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Fluorination of organic compounds and long-range coupling constants in carbonyl fluorides
JOURNAL
OF MAGNETIC
RESONANCE
7, 177-183 (1972)
Fluorination of Organic Compoundsand Long-Range Coupling Constantsin Carbonyl Fluorides KJELD SCHAUMBLJRG Department of Chemistry, University of Copenhagen, Denmark Presented at the Fourth International Symposium on Magnetic Resonance, Israel, August, 1971 Replacement of a hydroxyl group by fluorine through the use of 2-chloro-1,1,2trifluorotriethylamine is described. Results for chemical shifts and coupling constants in carbonyl fluorides derived from acids by this method are presented. INTRODUCTION
The present contribution is concerned with the application of a simple method of introducing fluorine as a substituent in organic compounds, replacing an {OH} group in the compound. In general {OH} is an undesirable functional group since it rarely gives rise to measurable spin-spin coupling to the other part of the compound. This is the case when the (OH) group occurs in alcohols as well as in carboxylic acids. One way to overcome this problem is by substitution of {OH} by fluorine using the method of Yarowenko and Raksha (I). Having obtained the fluorine-containing compounds the advantages are in general twofold; firstly, introduction of fluorine gives rise to chemical shift changes for nearby nuclei as observed in, e.g., ‘H spectra, and to 19F spectra, where the chemical shift variations as function of the nature of the substitution site are large. Secondly, spin-spin coupling constants involving fluorine can be observed both in ‘H and 19F spectra, and the data obtained may be interpreted in terms of a structure of the surroundings of the site of substitution. REACTION
Formally the reaction may be written ?, 'X'
c=c
H Cl-'cF'
IF 'F
F C-N F
-t
HN/,(C2H5)
/ v& ’ (C2H5)
’ CzH5
ROH ---+
Q 1972 by Academic
Press, Inc.
Cl-
+
H
;C-C-
40
N,N (c2H5)
F
l-
Here the fluorinating
JY5
> H&i-N
\ (C2H5)
(C2H+
>
agent is 2-chloro-1,1,2-trifluorotriethylamine 177
+ RF + HF
(alkene(s))
(FR).
178
SCHAUMBURG
The reaction takes place at room temperature in a testtube overnight and the hydrofluoride acid formed according to the reaction scheme is normally not observed, permitting the use of standard glass equipment. Aside from the reaction product (RF). an amide of chlorofluoroacetic acid is formed. Starting from alcohols, fluorides are formed, while carbonyl fluorides result from the fluorination of acids. The presently known limitations of the method are that the {OH} group in phenols does not react, and that elimination ROH + R’ + Hz0 may take place in compounds normally expected to show this tendency. The reaction mechanism is in general a mixture of SNl and SN2 and accordingly no stereospecific substitution can be obtained. The fluorides and carbonyl fluorides produced in the reaction are normally more volatile than the parent compounds and may be purified by fractional distillation on a vacuum line. Most fluorine-containing compounds are found to be unstable and to decompose in solution in sealed tubes at room temperature. In many cases, where spectra of the crude reaction mixtures are observed it is of some interest to know the spectroscopic parameters for FR as well as for the amide. In Table 1 the data observed for FR are listed. The difference between the two geminal TABLE CHEMICAL
F(a) F(a) F(b) F(c)
- -144.99”
SHIFTS AND COUPLING
F(b) -14.48 -90.18”
1
F(c)
CONSTANTS
H
-15.05 205.24 -87.70”
CH,@)
48.17 6.32 4.03 6.204b
H C&(b) CHAc) CH&) CH,(c)
0.40 2.01 2.15 0.0 2.964b
(IN Hz)
IN
CH,(c) 0.40 2.01 2.15 0.0 0.0 2.964”
CH,(b)
C&(c)
CO.1 -0.5 -0.5 0.0 7.11 0.0 1.100”
CO.1 -0.5 -0.5 0.0 0.0 7.11 0.0 1.100
(1In ppm relative to internal CFC13. b In ppm relative to internal TMS. fluorines is noticeable. The chemical shifts differ by 3.5 ppm and the vicinal HF and FF coupling constants are different. Assuming a cosine square dependence for both coupling constants, this leads to a prediction of the Cl F F F
@H
N
COUPLING
CONSTANTS
IN
CARBONYL
179
FLUORIDES
configuration as the least favorable. There is also a small difference between the two four-bond HF couplings from the geminal fluorines to the methylene groups. This difference does not violate symmetry. TABLE CHEMICAL
SHIFTS
F F H CH2(a) CJWO CH,(b) CHda) C&(b)
-142.97x
2
AND COUPLING
H 49.76 6.844y
CHAa)
CONSTANTS
CHAa’)
0.68
0.68
0.0
0.0
3.493y
-15.16 3.44oy
(IN Hz)
IN
CHAb)
CH&)
CH,(b)
0.0 0.0 0.0 0.0
0.0 0.0 7.13 7.13
0.0 0.0 0.0 0.0
3.389y
0.0
7.14
1.233"
0.0 1.12oy
x In ppm measured from internal CFCI,. Y In ppm measured from internal TMS. TABLE
3
Compound CH,COF CH,CH2COF CH,\ CHCOF CHs/ BrCH&OF ClCH&OF FCH,COF Cl,CHCOF (CHWOF Br&HCOF ICHzCOF C&\ CHCOF &I,/ C2H5CH2COF
6.60 7.20
49.4" 41.4"
7.80
33.6"
7.35 7.55 8.30 8.50 8.40 8.10 7.05
37.32 34.38 25.58 20.91 21.60 21.22 36.6
7.80
32.50
7.20
46.0"
a A. A. Nemysheva and I. L. Knunyants, Doklady. Akad. Nauk S.S.S.R. 177, 856 (1967).
b M. L. Huggins, J. Amer. Chem. Sot. 75, 4123
(1953).
’ W. Gordy and J. 0. Thomas, J. Chem. Phys. 24,439 (1956).
180
SCHAUMBURG
The amide data are reported in Table 2. As usual, separate signals due to each of the alkyl groups attached to the nitrogen can be observed. In the present case, nonequivalence of the protons in the methylene group marked (a) is observed as a result of the influence of the CFClH group. The measured geminal coupling constant is numerically large, but comparable to data available in ring-substituted diethylbenzamides (2, 3).
FIG.
1. Chemical shift as a function of the number of identical substituents, n, for carbonyl fluorides.
The application of the fluorine chemical shift can be illustrated by the series of compounds X,CH,-,-COF, where X represents various combinations of alkyl groups and halogen atoms. Table 3 includes the data for the compounds studied. Figure 1 shows the closely linear correlation found between the number of identical substituents and the igF chemical shift. Some of the data for X = CH, have earlier been correlated in this way (8). In Fig. 2 the chemical shift has been plotted against the summed electronegativity of the substituents on the a carbon, as given in Table 3. A closely linear relation is found, corresponding to increased shielding with increase in electronegativity. This trend may be explained by assuming an increase in excitation energies for the molecules with increasing electronegative substitution resulting in a smaller paramagnetic term. HF spin-spin coupling constants normally extend over 5 bonds in fluorides and carbonyl fluorides, yielding potential information about the configuration of the fluorine environment. Many articles have recently discussed the coupling constants in fluorides, and fluorination of alcohols would therefore yield data for which some models are at hand.
COUPLING
CONSTANTS
IN
CARBONYL
181
FLUORIDES
Carbonyl fluorides have rarely been reported before and we have therefore chosen to report data for a series of heterocyclic carbonyl fluorides given in Table 4. It is characteristic that the ring coupling constants are virtually unchanged compared to
*F pm
O-
-lO-
-20 -
-3o-
-LO -
L
I 11
, 10
9I
8I
7#bI
6
FIG. 2. Chemical shift as a function of electronegativity
9
*
of substituents on the OLcarbon.
the corresponding acids. The long-range coupling constants vary considerably in magnitude and some differ in sign. The sign determinations are relative to the ring coupling constants. TABLE COUPLING
3 3 4 COF COF COF
4 5 5 3 4 5
CONSTANTS
(Hz) IN FIVE-MEMBERED
3.15 3.88 0.89 1.22 1.I9 4.88 0.55 CO.2 0.78[0.3] 1.99 2.4310.771 2.44[0.9]
4.17 1.11 2.47 0.87 co.1 3.18[0.99]
4 HETEROCYCLIC
3.30 0.80 2.15[1.3]
CARBONYL
0.82 1.54 1.99 0.21 -0.70[-0.41 2.01[0.75]
FLUORIDES'
1.23 3.01 5.17 0.06 -0.65 2.69[0.7]
2 2 4 COF COF COF
’ All data better than ~tO.05 Hz. Results refer to 10% soln. in diethyl ether, at 32°C. [ ] contain literature data for the corresponding aldehydes. 7
4 5 5 2 4 5
182
SCHAUMBURG
The listed coupling constants represent an average of the data for the two planar configurations I and II.
If CND0/2 calculations of the rotational barriers are assumed to be of acceptable accuracy [6] it is expected that the energy difference between I and II is small resulting in an almost 50-50 distribution between I and II. In the corresponding aldehydes, experiments as well as theoretical calculations do indicate that the ratio I/II is different from one and the room temperature coupling constants therefore correspond to a different weighted average. With this reservation in mind, data for the two types of compounds are compared in Table 4. It can be seen that, in cases where similar data exist, a crude proportionality exists where the HF coupling constants are 3-5 times the magnitude of the HH coupling constants. Position 5 has in all cases the largest long-range coupling irrespective of the type of heterocycle and the position of the substituent. The long-range couplings to positions 2, 3 and 4 are all so small in the carbonyl fluorides that, provided the same TABLE
5
VICINAL COUPLING CONSTANTS3Jx,f Compound
X=H”
X=F
0 W--C: Cl d-d;
2.85
7.1
2.87b
2.15
4.25 b
1.20
1.31
1.1
1.69
0.8
2.40
10.2
0
tc x H 0 H&c// c; 1 0 CH,CH,-CI/
‘x 0
‘“,CHp*-t
H,C>ti-C@
k 0 ‘X
i-if V, lH I,c\//o H,C cxx ‘G. Chem. *G. J. Mol.
5.75
5.85
J. Karabatsos and N. Hsi, J. Amer. Sot. 87,2864 (1965). P. Van der Kelen and Z. Eeckhaut, Spectrosc. 10, 141 (1963).
COUPLING
CONSTANTS
IN CARBONYL
FLUORIDES
183
proportionality constant is applicable as for Position 5, the HH couplings would hardly be detectable. The sign and magnitude relation here found in the heterocyclic carbonyl fluorides was originally established by Castellano et al. (2) for substituted benzenes. In aliphatic systems, a similar relation cannot be established (Table 5) between aldehydes and carbonyl fluorides; only for acetyl fluoride does a similar ratio hold. Although the above data by no means have clarified the problems of chemical shift and long-range coupling constants involving the carbonyl fluoride group, they have increased the evidence for some empirical correlations which may prove useful in the interpretation of spectra. REFERENCES 1. N. N. YAROWENKO AND M. A. RAKSHA, Zh. Obshch. Khim. 29,2125 (1959). 2. T. H. SIDDAL AND R. H. GARNER, Cunad. J. Chem. 44,2387 (1966). 3. G. R. BEDFORD, D. GREATBANKS, AND D. B. ROGERS, Chem. Comm. 330 (1966). 4. K. SCHAUMBURG, J. Mugn. Resonance 3,360 (1970). 5. K. SCHAUMBURG, Canad. J. Chem. 49,1146 (1971). 6. L. RANDOM AND J. A. POPLE, J. Amer. Chem. Sot. 92,4786 (1970). 7. R. J. KOSTELNIK, M. P. WILLIAMSON, D. E. WISNOSKY, AND S. M. CASTELLANO, Canad. J. Chem. 47, 3313 (1969). 8. A. A. NEMYSHEVA AND I. L. KNUNYANTS DOKLADY, Akad. Nauk. S.S.S.R. 177,856 (1967).
OF MAGNETIC
RESONANCE
7, 177-183 (1972)
Fluorination of Organic Compoundsand Long-Range Coupling Constantsin Carbonyl Fluorides KJELD SCHAUMBLJRG Department of Chemistry, University of Copenhagen, Denmark Presented at the Fourth International Symposium on Magnetic Resonance, Israel, August, 1971 Replacement of a hydroxyl group by fluorine through the use of 2-chloro-1,1,2trifluorotriethylamine is described. Results for chemical shifts and coupling constants in carbonyl fluorides derived from acids by this method are presented. INTRODUCTION
The present contribution is concerned with the application of a simple method of introducing fluorine as a substituent in organic compounds, replacing an {OH} group in the compound. In general {OH} is an undesirable functional group since it rarely gives rise to measurable spin-spin coupling to the other part of the compound. This is the case when the (OH) group occurs in alcohols as well as in carboxylic acids. One way to overcome this problem is by substitution of {OH} by fluorine using the method of Yarowenko and Raksha (I). Having obtained the fluorine-containing compounds the advantages are in general twofold; firstly, introduction of fluorine gives rise to chemical shift changes for nearby nuclei as observed in, e.g., ‘H spectra, and to 19F spectra, where the chemical shift variations as function of the nature of the substitution site are large. Secondly, spin-spin coupling constants involving fluorine can be observed both in ‘H and 19F spectra, and the data obtained may be interpreted in terms of a structure of the surroundings of the site of substitution. REACTION
Formally the reaction may be written ?, 'X'
c=c
H Cl-'cF'
IF 'F
F C-N F
-t
HN/,(C2H5)
/ v& ’ (C2H5)
’ CzH5
ROH ---+
Q 1972 by Academic
Press, Inc.
Cl-
+
H
;C-C-
40
N,N (c2H5)
F
l-
Here the fluorinating
JY5
> H&i-N
\ (C2H5)
(C2H+
>
agent is 2-chloro-1,1,2-trifluorotriethylamine 177
+ RF + HF
(alkene(s))
(FR).
178
SCHAUMBURG
The reaction takes place at room temperature in a testtube overnight and the hydrofluoride acid formed according to the reaction scheme is normally not observed, permitting the use of standard glass equipment. Aside from the reaction product (RF). an amide of chlorofluoroacetic acid is formed. Starting from alcohols, fluorides are formed, while carbonyl fluorides result from the fluorination of acids. The presently known limitations of the method are that the {OH} group in phenols does not react, and that elimination ROH + R’ + Hz0 may take place in compounds normally expected to show this tendency. The reaction mechanism is in general a mixture of SNl and SN2 and accordingly no stereospecific substitution can be obtained. The fluorides and carbonyl fluorides produced in the reaction are normally more volatile than the parent compounds and may be purified by fractional distillation on a vacuum line. Most fluorine-containing compounds are found to be unstable and to decompose in solution in sealed tubes at room temperature. In many cases, where spectra of the crude reaction mixtures are observed it is of some interest to know the spectroscopic parameters for FR as well as for the amide. In Table 1 the data observed for FR are listed. The difference between the two geminal TABLE CHEMICAL
F(a) F(a) F(b) F(c)
- -144.99”
SHIFTS AND COUPLING
F(b) -14.48 -90.18”
1
F(c)
CONSTANTS
H
-15.05 205.24 -87.70”
CH,@)
48.17 6.32 4.03 6.204b
H C&(b) CHAc) CH&) CH,(c)
0.40 2.01 2.15 0.0 2.964b
(IN Hz)
IN
CH,(c) 0.40 2.01 2.15 0.0 0.0 2.964”
CH,(b)
C&(c)
CO.1 -0.5 -0.5 0.0 7.11 0.0 1.100”
CO.1 -0.5 -0.5 0.0 0.0 7.11 0.0 1.100
(1In ppm relative to internal CFC13. b In ppm relative to internal TMS. fluorines is noticeable. The chemical shifts differ by 3.5 ppm and the vicinal HF and FF coupling constants are different. Assuming a cosine square dependence for both coupling constants, this leads to a prediction of the Cl F F F
@H
N
COUPLING
CONSTANTS
IN
CARBONYL
179
FLUORIDES
configuration as the least favorable. There is also a small difference between the two four-bond HF couplings from the geminal fluorines to the methylene groups. This difference does not violate symmetry. TABLE CHEMICAL
SHIFTS
F F H CH2(a) CJWO CH,(b) CHda) C&(b)
-142.97x
2
AND COUPLING
H 49.76 6.844y
CHAa)
CONSTANTS
CHAa’)
0.68
0.68
0.0
0.0
3.493y
-15.16 3.44oy
(IN Hz)
IN
CHAb)
CH&)
CH,(b)
0.0 0.0 0.0 0.0
0.0 0.0 7.13 7.13
0.0 0.0 0.0 0.0
3.389y
0.0
7.14
1.233"
0.0 1.12oy
x In ppm measured from internal CFCI,. Y In ppm measured from internal TMS. TABLE
3
Compound CH,COF CH,CH2COF CH,\ CHCOF CHs/ BrCH&OF ClCH&OF FCH,COF Cl,CHCOF (CHWOF Br&HCOF ICHzCOF C&\ CHCOF &I,/ C2H5CH2COF
6.60 7.20
49.4" 41.4"
7.80
33.6"
7.35 7.55 8.30 8.50 8.40 8.10 7.05
37.32 34.38 25.58 20.91 21.60 21.22 36.6
7.80
32.50
7.20
46.0"
a A. A. Nemysheva and I. L. Knunyants, Doklady. Akad. Nauk S.S.S.R. 177, 856 (1967).
b M. L. Huggins, J. Amer. Chem. Sot. 75, 4123
(1953).
’ W. Gordy and J. 0. Thomas, J. Chem. Phys. 24,439 (1956).
180
SCHAUMBURG
The amide data are reported in Table 2. As usual, separate signals due to each of the alkyl groups attached to the nitrogen can be observed. In the present case, nonequivalence of the protons in the methylene group marked (a) is observed as a result of the influence of the CFClH group. The measured geminal coupling constant is numerically large, but comparable to data available in ring-substituted diethylbenzamides (2, 3).
FIG.
1. Chemical shift as a function of the number of identical substituents, n, for carbonyl fluorides.
The application of the fluorine chemical shift can be illustrated by the series of compounds X,CH,-,-COF, where X represents various combinations of alkyl groups and halogen atoms. Table 3 includes the data for the compounds studied. Figure 1 shows the closely linear correlation found between the number of identical substituents and the igF chemical shift. Some of the data for X = CH, have earlier been correlated in this way (8). In Fig. 2 the chemical shift has been plotted against the summed electronegativity of the substituents on the a carbon, as given in Table 3. A closely linear relation is found, corresponding to increased shielding with increase in electronegativity. This trend may be explained by assuming an increase in excitation energies for the molecules with increasing electronegative substitution resulting in a smaller paramagnetic term. HF spin-spin coupling constants normally extend over 5 bonds in fluorides and carbonyl fluorides, yielding potential information about the configuration of the fluorine environment. Many articles have recently discussed the coupling constants in fluorides, and fluorination of alcohols would therefore yield data for which some models are at hand.
COUPLING
CONSTANTS
IN
CARBONYL
181
FLUORIDES
Carbonyl fluorides have rarely been reported before and we have therefore chosen to report data for a series of heterocyclic carbonyl fluorides given in Table 4. It is characteristic that the ring coupling constants are virtually unchanged compared to
*F pm
O-
-lO-
-20 -
-3o-
-LO -
L
I 11
, 10
9I
8I
7#bI
6
FIG. 2. Chemical shift as a function of electronegativity
9
*
of substituents on the OLcarbon.
the corresponding acids. The long-range coupling constants vary considerably in magnitude and some differ in sign. The sign determinations are relative to the ring coupling constants. TABLE COUPLING
3 3 4 COF COF COF
4 5 5 3 4 5
CONSTANTS
(Hz) IN FIVE-MEMBERED
3.15 3.88 0.89 1.22 1.I9 4.88 0.55 CO.2 0.78[0.3] 1.99 2.4310.771 2.44[0.9]
4.17 1.11 2.47 0.87 co.1 3.18[0.99]
4 HETEROCYCLIC
3.30 0.80 2.15[1.3]
CARBONYL
0.82 1.54 1.99 0.21 -0.70[-0.41 2.01[0.75]
FLUORIDES'
1.23 3.01 5.17 0.06 -0.65 2.69[0.7]
2 2 4 COF COF COF
’ All data better than ~tO.05 Hz. Results refer to 10% soln. in diethyl ether, at 32°C. [ ] contain literature data for the corresponding aldehydes. 7
4 5 5 2 4 5
182
SCHAUMBURG
The listed coupling constants represent an average of the data for the two planar configurations I and II.
If CND0/2 calculations of the rotational barriers are assumed to be of acceptable accuracy [6] it is expected that the energy difference between I and II is small resulting in an almost 50-50 distribution between I and II. In the corresponding aldehydes, experiments as well as theoretical calculations do indicate that the ratio I/II is different from one and the room temperature coupling constants therefore correspond to a different weighted average. With this reservation in mind, data for the two types of compounds are compared in Table 4. It can be seen that, in cases where similar data exist, a crude proportionality exists where the HF coupling constants are 3-5 times the magnitude of the HH coupling constants. Position 5 has in all cases the largest long-range coupling irrespective of the type of heterocycle and the position of the substituent. The long-range couplings to positions 2, 3 and 4 are all so small in the carbonyl fluorides that, provided the same TABLE
5
VICINAL COUPLING CONSTANTS3Jx,f Compound
X=H”
X=F
0 W--C: Cl d-d;
2.85
7.1
2.87b
2.15
4.25 b
1.20
1.31
1.1
1.69
0.8
2.40
10.2
0
tc x H 0 H&c// c; 1 0 CH,CH,-CI/
‘x 0
‘“,CHp*-t
H,C>ti-C@
k 0 ‘X
i-if V, lH I,c\//o H,C cxx ‘G. Chem. *G. J. Mol.
5.75
5.85
J. Karabatsos and N. Hsi, J. Amer. Sot. 87,2864 (1965). P. Van der Kelen and Z. Eeckhaut, Spectrosc. 10, 141 (1963).
COUPLING
CONSTANTS
IN CARBONYL
FLUORIDES
183
proportionality constant is applicable as for Position 5, the HH couplings would hardly be detectable. The sign and magnitude relation here found in the heterocyclic carbonyl fluorides was originally established by Castellano et al. (2) for substituted benzenes. In aliphatic systems, a similar relation cannot be established (Table 5) between aldehydes and carbonyl fluorides; only for acetyl fluoride does a similar ratio hold. Although the above data by no means have clarified the problems of chemical shift and long-range coupling constants involving the carbonyl fluoride group, they have increased the evidence for some empirical correlations which may prove useful in the interpretation of spectra. REFERENCES 1. N. N. YAROWENKO AND M. A. RAKSHA, Zh. Obshch. Khim. 29,2125 (1959). 2. T. H. SIDDAL AND R. H. GARNER, Cunad. J. Chem. 44,2387 (1966). 3. G. R. BEDFORD, D. GREATBANKS, AND D. B. ROGERS, Chem. Comm. 330 (1966). 4. K. SCHAUMBURG, J. Mugn. Resonance 3,360 (1970). 5. K. SCHAUMBURG, Canad. J. Chem. 49,1146 (1971). 6. L. RANDOM AND J. A. POPLE, J. Amer. Chem. Sot. 92,4786 (1970). 7. R. J. KOSTELNIK, M. P. WILLIAMSON, D. E. WISNOSKY, AND S. M. CASTELLANO, Canad. J. Chem. 47, 3313 (1969). 8. A. A. NEMYSHEVA AND I. L. KNUNYANTS DOKLADY, Akad. Nauk. S.S.S.R. 177,856 (1967).