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Proton magnetic resonance spectra of pyrazole derivatives
Spectrochimica
Acta,
1964,
Vol.
20, pp.
1269 to 1273.
Per$amon PressLtd. Printedin Northern Ireland
Proton magnetic resonance spectra of pyrazole derivatives I. L. FINAR
and E. F. MOONEY
Northern Polytechic,
London, N.7
(Received 17 January 1964) Abstract-The chemical shifts of the 3, 4 and 5 ring hydrogen nuclei in pyrazoles fall into characteristic ranges, as do the 3 and 5 methyl-group chemical shifts. The range of chemical shift observed and the movement to low field on protonation permits the location of substituent groups to be made; the use of NMR spectra in differentiating pyrazole isomers would appear to be very promising. The very low field resonance obtained with 1-unsubstituted pyrazoles is shown t,o be due to the N-H group which is responsible for dimerisation of these compounds. INTRODUCTIVE
the exception of one short note [l] no nuclear magnetic studies on pyrazole derivatives have been made. It is here intended to give a brief account of the proton resonance spectra and to give chemical shift ranges for the 1,3,4 and 5 protons in pyrazole and for methyl groups in different positions; such ranges, and observations of spin-spin multiplicity, appear to be promising in leading to an unambiguous method for determining the position of substituents. From the little that has been published on the infra-red spectra of pyrazoles [Z] and from our own unpublished work, it is quite clear that the ring C-H deformation modes cannot be used, as is the case for benzene derivatives [3], to determine the position of substituent groups in the pyrazole ring. The NMR spectra have been recorded in both an “inert” solvent, such as carbon tetrachloride or chloroform-d, and in an acidic solvent, namely trifluoroacetic acid. The latter solvent was primarily chosen to examine the protonated pyrazole nucleus but it is also invaluable in the examination of pyrazoles which are insoluble in the normal solvents. The use of the acidic solvent also assists in the unambiguous identification of the low field 3-H and 5-H resonance, which are partly obscured by, or are very close to, the aromatic ring proton resonance (e.g. in 1-phenylpyrazole) when recorded in carbon tetrachloride. It has also been observed that the long-range couplings vary from one solvent to another. It is not intended to deal with this here since double resonance experiments will be dealt with elsewhere.
WITH
EXPERIMENTAL
The spectra have been recorded on a Perkin-Elmer NMR spectrometer operating at 40 MC/S. Spinning tubes of 0.180 + 0*0005 in o.d. have been used and solutions containing lo-20 ‘A of the pyrazole derivatives used. [l] L. FOWDEN, F. F. NOE, J. H. RIDD and R. F. M. WHITE, Proc. Chem. Sot. 31 (1959). [2] G. ZERBI and C. ALBERTI, Spectrochim. Acta 18, 407 (1962); 19, 1261 (1963). [3] R. R. RANDLE and D. H. WHIFFEN, MoZecuEarSpectroscopy, p. 111, Institute of Petroleum, London (1955). 1269
1270
I. L. FINAR and E. F. MOONEY
Table 1. Chemical shifts of pyrazole derivatives in 7 units; low field C,H,,.
R, = R, = R, = R, = Ht R, = R, = Ht R, = R, = Me R. = Met R;
=
R,
L R, =
those in parenthesis are in ppm to
4
4
R4
K 5
-3.65(12.21) -2.91(11.49)
2.4S6.11) 7.78iO.Slj
3.75f4.801 4.35i4.24j
2.45f6.111 7.78iO.Slj
6.19(1.38)
2.70(5+37)
3.86(4.71)
2.64(5.93)
2.45(6.12)
2.82(5.75)
3.68(4.89)
2.20(6.35)
7.70(0.90)
3+X9(4.70)
2.27(6.32)
2.61(5.98)
2.61(5.98)
3.91(4.6&J)
7.71(0.87)
2.64(5.95)
7.78(0.79)
4.12(4.46)
7,75(0.83)
2.3 -
2.8(%3 -
6.3)
%16(6.41)
1.7 -
2.5(6.1 -
6.9)
1.46(7.10)
H
R, = Pht R, = R, = R5 = H R, = Ph, R, = Met R, = R, = H R, = Ph, R, = Met R, = R, = H R, = Ph, R, = Ht R, = R, = Me R, = Ph, R, = Brt R, = R, = H R, = 3.NO,-C,H,*$ R, = R, = R, = H R, = Ph, R, = Me*S R, = NO,, R, = H R,=Ph, R,=Me*$ R, = R, = Br R, = 3-NH,-- -.C,H,R, = Me R, = Ph, R, = H§$*
2.4 -
3.0(6.1 -
5.0)
2.50(6.06)
1.76(6.80)
2.55(6.01)
7.68(0%3)
2.77(5.79)
7.67(0.89)
,
2.1tq6.41) 3.49(5.07)
3.75(4.81)
* Positions of substituents in the derivatives unknown to one of US at the time the spectra were interpreted. t Ccl, solution. $ CDCl, solution. 5 NH, resonance at 6.38 7
Table
2. Chemical
shifts
of pyrazole
derivatives
cyclohexane
R, R, R, R, R, R, R, R,
= = = = = = = =
R, = R, = R, = H R, = H R, = Me MB R, = R, = H CH,OH R, = R, = H
tl,
=
R, = R, = H Ph, R, = Me R, = H Ph, R, = Me R, = H Ph, R, = H R, = Me Ph, R, = Br R, = H 3.NOzpC,H,* R, = R, = H Ph, R, = Me* NO,, R, = H Ph, R3 = Me* R, = Br 7 3.NH,pC,H4* Mo Ph, R, = H 2: 4 diNO,-CGH,* Mr. R. = Ph. R. = H
R, = R, = R, = R, = R, = R, = 11, = R, = R, = R, = R, = R, = R, = R, = R, = R, = R, = R, = R. =
3.1 -- 3.6 (5.46 - 4.96)
k;JrJR3 N
I RI acid,
in ppm
to low field of
standard. R,
R4
R,
6.81
5.51
6.81
1.06
4.97
1.06
2.87
6.72
5.43
6.78
4+2t
6.85
5.46
6.83
6.27
6.98
5.65
6.9%
6.24
1.23
5.40
6.83
6.29
6.84
5.43
1.0;
6.25
0.97
5.16
1.1”
6.26
6.98
RI
-
in trifluoroacetic
as internal
1.52(7.04) 7.36(1.20)
Ph
* See Table 1.
7.16
6.98 5.78
7.28
6.21
7.26
1.28
6.20
1.20
6.00
1.25
5.46
6.36
6.6-7.7
1.33
5.58
5.!)9
Proton magnetic resonance spectra of pyrazole derivatives
1271
RESULTS The proton chemical shifts for the pyrazole derivatives examined in carbon tetrachloride, chloroform-d, and trifluoroacetic acid are shown in Tables 1 and 2. Since cyclohexane was used as the internal standard in trifluoroacetic acid, the chemical shifts recorded in both of the first two solvents are quoted in ppm to low field of cyclohexane and in the conventional tau scale using tetramethylsilane as internal standard. DISCUSSION Pyrazole. The most striking feature of the proton resonance spectrum of this compound is the very low field l-NH resonance (13.65 ppm to low field of T.M.S.), which implies that the N-H bond is highly polarised, since this is the region in which the proton resonance of sulphuric and trifluoroacetic acids occur. The spectrum also clearly shows that the 3-H and 5-H are equivalent and this, considered with the low field l-NH resonance, is consistent with the dimer (I) or trimer form of the pyrazole ; infra-red studies have previously shown the predominance of dimertrimer formation [4]. C-H
H-C-
(1)
i/N\C_H H-C-
II
II
C-H
3,5-Dimethylpyrazole. This compound also shows the presence of a very low field resonance due to the bonded l-NH group ; the resonance is to slightly higher field (11.49 ppm to low field T.M.S.) than that found in pyrazole which, in agreement with previous data [5], shows that the basic strength of pyrazole is less than 3,5Here again, due to association through hydrogen-bonding, the dimethylpyrazole. 3- and 5-methyl groups are magnetically equivalent, and remain equivalent. in trifluoroacetic acid solution. 1- Phen yip yrazoles . In carbon tetrachloride solution the A,B,C spectrum of the phenyl group makes the assignment of the 3- and 5- proton resonance a little uncertain since these occur in a similar region to that of the aromatic protons. However, in trifluoroacetic acid solution, the proton resonance of the phenyl group is simplified, in many cases essentially corresponding to an A, spectrum. Consequently comparison of the spectra in two different solvents assists in the identification of the low field 3- and 5- proton resonance. [4] D. M. W. ANDERSON, J. L. DUNCAN and F. J. C. ROSSOTIT,J.Chern.Sot. 140 and 4201 (1961). [Yj] G. DEDICHEN, Ber., 39, 1831 (1906).
1272
I.
L. FINAR and E. F. MOONEY
In all the I-phenylpyrazoles examined, where there is no 5-substituent, the B-proton resonance occurs at 2.22 f 096 r, that is, at lower field than found in I-methylpyrazole (2.67 T) or in pyrazole itself (245 T); this suggests that there is some de-activation of the 5-position by the 1-phenyl group. In trifluoroacetic acid the chemical shift of the 5-proton is more consistent and occurs in the range 6.9 f 0.1 ppm. The most significant feature is that the 4-proton resonance is to higher field than that of either the 3- or 5- protons, which implies that the electron density at the Table 3. Shifts to low field on protonation of pyrazole nucleus, in ppm Shift of 3-H
Shift of 4-H
Shift of 5-H
Pyrazole 1 -Ph-pyrazole
0.70 1.23
Pyrazole 3,5-Mez-pyrazole
0.71 0.73
Pyrazole 1 -Ph-pyrazole
I-Ph-5-Me-pyrazole 4-Br-1-Ph-pyrazole I-(3-nitrophenyl)-
0.86 0.57 0.06
1 -Ph-pyrazole 1-Ph-3-Me-pyrazole I-Ph-5-Me-pyrazole
0.76 0.70 0.75
1-Ph-3-Me-pyrazole 4-Br-1 -Ph-pyrazole I-(3-nitrophenyl)-
1-Ph-3,5-Me,-pyrazole 1-( 3-nitrophenyl)pyrazole 1-(3-aminophenyl)-3methyl-5-phenyl-pyrazole
0.70 0.7 1
pyrazole l-Ph-4-NO,-5-Mepyrazole
0.46
pyrazole
0.70 0.61 0.51 0.57 0.24
0.65
4-position is considerably higher than that of either the 3- or 5-positions ; this is consistent with the fact that electrophilic substitution occurs in the 4-position [6]. The shifts to low field which occur on protonation of the pyrazole nucleus are shown in Table 3. The shift of the 4-proton to low field is remarkably constant, namely 0.73 & 0.03 ppm, whereas the corresponding shift of the 3-proton resonance is equal to, or considerable larger than, the shift of the B-proton resonance. If the high-field of the 4-proton resonance is considered together with the relatively smaller effect on the 5-proton resonance on protonation, then the structure of pyrazole is best represented by (III), there being smaller contribution from (II), (IV) and (V). v
G,N: I
R (II)
Application We groups methyl tion of
+--•f -:ha,l. k (III)
t-f .
-: G=j.A. I
+
&I&N:
R
k
(IV)
(V)
to structural determination
have used the above observations to establish the position of substituent in the pyrazole nucleus. It is also possible to determine the position of substituents by considering the shift which occurs on protonation. Applicathis work is demonstrated in Tables 1 and 2 as the positions of substituents
[6] T. L. JACOBS, Heterocyclic Coq~oun&, London (1957).
p. 45, Vol. 5, (Ed. R. C. ELDERFIELD) John Wiley,
Proton magnetic resonancespectra of pyrazole derivatives in the derivatives
1273
marked (*) were unknown to one of us at the time the spectra
were interpreted.
CONCLUSION Although this work has been confined to pyrazoles having the following substitaminophenyl and bromophenyl), uent groups-phenyl, aryl (i.e. nitrophenyl, nitro, bromo and methyl-it is evident that NMR spectroscopy has considerable possibilities in discrimination between possible isomers. AcknowZedgeme&--Oneof us (E. F. M.) gratefully acknowledgesa grant from the Department of Scientificand Industrial Research to purchasethe Perkin-Elmer NMR Spectrometer.
Acta,
1964,
Vol.
20, pp.
1269 to 1273.
Per$amon PressLtd. Printedin Northern Ireland
Proton magnetic resonance spectra of pyrazole derivatives I. L. FINAR
and E. F. MOONEY
Northern Polytechic,
London, N.7
(Received 17 January 1964) Abstract-The chemical shifts of the 3, 4 and 5 ring hydrogen nuclei in pyrazoles fall into characteristic ranges, as do the 3 and 5 methyl-group chemical shifts. The range of chemical shift observed and the movement to low field on protonation permits the location of substituent groups to be made; the use of NMR spectra in differentiating pyrazole isomers would appear to be very promising. The very low field resonance obtained with 1-unsubstituted pyrazoles is shown t,o be due to the N-H group which is responsible for dimerisation of these compounds. INTRODUCTIVE
the exception of one short note [l] no nuclear magnetic studies on pyrazole derivatives have been made. It is here intended to give a brief account of the proton resonance spectra and to give chemical shift ranges for the 1,3,4 and 5 protons in pyrazole and for methyl groups in different positions; such ranges, and observations of spin-spin multiplicity, appear to be promising in leading to an unambiguous method for determining the position of substituents. From the little that has been published on the infra-red spectra of pyrazoles [Z] and from our own unpublished work, it is quite clear that the ring C-H deformation modes cannot be used, as is the case for benzene derivatives [3], to determine the position of substituent groups in the pyrazole ring. The NMR spectra have been recorded in both an “inert” solvent, such as carbon tetrachloride or chloroform-d, and in an acidic solvent, namely trifluoroacetic acid. The latter solvent was primarily chosen to examine the protonated pyrazole nucleus but it is also invaluable in the examination of pyrazoles which are insoluble in the normal solvents. The use of the acidic solvent also assists in the unambiguous identification of the low field 3-H and 5-H resonance, which are partly obscured by, or are very close to, the aromatic ring proton resonance (e.g. in 1-phenylpyrazole) when recorded in carbon tetrachloride. It has also been observed that the long-range couplings vary from one solvent to another. It is not intended to deal with this here since double resonance experiments will be dealt with elsewhere.
WITH
EXPERIMENTAL
The spectra have been recorded on a Perkin-Elmer NMR spectrometer operating at 40 MC/S. Spinning tubes of 0.180 + 0*0005 in o.d. have been used and solutions containing lo-20 ‘A of the pyrazole derivatives used. [l] L. FOWDEN, F. F. NOE, J. H. RIDD and R. F. M. WHITE, Proc. Chem. Sot. 31 (1959). [2] G. ZERBI and C. ALBERTI, Spectrochim. Acta 18, 407 (1962); 19, 1261 (1963). [3] R. R. RANDLE and D. H. WHIFFEN, MoZecuEarSpectroscopy, p. 111, Institute of Petroleum, London (1955). 1269
1270
I. L. FINAR and E. F. MOONEY
Table 1. Chemical shifts of pyrazole derivatives in 7 units; low field C,H,,.
R, = R, = R, = R, = Ht R, = R, = Ht R, = R, = Me R. = Met R;
=
R,
L R, =
those in parenthesis are in ppm to
4
4
R4
K 5
-3.65(12.21) -2.91(11.49)
2.4S6.11) 7.78iO.Slj
3.75f4.801 4.35i4.24j
2.45f6.111 7.78iO.Slj
6.19(1.38)
2.70(5+37)
3.86(4.71)
2.64(5.93)
2.45(6.12)
2.82(5.75)
3.68(4.89)
2.20(6.35)
7.70(0.90)
3+X9(4.70)
2.27(6.32)
2.61(5.98)
2.61(5.98)
3.91(4.6&J)
7.71(0.87)
2.64(5.95)
7.78(0.79)
4.12(4.46)
7,75(0.83)
2.3 -
2.8(%3 -
6.3)
%16(6.41)
1.7 -
2.5(6.1 -
6.9)
1.46(7.10)
H
R, = Pht R, = R, = R5 = H R, = Ph, R, = Met R, = R, = H R, = Ph, R, = Met R, = R, = H R, = Ph, R, = Ht R, = R, = Me R, = Ph, R, = Brt R, = R, = H R, = 3.NO,-C,H,*$ R, = R, = R, = H R, = Ph, R, = Me*S R, = NO,, R, = H R,=Ph, R,=Me*$ R, = R, = Br R, = 3-NH,-- -.C,H,R, = Me R, = Ph, R, = H§$*
2.4 -
3.0(6.1 -
5.0)
2.50(6.06)
1.76(6.80)
2.55(6.01)
7.68(0%3)
2.77(5.79)
7.67(0.89)
,
2.1tq6.41) 3.49(5.07)
3.75(4.81)
* Positions of substituents in the derivatives unknown to one of US at the time the spectra were interpreted. t Ccl, solution. $ CDCl, solution. 5 NH, resonance at 6.38 7
Table
2. Chemical
shifts
of pyrazole
derivatives
cyclohexane
R, R, R, R, R, R, R, R,
= = = = = = = =
R, = R, = R, = H R, = H R, = Me MB R, = R, = H CH,OH R, = R, = H
tl,
=
R, = R, = H Ph, R, = Me R, = H Ph, R, = Me R, = H Ph, R, = H R, = Me Ph, R, = Br R, = H 3.NOzpC,H,* R, = R, = H Ph, R, = Me* NO,, R, = H Ph, R3 = Me* R, = Br 7 3.NH,pC,H4* Mo Ph, R, = H 2: 4 diNO,-CGH,* Mr. R. = Ph. R. = H
R, = R, = R, = R, = R, = R, = 11, = R, = R, = R, = R, = R, = R, = R, = R, = R, = R, = R, = R. =
3.1 -- 3.6 (5.46 - 4.96)
k;JrJR3 N
I RI acid,
in ppm
to low field of
standard. R,
R4
R,
6.81
5.51
6.81
1.06
4.97
1.06
2.87
6.72
5.43
6.78
4+2t
6.85
5.46
6.83
6.27
6.98
5.65
6.9%
6.24
1.23
5.40
6.83
6.29
6.84
5.43
1.0;
6.25
0.97
5.16
1.1”
6.26
6.98
RI
-
in trifluoroacetic
as internal
1.52(7.04) 7.36(1.20)
Ph
* See Table 1.
7.16
6.98 5.78
7.28
6.21
7.26
1.28
6.20
1.20
6.00
1.25
5.46
6.36
6.6-7.7
1.33
5.58
5.!)9
Proton magnetic resonance spectra of pyrazole derivatives
1271
RESULTS The proton chemical shifts for the pyrazole derivatives examined in carbon tetrachloride, chloroform-d, and trifluoroacetic acid are shown in Tables 1 and 2. Since cyclohexane was used as the internal standard in trifluoroacetic acid, the chemical shifts recorded in both of the first two solvents are quoted in ppm to low field of cyclohexane and in the conventional tau scale using tetramethylsilane as internal standard. DISCUSSION Pyrazole. The most striking feature of the proton resonance spectrum of this compound is the very low field l-NH resonance (13.65 ppm to low field of T.M.S.), which implies that the N-H bond is highly polarised, since this is the region in which the proton resonance of sulphuric and trifluoroacetic acids occur. The spectrum also clearly shows that the 3-H and 5-H are equivalent and this, considered with the low field l-NH resonance, is consistent with the dimer (I) or trimer form of the pyrazole ; infra-red studies have previously shown the predominance of dimertrimer formation [4]. C-H
H-C-
(1)
i/N\C_H H-C-
II
II
C-H
3,5-Dimethylpyrazole. This compound also shows the presence of a very low field resonance due to the bonded l-NH group ; the resonance is to slightly higher field (11.49 ppm to low field T.M.S.) than that found in pyrazole which, in agreement with previous data [5], shows that the basic strength of pyrazole is less than 3,5Here again, due to association through hydrogen-bonding, the dimethylpyrazole. 3- and 5-methyl groups are magnetically equivalent, and remain equivalent. in trifluoroacetic acid solution. 1- Phen yip yrazoles . In carbon tetrachloride solution the A,B,C spectrum of the phenyl group makes the assignment of the 3- and 5- proton resonance a little uncertain since these occur in a similar region to that of the aromatic protons. However, in trifluoroacetic acid solution, the proton resonance of the phenyl group is simplified, in many cases essentially corresponding to an A, spectrum. Consequently comparison of the spectra in two different solvents assists in the identification of the low field 3- and 5- proton resonance. [4] D. M. W. ANDERSON, J. L. DUNCAN and F. J. C. ROSSOTIT,J.Chern.Sot. 140 and 4201 (1961). [Yj] G. DEDICHEN, Ber., 39, 1831 (1906).
1272
I.
L. FINAR and E. F. MOONEY
In all the I-phenylpyrazoles examined, where there is no 5-substituent, the B-proton resonance occurs at 2.22 f 096 r, that is, at lower field than found in I-methylpyrazole (2.67 T) or in pyrazole itself (245 T); this suggests that there is some de-activation of the 5-position by the 1-phenyl group. In trifluoroacetic acid the chemical shift of the 5-proton is more consistent and occurs in the range 6.9 f 0.1 ppm. The most significant feature is that the 4-proton resonance is to higher field than that of either the 3- or 5- protons, which implies that the electron density at the Table 3. Shifts to low field on protonation of pyrazole nucleus, in ppm Shift of 3-H
Shift of 4-H
Shift of 5-H
Pyrazole 1 -Ph-pyrazole
0.70 1.23
Pyrazole 3,5-Mez-pyrazole
0.71 0.73
Pyrazole 1 -Ph-pyrazole
I-Ph-5-Me-pyrazole 4-Br-1-Ph-pyrazole I-(3-nitrophenyl)-
0.86 0.57 0.06
1 -Ph-pyrazole 1-Ph-3-Me-pyrazole I-Ph-5-Me-pyrazole
0.76 0.70 0.75
1-Ph-3-Me-pyrazole 4-Br-1 -Ph-pyrazole I-(3-nitrophenyl)-
1-Ph-3,5-Me,-pyrazole 1-( 3-nitrophenyl)pyrazole 1-(3-aminophenyl)-3methyl-5-phenyl-pyrazole
0.70 0.7 1
pyrazole l-Ph-4-NO,-5-Mepyrazole
0.46
pyrazole
0.70 0.61 0.51 0.57 0.24
0.65
4-position is considerably higher than that of either the 3- or 5-positions ; this is consistent with the fact that electrophilic substitution occurs in the 4-position [6]. The shifts to low field which occur on protonation of the pyrazole nucleus are shown in Table 3. The shift of the 4-proton to low field is remarkably constant, namely 0.73 & 0.03 ppm, whereas the corresponding shift of the 3-proton resonance is equal to, or considerable larger than, the shift of the B-proton resonance. If the high-field of the 4-proton resonance is considered together with the relatively smaller effect on the 5-proton resonance on protonation, then the structure of pyrazole is best represented by (III), there being smaller contribution from (II), (IV) and (V). v
G,N: I
R (II)
Application We groups methyl tion of
+--•f -:ha,l. k (III)
t-f .
-: G=j.A. I
+
&I&N:
R
k
(IV)
(V)
to structural determination
have used the above observations to establish the position of substituent in the pyrazole nucleus. It is also possible to determine the position of substituents by considering the shift which occurs on protonation. Applicathis work is demonstrated in Tables 1 and 2 as the positions of substituents
[6] T. L. JACOBS, Heterocyclic Coq~oun&, London (1957).
p. 45, Vol. 5, (Ed. R. C. ELDERFIELD) John Wiley,
Proton magnetic resonancespectra of pyrazole derivatives in the derivatives
1273
marked (*) were unknown to one of us at the time the spectra
were interpreted.
CONCLUSION Although this work has been confined to pyrazoles having the following substitaminophenyl and bromophenyl), uent groups-phenyl, aryl (i.e. nitrophenyl, nitro, bromo and methyl-it is evident that NMR spectroscopy has considerable possibilities in discrimination between possible isomers. AcknowZedgeme&--Oneof us (E. F. M.) gratefully acknowledgesa grant from the Department of Scientificand Industrial Research to purchasethe Perkin-Elmer NMR Spectrometer.