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Substituent effects on the NMR spectra of substituted acetanilides and phenylureas
JOURNAL
OF MAGNETIC
RESONANCE
l&230-234
(1975)
SubstituentEffects on the NMR Spectraof Substituted Acetauilidesand Phenylureas* C.
JANET
GIFFNEY
AND CHARMIAN
Chemistry Department, University of’duckland,
J. O’CONNOR
Privafe Bag, Auckland, New Zealand
Received October 2, 1974 The substituent effects on the NMR spectra (&, and &n,) of phenylureas and (SNH and BCH1)of acetanilides have been reported. The chemical shifts correlate well with Hammett sigma values. INTRODUCTION
In the 1930’s Hammett (I) considered the effects of substituents (R) on the reactivity of a side chain (Y) in compounds of the type
A quantitative
relationship log,, k = log,, k” + ap
was proposed, where k is either a rate constant (k) or an equilibrium constant (K) for reactions of a meta- orpara-substituted benzene derivative, and k” is the corresponding value for the unsubstituted compound. 0 is the substituent constant that is characteristic of the nature and position of the substituent and is independent of the reaction; p is the reaction constant and is determined by the conditions under which the reaction takes place and the nature of the side chain Y. The need for dual (Tvalues for some substituents was first recognized by Hammett (la) who found it necessary to assign two different substituent constants to the nitro group in thepara position. In general, for side-chain reactions involving the formation of an electron-deficient reaction center in direct conjugation with the benzene nucleus, electron acceptor puru substituents (+R) have enhanced 0 values termed C+ constants and these have been defined by Brown and Okamoto (2). The Hammett equation has frequently been used to find relationships between the chemical structure of a compound, defined by reactivity parameters, and its physicochemical properties. In particular, attempts have been made to correlate the equation with the spectral characteristics of the ground-state molecules. These ground-state molecules are in a state of dynamic equilibrium, undergoing rotational and vibrational transitions which require somewhat lower energies than are usually necessary for bondmaking and -breaking processes in reactions. Using the Hammett equation, Marcus * Abstracted from a thesis submitted by C. J. Giffney (nee Hyland) for the Ph.D. degree from the University of Auckland. 230 Copyright 0 1975 by Academic Press, Inc. All rights of reproduction Printed in Great Britain
in any form
reserved.
SHIFTS
IN
ACETANILIDES
AND
231
PHENYLUREAS
et al. (3) studied the transmission of electronic effects through Tin compounds of the type RC6H4T-H, where R is the substituent, C6H4T is the transmitting group and H is the reaction site. As a substituent is moved down a chain from a terminal proton the effect of R on the chemical shift, 6, of the proton diminishes and, if the chemical shift of the proton is plotted against 0, the resultant value of p characterizes T as well as the conditions of the NMR measurements. Marcus et al. (3) found that the minimum attenuation factor per connecting atom is ca. 2-3 in carbon tetrachloride; for T = 0, 1 and 2 atoms in a chain, the “standard” p values in cps/a are ca. 36, 13 and 7, with a levelling off when T > 3. A similar fall-off factor was observed by Taft et al. (4) in their study of the fluorine NMR shielding of meta- andpara-substituted fluorobenzenes and it is also closely similar to that observed in the reactivities of such compounds (5). When T contains oxygen, nitrogen, a carbon-carbon double or triple bond, or in general, groups that conjugate readily with the aromatic ring, then the sensitivity of the chemical shift of the proton to remote substituents is magnified.
RESULTS
AND
DISCUSSION
In the present study the NMR spectra of the substituted phenylureas (Y= NHCONH,) and acetanilides (Y= NHCOCH,) have been measured in deuterated DMSO; the values of 6,,, 6NHZand Scn, (in ppm) are given in Table 1. These chemical TABLE CHEMICAL
SHIFTS,
6, OF THE SUBSTITUTED
1 ACETANILIDES
Phenylureas
Substituent 4-Me0 4-Et0 4-Me 4-i-Pr 4-n-Bu 3-Me H 4-F 4-Cl 4-Br 3-NO2 4-NO2
s (Pi% 8.27 8.25 8.37 8.32 8.57 8.43 8.50 8.40 8.67 8.72 9.10 9.33
AND PHENYLUREAS
Acetanilides 6 NH2 (mm) 5.69 5.73 5.78 5.67 5.87 5.82 5.83 5.75 5.92 5.93 6.12 6.22
Substituent
6 (PE4
6 CH3 (w-d
4-OH 4-Me0 4-Et0 4-Me H 4-F 4-Cl 4-Br 4-I 4-NO2 4-CO,H 4-NH1
9.64 9.78 9.76 9.85 9.90 9.98 10.05 10.08 10.04 10.57 10.24 9.47
2.03 2.07 2.05 2.07 2.07 2.08 2.08 2.12 2.10 2.17 2.13 2.00
shifts have been plotted against a and a+ and the results are given in Table 2. The correlation with a is better than with a+, and this is not surprising since the nitrogen atom situated between the benzene ring and carbonyl group will prevent conjugation between an electron-donating group, such as MeO, and the carbon-oxygen double
232
GIFFNEY
AND
TABLE
O’CONNOR
2 aando+
CORRELATIONOFCHEMICALSHIFTS,~,WITHTHEHAMMETTSUBS~TUENTCONSTANTS
Ordinate, substrate series BNH, phenylureas
Abscissa”* *
Correlation coefficient
u u+
0.962 0.938 0.939 0.936 0.992 0.960 0.964 0.933
SNH2,phenylureas :+ CT CT+
&n, acetanilides 8cH3, acetanilides
z+
Slope = p
SD.,
Intercept
SD.,,,
0.92
0.08 0.08 0.05 0.04 0.03 0.04 0.09 0.008
8.51 8.59 5.83 5.87 9.93 10.04 2.08 2.10
0.03 0.04 0.02 0.02 0.01 0.02 0.003 0.005
0.71 0.45 0.37 0.73 0.46 0.11 0.07
a Values of o defined by D. H. McDaniel and H. C. Brown, J. Org. Chem. 23,420 (1958). b Values of u+ defined by H. C. Brown and Y. Okamoto, J. Amer. Chem. Sot. 80,4979 (1958).
bond. The plots of bnn and &n, vs crfor the phenylureas and the plots of a,, and 8eH3 vs o for the acetanilides are given in Fig. 1. For the phenylureas the chemical shifts, 8nH and 8nH2, are related to the reactivity parameter, (r, by Eq. [2] and [3], respectively: iSNH= 0.920 + 8.51,
PI
6NH,= 0.45a+ 5.83.
[31
The higher value of p ppm/6 for BNHcompared to 6,,, is to be expected since this proton is closer to the benzene ring than the protons ofthe-NH, group and will, therefore, be more sensitive to effects of varying the substituent. Combination of Eq. [2] and Eq. [3] gives Eq. [4], a relationship between SNH2and 6 NH) 6 NH2
= 0.496,,+1.66.
I41
For the acetanilides, the values of f&n and Ben, are related to rr by Eqs. [5] and [6], respectively :
Combination
BNH=0.73a+9.93,
I51
6‘=a = 0.1 lo + 2.08.
161
of these equations gives [7],
6Ch =&15&H + 0.59. [71 The results of Eqs. [5]-[7] are close to those reported by Bennett et al. (6), who correlated the chemical shifts of the protons in a series of p-substituted acetanilides with the Hammett cr constant. One can compare the values of p ppm/o obtained for the acetanilides with those of the phenylureas and it is obvious that the substituents in the benzene ring have a greater effect on the chemical shifts of the phenylureas, 8Nn and a,,, than on the
SHIFTS
IN
ACETANILIDES
AND
233
PHENYLUREAS
6.2
A B/ !! 6.0
2.1!
,:ti
5.6
0
2.11
00 2.0'
2
0
1
1 5.6
0
9.5 2.0 6
6 9.0
9 0 10.
0
cl
0
6.5
> 10.
9.
1 - 0.4
0.0
0.4
L
0.
FIG. 1. Hammett plots of (A) SNHZand (C) 6 NWof substituted phenylureas vs o and of(B) 6,,, and (D) SNH of substituted acetanilides vs 0.
chemical shifts of the acetanilides, 6,” and 6,” . This is to be expected, since the presence of two nitrogen atoms attached to the3carbonyl group in the phenylureas (compared to one in the acetanilides) means that there is an additional species available for mesomeric stabilization and this will result in a more efficient transmission of the substituent effects. EXPERIMENTAL
Acetanilides 4-Acetamidophenol (Koch-Light), 4-acetamidobenzoic acid (Aldrich), 4-fluoroacetanilide (Koch-Light), 4-aminoacetanilide (B.D.H) and 4-nitroacetanilide (B.D.H.) were recrystallized from aqueous ethanol and had melting points of 169, 260, 152, 162
234
GIFFNEY AND O’CONNOR
and 216°C respectively. Acetanilide (B.D.H.) was recrystallized from water (mp = 113.5-l 14.O”C). 4-Methyl-, 4-methoxy-, 4-ethoxy-, 4-chloro-, 4-bromo- and 4-iodoacetanilides were prepared by dissolving the substituted aniline in acetic anhydride and, to this solution, adding two drops of concentrated sulfuric acid. The acetanilide precipitated out on standing. The melting points of these derivatives were 148, 13 1,137,179,168 and 184°C respectively. A sample of acet-o-toluidide (mp = 111.5-112.5”C) was supplied by Dr. R. B. Moodie. Ureas Phenylurea (Fluka) and 3-methylphenylurea (Fluka) were recrystallized from ethanol (mp = 146-148 and 143°C respectively). 4-Methyl-, 4-methoxy-, 4-ethoxy-, 4-fluoro-,4-chloro-, 4-bromo-, 4-isopropyl- and 4-n-butylphenylureas were prepared using the method of Vogel (7). The appropriately substituted aniline was dissolved in acetic acid/water and to this solution was added a hot solution of sodium cyanate in water ; the phenylurea precipitated out. The products were recrystallized from aqueous ethanol and had mp’s of 185-187,168-169,173.5-175,190-191,213,226-227, 157-158.5 and 126-126.5”C, respectively. These values were obtained using a Reichert microscopic melting point apparatus. The meta- andpara-nitrophenylureas were prepared using the method of Wheeler and Walker (8): The substituted aniline (5 g) was dissolved in warm glacial acetic acid (25 ml) and to this was added powdered sodium cyanate (4 g). The hot solution was quickly filtered and poured into an excess of cold water. Both the meta- and paranitrophenylureas were recrystallized from hot aqueous acetic acid. Elemental analysis of m-NO,-phenylurea gave the following figures (expected values in parentheses) C 46.56 (46.41), H 4.03 (3.87), N 23.14 (23.20). 3-Nitrophenylurea had a mp of 189.5191°C (using a Reichert apparatus). With 4-nitrophenylurea it was necessary to use a Kofler graduated hot bench in order to obtain a clean melting point; this was measured at 227.5-228°C. NMR spectra were measured on a Varian T60 recording spectrophotometer. The computation of data was on a Burroughs B6700 computer. ACKNOWLEDGMENTS Technical assistance from Dr. J. W. Barnett and Mr. D. J. Calvert is gratefully acknowledged. REFERENCES 1. L. P. HAMMETT, (a) J. Amer. Chem. Sot. 59,96 (1937); (b) Trans. 2. H. C. BROWN AND Y. OKAMOTO, (a) J. Amer. Chem. Sot. 79,1913
Sot. 34, 156 (1938). (1957); (b) J. Amer. Chem. Sot.
Faraday
80,4979 (1958). W. F. REYNOLDS, AND S. I. MILLER, J. Org. Chem. 31,1872 (1966). 4. R. W. TAFT, E. PRICE,I. R. Fox, I. C. LEWIS, K. K. ANDERSEN, AND G. T. DAVIS, J. Amer. Chem. Sac. 85,709 (1963). “The Theory of Organic Chemistry,” Chap. VI, Prentice-Hall, 5. G. E. BRANCH AND M. CALVIN, New York, 1941. 6. J. BENNETT, M. DELMAS, AND J. C. MAIRE, Org. Mugn. Resonance 1, 319 (1969). 7. A. I. VOGEL, “Elementary Practical Organic Chemistry,” p. 274, Longmans, New York, 1966. 8. A. S. WHEELER AND T. T. WALKER, J. Amer. Chem. Sot. 47,2973 (1925). 3. S. H. MARCUS,
OF MAGNETIC
RESONANCE
l&230-234
(1975)
SubstituentEffects on the NMR Spectraof Substituted Acetauilidesand Phenylureas* C.
JANET
GIFFNEY
AND CHARMIAN
Chemistry Department, University of’duckland,
J. O’CONNOR
Privafe Bag, Auckland, New Zealand
Received October 2, 1974 The substituent effects on the NMR spectra (&, and &n,) of phenylureas and (SNH and BCH1)of acetanilides have been reported. The chemical shifts correlate well with Hammett sigma values. INTRODUCTION
In the 1930’s Hammett (I) considered the effects of substituents (R) on the reactivity of a side chain (Y) in compounds of the type
A quantitative
relationship log,, k = log,, k” + ap
was proposed, where k is either a rate constant (k) or an equilibrium constant (K) for reactions of a meta- orpara-substituted benzene derivative, and k” is the corresponding value for the unsubstituted compound. 0 is the substituent constant that is characteristic of the nature and position of the substituent and is independent of the reaction; p is the reaction constant and is determined by the conditions under which the reaction takes place and the nature of the side chain Y. The need for dual (Tvalues for some substituents was first recognized by Hammett (la) who found it necessary to assign two different substituent constants to the nitro group in thepara position. In general, for side-chain reactions involving the formation of an electron-deficient reaction center in direct conjugation with the benzene nucleus, electron acceptor puru substituents (+R) have enhanced 0 values termed C+ constants and these have been defined by Brown and Okamoto (2). The Hammett equation has frequently been used to find relationships between the chemical structure of a compound, defined by reactivity parameters, and its physicochemical properties. In particular, attempts have been made to correlate the equation with the spectral characteristics of the ground-state molecules. These ground-state molecules are in a state of dynamic equilibrium, undergoing rotational and vibrational transitions which require somewhat lower energies than are usually necessary for bondmaking and -breaking processes in reactions. Using the Hammett equation, Marcus * Abstracted from a thesis submitted by C. J. Giffney (nee Hyland) for the Ph.D. degree from the University of Auckland. 230 Copyright 0 1975 by Academic Press, Inc. All rights of reproduction Printed in Great Britain
in any form
reserved.
SHIFTS
IN
ACETANILIDES
AND
231
PHENYLUREAS
et al. (3) studied the transmission of electronic effects through Tin compounds of the type RC6H4T-H, where R is the substituent, C6H4T is the transmitting group and H is the reaction site. As a substituent is moved down a chain from a terminal proton the effect of R on the chemical shift, 6, of the proton diminishes and, if the chemical shift of the proton is plotted against 0, the resultant value of p characterizes T as well as the conditions of the NMR measurements. Marcus et al. (3) found that the minimum attenuation factor per connecting atom is ca. 2-3 in carbon tetrachloride; for T = 0, 1 and 2 atoms in a chain, the “standard” p values in cps/a are ca. 36, 13 and 7, with a levelling off when T > 3. A similar fall-off factor was observed by Taft et al. (4) in their study of the fluorine NMR shielding of meta- andpara-substituted fluorobenzenes and it is also closely similar to that observed in the reactivities of such compounds (5). When T contains oxygen, nitrogen, a carbon-carbon double or triple bond, or in general, groups that conjugate readily with the aromatic ring, then the sensitivity of the chemical shift of the proton to remote substituents is magnified.
RESULTS
AND
DISCUSSION
In the present study the NMR spectra of the substituted phenylureas (Y= NHCONH,) and acetanilides (Y= NHCOCH,) have been measured in deuterated DMSO; the values of 6,,, 6NHZand Scn, (in ppm) are given in Table 1. These chemical TABLE CHEMICAL
SHIFTS,
6, OF THE SUBSTITUTED
1 ACETANILIDES
Phenylureas
Substituent 4-Me0 4-Et0 4-Me 4-i-Pr 4-n-Bu 3-Me H 4-F 4-Cl 4-Br 3-NO2 4-NO2
s (Pi% 8.27 8.25 8.37 8.32 8.57 8.43 8.50 8.40 8.67 8.72 9.10 9.33
AND PHENYLUREAS
Acetanilides 6 NH2 (mm) 5.69 5.73 5.78 5.67 5.87 5.82 5.83 5.75 5.92 5.93 6.12 6.22
Substituent
6 (PE4
6 CH3 (w-d
4-OH 4-Me0 4-Et0 4-Me H 4-F 4-Cl 4-Br 4-I 4-NO2 4-CO,H 4-NH1
9.64 9.78 9.76 9.85 9.90 9.98 10.05 10.08 10.04 10.57 10.24 9.47
2.03 2.07 2.05 2.07 2.07 2.08 2.08 2.12 2.10 2.17 2.13 2.00
shifts have been plotted against a and a+ and the results are given in Table 2. The correlation with a is better than with a+, and this is not surprising since the nitrogen atom situated between the benzene ring and carbonyl group will prevent conjugation between an electron-donating group, such as MeO, and the carbon-oxygen double
232
GIFFNEY
AND
TABLE
O’CONNOR
2 aando+
CORRELATIONOFCHEMICALSHIFTS,~,WITHTHEHAMMETTSUBS~TUENTCONSTANTS
Ordinate, substrate series BNH, phenylureas
Abscissa”* *
Correlation coefficient
u u+
0.962 0.938 0.939 0.936 0.992 0.960 0.964 0.933
SNH2,phenylureas :+ CT CT+
&n, acetanilides 8cH3, acetanilides
z+
Slope = p
SD.,
Intercept
SD.,,,
0.92
0.08 0.08 0.05 0.04 0.03 0.04 0.09 0.008
8.51 8.59 5.83 5.87 9.93 10.04 2.08 2.10
0.03 0.04 0.02 0.02 0.01 0.02 0.003 0.005
0.71 0.45 0.37 0.73 0.46 0.11 0.07
a Values of o defined by D. H. McDaniel and H. C. Brown, J. Org. Chem. 23,420 (1958). b Values of u+ defined by H. C. Brown and Y. Okamoto, J. Amer. Chem. Sot. 80,4979 (1958).
bond. The plots of bnn and &n, vs crfor the phenylureas and the plots of a,, and 8eH3 vs o for the acetanilides are given in Fig. 1. For the phenylureas the chemical shifts, 8nH and 8nH2, are related to the reactivity parameter, (r, by Eq. [2] and [3], respectively: iSNH= 0.920 + 8.51,
PI
6NH,= 0.45a+ 5.83.
[31
The higher value of p ppm/6 for BNHcompared to 6,,, is to be expected since this proton is closer to the benzene ring than the protons ofthe-NH, group and will, therefore, be more sensitive to effects of varying the substituent. Combination of Eq. [2] and Eq. [3] gives Eq. [4], a relationship between SNH2and 6 NH) 6 NH2
= 0.496,,+1.66.
I41
For the acetanilides, the values of f&n and Ben, are related to rr by Eqs. [5] and [6], respectively :
Combination
BNH=0.73a+9.93,
I51
6‘=a = 0.1 lo + 2.08.
161
of these equations gives [7],
6Ch =&15&H + 0.59. [71 The results of Eqs. [5]-[7] are close to those reported by Bennett et al. (6), who correlated the chemical shifts of the protons in a series of p-substituted acetanilides with the Hammett cr constant. One can compare the values of p ppm/o obtained for the acetanilides with those of the phenylureas and it is obvious that the substituents in the benzene ring have a greater effect on the chemical shifts of the phenylureas, 8Nn and a,,, than on the
SHIFTS
IN
ACETANILIDES
AND
233
PHENYLUREAS
6.2
A B/ !! 6.0
2.1!
,:ti
5.6
0
2.11
00 2.0'
2
0
1
1 5.6
0
9.5 2.0 6
6 9.0
9 0 10.
0
cl
0
6.5
> 10.
9.
1 - 0.4
0.0
0.4
L
0.
FIG. 1. Hammett plots of (A) SNHZand (C) 6 NWof substituted phenylureas vs o and of(B) 6,,, and (D) SNH of substituted acetanilides vs 0.
chemical shifts of the acetanilides, 6,” and 6,” . This is to be expected, since the presence of two nitrogen atoms attached to the3carbonyl group in the phenylureas (compared to one in the acetanilides) means that there is an additional species available for mesomeric stabilization and this will result in a more efficient transmission of the substituent effects. EXPERIMENTAL
Acetanilides 4-Acetamidophenol (Koch-Light), 4-acetamidobenzoic acid (Aldrich), 4-fluoroacetanilide (Koch-Light), 4-aminoacetanilide (B.D.H) and 4-nitroacetanilide (B.D.H.) were recrystallized from aqueous ethanol and had melting points of 169, 260, 152, 162
234
GIFFNEY AND O’CONNOR
and 216°C respectively. Acetanilide (B.D.H.) was recrystallized from water (mp = 113.5-l 14.O”C). 4-Methyl-, 4-methoxy-, 4-ethoxy-, 4-chloro-, 4-bromo- and 4-iodoacetanilides were prepared by dissolving the substituted aniline in acetic anhydride and, to this solution, adding two drops of concentrated sulfuric acid. The acetanilide precipitated out on standing. The melting points of these derivatives were 148, 13 1,137,179,168 and 184°C respectively. A sample of acet-o-toluidide (mp = 111.5-112.5”C) was supplied by Dr. R. B. Moodie. Ureas Phenylurea (Fluka) and 3-methylphenylurea (Fluka) were recrystallized from ethanol (mp = 146-148 and 143°C respectively). 4-Methyl-, 4-methoxy-, 4-ethoxy-, 4-fluoro-,4-chloro-, 4-bromo-, 4-isopropyl- and 4-n-butylphenylureas were prepared using the method of Vogel (7). The appropriately substituted aniline was dissolved in acetic acid/water and to this solution was added a hot solution of sodium cyanate in water ; the phenylurea precipitated out. The products were recrystallized from aqueous ethanol and had mp’s of 185-187,168-169,173.5-175,190-191,213,226-227, 157-158.5 and 126-126.5”C, respectively. These values were obtained using a Reichert microscopic melting point apparatus. The meta- andpara-nitrophenylureas were prepared using the method of Wheeler and Walker (8): The substituted aniline (5 g) was dissolved in warm glacial acetic acid (25 ml) and to this was added powdered sodium cyanate (4 g). The hot solution was quickly filtered and poured into an excess of cold water. Both the meta- and paranitrophenylureas were recrystallized from hot aqueous acetic acid. Elemental analysis of m-NO,-phenylurea gave the following figures (expected values in parentheses) C 46.56 (46.41), H 4.03 (3.87), N 23.14 (23.20). 3-Nitrophenylurea had a mp of 189.5191°C (using a Reichert apparatus). With 4-nitrophenylurea it was necessary to use a Kofler graduated hot bench in order to obtain a clean melting point; this was measured at 227.5-228°C. NMR spectra were measured on a Varian T60 recording spectrophotometer. The computation of data was on a Burroughs B6700 computer. ACKNOWLEDGMENTS Technical assistance from Dr. J. W. Barnett and Mr. D. J. Calvert is gratefully acknowledged. REFERENCES 1. L. P. HAMMETT, (a) J. Amer. Chem. Sot. 59,96 (1937); (b) Trans. 2. H. C. BROWN AND Y. OKAMOTO, (a) J. Amer. Chem. Sot. 79,1913
Sot. 34, 156 (1938). (1957); (b) J. Amer. Chem. Sot.
Faraday
80,4979 (1958). W. F. REYNOLDS, AND S. I. MILLER, J. Org. Chem. 31,1872 (1966). 4. R. W. TAFT, E. PRICE,I. R. Fox, I. C. LEWIS, K. K. ANDERSEN, AND G. T. DAVIS, J. Amer. Chem. Sac. 85,709 (1963). “The Theory of Organic Chemistry,” Chap. VI, Prentice-Hall, 5. G. E. BRANCH AND M. CALVIN, New York, 1941. 6. J. BENNETT, M. DELMAS, AND J. C. MAIRE, Org. Mugn. Resonance 1, 319 (1969). 7. A. I. VOGEL, “Elementary Practical Organic Chemistry,” p. 274, Longmans, New York, 1966. 8. A. S. WHEELER AND T. T. WALKER, J. Amer. Chem. Sot. 47,2973 (1925). 3. S. H. MARCUS,