEMISTRY, CALIFORNIA INSTITUTE OF TECHNOLOGY,*
PASADENA, CALIFORNIA
Communicated May 16, 1958
The relative basicities of oxygen versus nitrogen in amides is a problem which
has not been satisfactorily resolved. However, it might be anticipated from con-
siderations of resonance and structural parameters that in strongly acidic solutions
the proton will attach to oxygen rather than to nitrogen, to give I rather than II:
+ + ±
HO-C=N-; HO==C-N- O=C-NH-
(I) ~~~~~~(II)
It is generally recognized that amides are monoprotonated in 100 per cent sul-
furic acid. For example, O'Brien and Niemann' reported i-factors of 2.0, 2.7, 2.0,
688 PRoc. N. A. S.
CHEMISTRY: FRAENKEL AND NIEMANN
TABLE 1
CHEMICAL SHIFrS OF AMIDES IN VARIOUS MEDIA*
RCONR1R2
HCON(CH3)2
CH3CON(CH3),
(CH3)2CHCON(CH3 )2
C3H5CON(CH3 )2
CH3CONHCH3
CH3CONH2
SOLVENT
Pure liquid
H20
12MHC1
48% HBr
98% H2SO4
100% D2SO4
H20
D20
4 M Na2SO4 in H20
10 M HCl04
5 M HCl04
3 M HCl04
1 M HCl04
Pure liquid
100% H2SO4
100% D2SO4
Pure liquid
100% H2SO4
Pure liquid
H20
D20
0.1 M HC0
0.1 M NaOH
60% HCl04
1% HCl04
100% H2SO4
100% D2SO4
H20
100% H2SO4
SHIFT
Solvent RCO NR1R2 Apt
. . -i17.7
2.4 -125.9
-122.1 -143.9
-95.7 -154.6
-271.3 -141.1
-280.5§ -144.9
5.9 106.8
106.8
-4.4 98.8
-85.1 90.6
-24.3 98.8
-15.3 101.8
-3.6 105.4
113.9$I11
120.9
152.7t, #
158.8
-261.6 137.6*2#
124.9
-281.5§ 135.3t1#
128.9
162.5t***
169.1
109.4tt, 11
115.7
122.1
127.6
134.1
140.6
-267.5 134.0$ **
128.8
124.7
1.8 113.4
3.6§ 113.3
*.. 95.4
111.0
-85.1 96.5
-5.2 112.1
-271.9 87.7
-286.5§ 84.7
5.0 112.8
-289.7 87.4
85.9 203.6
92.0
75.l1 201.1
81.8
59.5 203.4
65.4
48.2: 202.7
53.9
51.0t 192.1
55.7
49.4t 194.3
54.0
68.0t 38.7
74.0
68.0: 38.7
74.0
60.4: 38.4
66.2
58.2 33.3
64.2 34.6
67.4 34.4
69.3 36.1
76.1$
84.2
53.Ot .
56.0
49.0$
51.7
65.3$
75.9
45.0t
52.3
97.5
82.5*
86.3
83.4
69.4
81.9
71.4
82.1
69.7$-144.8tt
65.5 .
55.9
-98.0tt
-147.9$t
SPLIrrING
NR1R!
6.9
6.7
5.9
5.7
4.7
4.6
6.0
6.0
5.8
8.1
3.0
2.7
10. 6
7.3
4.0
3.8
4.2
* In cycles from H20 at 40 megacycles.
t Intramolecular chemical shift between N-methyl hydrogens and hydrogens of R group except where otherwise
noted.
Doublet.
§ Hydrogen of exchange and/or impurity.
II Methine hydrogen.
# Methyl hydrogens.
** Methylene hydrogens.
ft Sextuplet.
tt N-H chemical shift.
VOL. 44, 1958 689
CHEMISTRY: FRAENKEL AND NIEMANN
2.9, and 1.9 for benzamide, glycinamide, trichloroacetamide, benzoylglycinamide,
and phthalimide, respectively, in this solvent. Similarly, in this study we have
found the i-factors of NN-dimethylformamide, N,N-dimethylacetamide, and
acetamide to be 2.1, 2.1, and 2.0, respectively. Thus the problem is to locate the
locus of protonation in singly protonated primary, secondary, and tertiary amides.
Tertiary Amides. It was thought that one might determine the site of proton-
ation of a representative tertiary amide by examining the nuclear magnetic reso-
nance (n-m-r) spectra of N,N-dimethylformamide in strongly acidic solutions. The
pure liquid compound, as well as solutions of it in carbon tetrachloride and in water,
has an n-m-r spectrum of three lines, one for the formyl hydrogen and a doublet
for the methyl hydrogens. This splitting has been traced to a chemical shift be-
tween the methyl groups which results from hindered rotation about the carbon-
nitrogen bond considered in I and 11.2 In strong acids, if the proton attached to
oxygen one might expect retention of the methyl doublet since the carbon-nitrogen
bond would still have considerable double-bond character as indicated in I. On
the other hand, protonation on nitrogen should yield free rotation about the carbon-
nitrogen bond and therefore collapse of the doublet. In fact, the methyl splitting
of NN-dimethylformamide was preserved in a variety of strong acids, e.g., 12 M
HCl, 48 per cent HBr, 0.1-10 M HCl04, including 100 per cent H2S04 and D2SO4
(ef. Table 1).'
It might be argued, in the case of the hydrogen acids, that N-protonation had
occurred, the N-H proton splitting the methyl hydrogens by spin-coupling. Deu-
terium couples very weakly,4 especially through nitrogen.5 Accordingly, the n-m-r
spectrum of N,N-dimethylformamide was observed in 100 per cent D2SO4. The
magnitude of the methyl splitting in this as well as in all other media tried was rela-
tively constant throughout. Whereas the absolute positions of the peaks varied
from one solvent to the next, the difference between the chemical shift of formyl
hydrogen and the methyl hydrogens was substantially constant, indicating that
the methyl hydrogens and the formyl hydrogen were equidistant from the center
of charge on the molecule. The behavior of N,N-dimethylcyclopropylcarboxamide
and N,N-dimethylisobutyramide also fell into this pattern. The methyl doublet
of NN-dimethylacetamide collapses reversibly in acidic solutions, from 0.1 M
HCl04 upward (cf. Table 1).
Secondary Amides. The n-m-r absorption spectrum of N-methylacetamide in
the liquid state, in nonpolar media, and in water at pH 7 consists of three peaks, a
singlet for acetyl methyl and a doublet for the N-methyl hydrogens, which collapses
to a singlet in the presence of most acids and bases and in D20. The effect of the
first two types of solvents has been traced to a rapid exchange between N-H and
solvent, i.e., the relaxation time for the N-methyl proton spins must exceed the
half-life of N-H exchange.5' 6 Since deuterium spin-couples but weakly,4 N-deu-
tero-N-methylacetamide would be expected to yield a single peak for the N-methyl
hydrogens. The N-H peak itself is weak and quadrupole-broadened and is observ-
able only in the pure compound.
In 96-100 per cent H2SO4 the methyl doublet returns, as does the N-H absorp-
tion. The doublet peaks are of equal amplitude with about the same separation
as in the pure liquid. In D2SO4 the N-methyl doublet again collapses.
The above results again are consistent with 0-protonation. There can be only
PROC. N. A. $.690
GENETICS: GRIFFEN
one proton on nitrogen, the other must be on oxygen. Acetylglycine shows the
same behavior. It can also be concluded that the bisulfate ion is a poor base for
exchanging the N-H proton of secondary amides in sulfuric acid.
Primary Amides.-The N-H proton magnetic resonance absorption of acetamide
has been observed in saturated aqueous solutions at pH 7 and in 100 per cent sul-
furic acid. Here, also, exchange of the N-H proton in sulfuric acid appears to be
slow in comparison with its relaxation time. By measuring the areas under the ab-
sorption peaks it has been possible tentatively to assign O-protonation of acetamide
in 100 per cent sulfuric acid. This interpretation is in accord with that of Hantzch,
based upon ultraviolet spectroscopy,7 and that of Huisgen and Brade,8 based upon
potentiometric pK determinations.
Experimental.-All spectra were determined with the Varian 4300 B, 40-mc.,
9,400-gauss n-m-r spectrometer, equipped with spinner and superstabilizer. Sam-
ples were sealed in 5-mm. o.d. Pyrex tubes. Chemical shifts were calibrated by a
combination of the method of side bands9 and the use of toluene markers in cap-
illary tubes as secondary standards. The cryoscopic measurements in 100 per cent
sulfuric acid were conducted as described by O'Brien and Niemann.I The N,N-
dimethylcyclopropylcarboxamide was kindly supplied by Mr. David Schuster.
All other materials were obtained by the purification of samples of commercial origin.
The authors are indebted to Professor J. D. Roberts for his assistance during
the course of this investigation.
* Contribution No. 2337.
l J. L. O'Brien and C. Niemann, J. Am. Chem. Soc., 79, 1386, 1957.
2 H. S. Gutowsky and C. H. Holm, J. Chem. Phys., 25, 1228, 1956.
3This phenomena has also been observed by Dr. W. D. Phillips, of the Central Research Depart-
ment, E. I. du Pont de Nemours and Co., Wilmington, Delaware.
4E. R. Andrew, Nuclear Magnetic Resonance (Cambridge: Cambridge University Press,
1956), p. 145.
5 G. Fraenkel, unpublished observations.
6 H. S. Gutowsky, private communication.
I A. Hantzsch, Ber., 64, 661, 1931.
8 R. Huisgen and H. Brade, Ber., 90, 432, 1957.
9 J. T. Arnold and M. E. Packard, J. Chem. Phys., 19, 1608, 1951.
OCCURRENCE OF CHROMOSOMAL ABERRATIONS IN
PRE-SPERMATOCYTIC CELLS OF IRRADIATED MALE MICE*
BY A. B. GRIFFEN
ROSCOE B. JACKSON MEMORIAL LABORATORY, BAR HARBOR, MAINE
Communicated by C. C. Little, May 23, 1958
In both insects and mammals, only sperm which are mature at the time of irradi-
ation are considered to form F1 individuals, which bear major chromosome aberra-
tions and particularly translocations. In the male mouse there is an initial period
of approximately 1 month after the irradiation during which fertility remains
good; offspring sired during this period bear appreciable numbers of genetic effects,
VOL. 44, 1958 691


The Mode of Protonation of Amides

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