T h e ketone, 2-octanone, was added t o relate efficiency of nebulization t o boiling point of the organic solvent. As can be seen from Table 11, the lower the boiling point, the greater the volatility, the higher the efficiency of nebulization. 3-Heptanone is proposed as a n alternative solvent to MIBK for the extraction of metal chelates in atomic absorption analysis, particularly when the solubility of MIBK
in the aqueous phase is of concern. MIBK is 4.5 times more soluble in aqueous phase a t 25 “C than 3-heptanone. T h e greater efficiency of nebulization of MIBK, on the other hand, should be taken into consideration when the sensitivity of a procedure is important.
RECEIVEDfor review December 20, 1973. Accepted July 25, 1974.
Use of Shielding Parameters for the Calculation of Chemical Shifts in the Nuclear Magnetic Resonance Spectra of Substituted Pyridines Murray Zanger Department of Chemistry, Philadelphia College of Pharmacy and Science, Philadelphia, Pa. 19 104
William W. Simons Sadtler Research Laboratories, Philadelphia, Pa. 19 104
The use of shielding parameters for the calculation of theoretical chemical shifts has been applied to substituted benzenes (1-71, methylenes ( 8 ) ,steroids (9),ethylenes (IO), furans (111, thiopenes (121, quinazolines (13), pyrazines (14), and pyridines (15). In the latter case, only 4-substituted pyridines were considered. T h e NMR spectra of substituted pyridines are usually difficult t o assign since the ring nitrogen, a “built-in” substituent causes pronounced differences in the chemical shifts of the cy-, @-,and y-protons. This substituent effect when coupled with the addition of one or more other substituents produces chemical shifts for the remaining protons which are difficult to predict and are often misassigned. It would be a distinct advantage if it were possible t o make tentative assignments based on the calculation of chemical shifts using a reliable set of shielding parameters. This then is the main object of the work reported herein. Additionally it would be of interest to compare the relative effects of the same substituent in the benzene and pyridine series. Wu and Dailey (15) have shown that the substituents on pyridine (in the 4-position) d o not exert their effect solely by affecting r-electron density. Obviously, the over-all effect of substituents is more complex with pyridines than with benzenes. Another point which would be of interest is whether the effect of a substituent on its (1) (2) (3) (4) (5) (6) (7)
(8) (9)
(10) (11) (12) (13) (14) (15)
P. L. Corio and E. P. Dailey, J . Amer. Chem. SOC.,78, 3043 (1956). H. Spiesecke and W. G. Schneider, J . Chem. Phys., 35, 731 (1961). J. S. Martin and B. P. Dailey, J. Chem. Phys., 37, 2594 (1962). J. S. Martin and B. P. Dailey, J . Chem. Phys., 39, 1722 (1963). T. K. Wu and B. P. Dailey, J. Chem. Phys., 41, 2796 (1964). J. J. R. Reed, Anal. Chem., 39, 1586 (1967). J. Beeby, S. Sternhell, T. Hoffmann-Ostenhof, E. Pretsch, and W. Simon, Anal. Chem., 45, 1571 (1973). J. N. Shooiery, No. 2 Technical Information Bulletin, Varian Associates, Palo Alto, Calif., 1959. N. S. Bhacca and D. H. Williams, “Application of NMR Spectroscopy in Organic Chemistry, Illustration trom the Steroid Field,” Prentice-Hall, San Francisco, Calif., 1964. C. Pascual, J. Meier, and W. Simon, Helv. Chim. Acta, 49, 164 (1964). Y. Pascal, J. P. Marizur, and J. Wiemann. Bull. SOC. Chem. Fr., 2211 (1965). S. Gronowitz and R. A. Hoffmann, Ark. Kemi, 16, 539 (1961). A. R. Katritsky, R. E. Reavill, and F. J. Swinboirne, J . Chem. SOC.6, 351 (1966). G. S. Marx and P. E. Spoerri, J. Org. Chem.,37, 111 (1972). T. K. Wu and E. P. Dailey, J. Chem. Phys., 41, 3307 (1964).
2042
“ortho,” “meta” and “para” protons remains constant regardless of the position of the substituent. Finally, it is also hoped that results from a purely empirical approach may suggest answers to theoretical questions concerning the interaction of substituents with a heteroaromatic ring.
EXPERIMENTAL T h e proton magnetic spectra were run on Yarian Associates A60A and Perkin-Elmer R-12 spectrometers. TMS was used as a n internal standard and duplicate runs were reproducible to better than 0.02 ppm. The pyridines studied were all commercially obtained and were used without further purification, unless significant impurity bands were observed. The pyridines, dissolved in CDCI,I or CC14 (in a few cases DMSO-& and acetone-ds were employed), were run as 10-30% ( v h ) solutions. A representative sampling of the compounds were run over the whole concentration range and concentration shifts were less than 0.05 ppm. Although many investigators calculate the chemical shifts at infinite dilution, this was intentionally not done in this investigation. The results reported here are to be used as a quick, analytical technique for assigning ring protons approximately.
RESULTS AND DISCUSSION 2-Substituted Pyridines. A series of eighteen, 2-substituted pyridines were obtained and their NMR spectra were determined in CDC13 or CC14. Using values for the chemical shifts of 0-,fl-, and y-protons for a solution of pure pyridine in CDC13, and the values for the same protons in substituted pyridines, Table I was constructed to reflect the effect of the substituent on the remaining protons (3 through 6). A (-) a-value ( e . g . , NH2 group) denotes shielding by the substituent and indicates that this value is subtracted from the value for the chemical shift of a proton in the same position on a n unsubstituted pyridine. A (+) a-value indicates deshielding and requires an addition of that parameter to the value for the comparable proton on the unsubstituted pyridine. The U-values for the 3-. 4-, and 5-protons are the equivalent of the ortho, meta. and para values in benzene. T h e values obtained are a t least qualitatively similar to those obtained in the benzene series. T h e 6-proton value, however, is unique since it is meta to the substituent but has an intervening ring nitrogen which
ANALYTICAL CHEMISTRY, VOL. 46, NO. 13, NOVEMBER 1974
~~~
~~~
~~
~~
~~
~~
Table I. Additivity Constants for 2-Pyridine Derivatives Shift relative to pyridine, ppm Proton Sdbstituenr
No.:
:,
- 0.83
2 -NH2 2-0Et 2 -OBU 2 -OCH, 2F 2-CH, 2 -Et 2 -c1 2 -Ur (2 -1P 2 -CN 2 -CHO 2 -C051e 2 -CO,Et 2 -CONHZ 2 -SHCOMe 2 -COOH (2 -S@Y
-0.58 -0.57 -0.49 -0.30 -0.19 -0.16 0.08 0.21 0.55 0.72 0.74 0.93 1.02 1.08 1.10
...
4
-0.33 -0.08 -0.12 -0.05 0.22 -0.15 -0.07. -0.11 -0.05 (-0.02) 0.38 0.36 0.24 0.32 0.28 0.16 0.54 (0.45)
Solvent
-0.79 -0.49 -0.48
-3.61
-0.46 -0.49 -U.36 -0.36 -0.17 -0.09 -0.20 -0.28 (-0.27) 0.22 0.24 0.05 0.21 0.03 0.22 0.27 3.07)
-0.41 -0.11 -0.26 -0.20 0.00 0.00 (-0.02) 0.41 0.39 0.22 0.31 0.22
--0.16
-
0.51
(0.45)
CDC13 cc1,
cc1, cc1,
cc1, cc1, CCL, cc1,
cc1, DMSO- i i t i l t e d pyridines
h& t o shielding parameters signii'icantly ditlerent I'roi11 the riormal meta values. 3-Substituted Pyridines. A set of XLIR spectra tor ai.\teer; dit ~ ' e r e nX-substituted ~ pyridines was obtained. From al taken from these spectra and the shifts tht. t ~ h ~ r n i c shifts ( i t t i l t ;irutons in unsubstituted pyridine, Table I i \vas t'cirn i u l u ~ e d .As before, i+)and ( - ) denote deshielding ailti r,iding groups. respectively. I:; i i & series, the shielding parameters f o r t.he 2- and 4prt,i o i i h might both be termed ortho cr-vaiues. 'Ihe results, h(iw.rver. show that both values are significantly lower than tile tjrtlio values in the %series. T h e a:j-meta values tend i o be hiightiy smaller than the ui values. T h e para values are nlho 3niiLiler in this series compared to the 2-sul)stii tiic$(i pyri;iint.s. ANALYTICAL CHEMISTRY. VOL. 46, NO. 13, NOVEMBER 1974
0
2043
Table 111. Additivity Constants for 4-Pyridine Derivatives Shift relative to pyridine, pprn Proton
No.:
Substituent
4-NH2 4 -OH 4 -CH3 4 -Et 4 -c1 4 -Br 4 -CN 4 -CHO 4 -COCH3 4 -COOEt 4 -COOMe 4 -CONH, 4 -COOH 4-NOza a
2
3
5
6
Solvent
-0.51 - 0.62 -0.17 -0.13 - 0.03 -0.11 0.31 0.28 0.25 0.16 0.45 0.14 0.21 0.33
-0.68 -0.57 -0.21 -0.17 0.12 0.30 0.42 0.45 0.53 0.54 0.79 0.59 0.61 0.82
-0.68 - 0.57 -0.21 -0.17 0.12 0.30 0.42 0.45 0.53 0.54 0.79 0.59 0.61 0.82
-0.51 -0.62 -0.17 -0.13 -0.03 -0.11 0.31 0.28 0.25 0.16 0.45 0.14 0.21 0.33
Polysol DZO cc1, cc1, CDC13 CDC1, CDC13 cc1, CDC1, cc1, cc1, Polysol DMSO-(i,
Ref. (15).
Table IV. Chemical Shifts of Disubstituted Pyridines; Observed us. (Calculated) Sample No.
2
Pyridine 1 2 3 4 5 6 7 8 9 10 11 12
8.54 2"
c1 2"
COOEt 2"
c1 OEt COMe 8.18(8.18) 8.20(8.22) 8.69(8.70) 9.29(9.34)
3
4
5
6
7.19 CH3 NO2 6.29(6.15) 7.32(7.55) 6.34(6.18) 7.60(7.67) 6.61(6.61) 7.81(7.67) Me Me Me COOH
7.55 7.10(7.02) 8.29(8.30) CH3 OH 7.13(7.02) 8.51(8.30) 7.50(7.36) 7.69(7.64) Me Et 7.82(7.91) 8.70(9.01)
7.19 6.42(6.22) 7.52(7.59) 6.42(6.19) 6.77(6.93) CH3 NO2 6.88(6.78) 7.30(7.22) 6.88(6.80) 6.93 (6.84) CN COOH
8.54 7.83(7.79) 8.68(8.67) 7. gl(7.76) 7.98(8.13) 7.84(7.74) 9.27(9.20) c1 Me 8.18(8.23) 8.24(8.27) 8.69(8.78) 9.29(9.34)
where 6 ~ = " chemical shift (pprn) of proton (n);uzW(3)= shielding parameter for substituent w (x, etc.) on position 2 (3, etc.) as it affects the proton whose shift is being calculated; and ( a ) = the value assigned to the proton in unsubstituted pyridine. Sample Calculation.
Test of the Method. A set of thirty-six disubstituted test compounds was used to verify the accuracy of the method. Spectra on all of these compounds were obtained and chemical shift values measured for each of the ring protons. Values for these protons were also calculated using the method and constants described. A representative sample of the results is shown in Table IV. Of the 107 points which were calculated, 70 points (65%) were within 0.1 ppm of the observed values; 22 points (21%) were between 0.11 to 0.20 ppm of the observed value and only 15 points or 2044
Solvent
CDC1, cc1, CDC1, CDC1, CDC13 CDC1, CDC13 CDC13 CDC13 cc1, cc1, CDC13 DMSO-d,
14% had calculated shifts in excess of 0.20 ppm of the observed values. Comparison of ortho, meta, and para Effects. The effect of substituents on protons ortho to them for all of the pyridine series and for benzene are compared in Table V. In general, the results parallel each other for all of the series. The 2-substituents, however, seem to produce the largest effect both for strong shielding as well as deshielding groups. At the present time, we can offer no explanation for this apparently real effect. Additionally, a second feature which is observed is that the ortho effect of a h u b stituent is not equal on its two ortho neighbors, the 2- and 4-protons. The "meta" effects (Table VI) also parallel each other well although some of the comparable shielding parameters are quite disparate. In comparing the effect of a 2-substituent on the 4- and 6-protons, an unusual trend is observed; namely, that the shielding effects are larger on the 6-protons while the deshielding effects are greater on the 4-protons. This suggests some interaction between the ring nitrogen and the substituent on position three, but again no simple explanation is evident. The para effects (Table VII) show the closest similarities
ANALYTICAL CHEMISTRY, VOL. 46, NO. 13, NOVEMBER 1974
Table V. Comparison of Ortho Effect
Substituent
(r)
2"
OH OEt OMe F Me Et
c1 Br I CN CHO COMe COOMe COOEt CONHZ COOH NO2
Table VII. Comparison of ParaEffects
Benzenei a'
-0.75 -0.56 -0.46 -0.48 -0.26 -0.20 -0.14 0.03 0.18 0.39 0.36 0.56 0.62 0.71
... 0.61 0.85 0.95
-0.83
... -0.58 .-0.49 -0.30 -0.19 -0.16 0.08 0.21
... 0.55 0.72 0.74
... 0.93 1.02 1.10
-0.52 -0.32 -0.30
...
... -0.19 -0.15 -0.02 0.12 0.27 0.38 0.49 0.53 0.69 0.65 0.66 0.56 0.86
-0.62 -0.32 -0.48
- 0.68 -0.57
*..
-0.43*
...
...
-0.20 -0.13 0.05 0.19 0.38 0.56 0.57 0.56 0.76 0.72 0.81 0.73 0.86
-0.21 -0.17 0.12 0.30
...
... 0.42 0.45 0.53 0.79 0.54 0.59 0.61 0.82
a Ref. (7). Ref. ( 1 5 ) . The first number indicates the position of the substituent (x). The second number indicates the number of the proton affected.
Table VI. Comparison of Meta Effects Shift, ppm Substiment
"2
OH OEt OMe F
Me Et c1 Br I CN
CHO COMe COOMe COOEt CONH? COOHNO2
Benzene(a)
-0.25 -0.12 -0.10 -0.09 0.00 -0.12 -0.06 -0.02 -0.08 -0.21 0.18 0.22 0.14 0.11
2-r-4(~)
2-x-6(c)
3-x-5(c)
4-x-2(c)
-0.33
-0.61
...
...
-0.25 0.04
-0.51 -0.62
-0.08 -0.05 0.22 -0.15 -0.16 0.08 0.21
-0.46 -0.36 -0.36 -0.17 -0.15 -0.02 0.12
... ...
...
0.38 0.36 0.24
0.22 0.24 0.05
0.10
0.32 0.28
o'26
0'54 0'45
...
0.21b
...
...
-0.17 -0.17 0.12 0.30
0.21 0.03
-0.18 -0.13 0.05 0.19 -0.17 0.36 0.28 0.17 0.22 0.16 0.35
o'27 0'07
0'32 0'40
o'21
...
0.31 0.28 0.25 0.45 0.16 0.14 0'33b
a Ref. (7). b Ref. (15). The first number indicates the position of the substituent ( x ) . The second number indicates the number of the proton affected. 1.
"2
OH OEt OMe F Me Et
c1 Br I CN CHO COMe COOMe COOEt CONHz COOH NO2
-0.65 -0.45 -0.43 - 0.44 -0.20 -0.22 -0.17 -0.09 -0.04 0.00 0.28 0.29 0.21 0.21
-0.79
... -0.46 -0.41 -0.11 -0.26 -0.20 0.00 0.00
... 0.41 0.39 0.22
...
...
0.31 0.22 0.51 0.45
0.17 0.27 0.38
-0.59 -0.38 -0.48
... ...
-0.19 -0.17 -0.13 -0.06 - 0.04 0.35 0.25 0.15 0.26 0.19 0.25 0.25 0.33
Fkf. (7). The first number indicates the position of the substituent (x). The second number indicates the number of the proton affected.
of any of the effects studied with the values for a particular shielding parameter occurring over narrow ranges for the two pyridine series and the benzene. Since the substituent in this case is farthest removed from the ring nitrogen, any interaction between the two would be expected to be minimal. T h e results seem to verify this.
CONCLUSION The original intent of this paper was to develop a set of additivity constants which could be used to calculate the chemical shifts for the ring protons in substituted pyridines. As the results demonstrate, this objective has been achieved and the results are a t least as good as those currently available in the benzene series. As with the benzene series (16),a complementary technique for assigning pyridine compounds is also available, namely the determination of the substitution patterns caused by spin-spin coupling. Together the techniques permit the spectroscopist, a t least in theory, t o create a theoretical spectrum which in all respects matches the actual spectrum of the compound being studied. RECEIVEDfor review March 22, 1974. Accepted July 8, 1974. This research was supported in part by a Summer Research Grant from the Philadelphia College o f Pharmacy and Science. (16) M. Zanger, Org. Mag. Res.. 4, i(1972).
ANALYTICAL CHEMISTRY, VOL. 46, NO.
13, NOVEMBER 1974
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