`
`1.
`2.
`
`3.
`
`6.
`
`7.
`8.
`
`9.
`
`K. Monah, K. Bharamaramba, and R. V. Venkataraman, Chem. 1nd., 125 (1978).
`G. Henbach. L. Emmel, and A. Waltersdorfer, Ger. Offen 2725148; Chem. Abstr., 29,
`196956 (1979).
`Ischikawa, and T. Kawano, Japan Kokai Tokkyo Koho 78135981;
`S.
`lwai, M. Eatano, I.
`Chem. Abstr., 29. 152195 (1979).
`4. W. Manchot and R. Noll, 54}, 1 (1905).
`5.
`G. I. Chipens, R. P. Bokaldere, and V. Ya. Grinshtein, Khim. Geterotsikl. Soedin., No.
`1, 110 (1966).
`C. F. Kroger, K. Mietchen, H. Frank, M. Siemer, and S. Pilz, Chem. Ber., 192, 755
`(1969).
`‘
`G. I. Chipens and R. P. Bokaldere, Khim. Geterotsikl. Soedin., No. 2, 159 (1969).
`T. P. Kofman, I. V. Vasil'eva, and M. S. Pevzner, Khim. Geterotsikl. Soedin., No. 10,
`1407 (1977).
`T. P. Kofman, M. S. Pevzner, L. N. Zhukova, T. A. Kravchenko, and G. M. Frolova, Zh.
`Org. Khim., 16, 420 (1980).
`L. I. Bagal, M. S. Pevzner, and V. Ya. Samarenko, Khim. Geterotsikl. Soedin., No. 2,
`269 (1970).
`11. M. S. Pevzner, T. P. Kofman, E. N. Kibasova, L. F. Sushchenko, and T. L. Uspenskaya,
`Khim. Geterotsikl. Soedin., No. 2, 257 (1980).
`T. P. Kofman, T. L. Uspenskaya, N. Yu. Medvedeva, and M. S. Pevzner, Khim. Geterotsikl.
`Soedin., No. 7, 991 (1976).
`T. P. Kofman, N. Yu. Medvedeva, T. L. Uspenskaya, and M. S. Pevzner, Khim. Geterotsikl.
`Soedin., No. 9, 1271 (1977).
`A. M. Ostapkovich, T. P. Kofman, L. V. Lisitsyna, and M. S. Pevzner, Izv. Vyssh.
`.
`Uchebn. Zaved., Khim. Khim. Tekhnol., 22, 402 (1979).
`T. P. Kofman, G. A. Zykova, V. I. Manuilova, T. N. Timofeeva, and M. S. Pevzner. Khim.
`Geterotsikl. Soedin., No. 7, 997 (1974).
`16. A. A. Stotskii and N. N. Tkacheva, Zh. Org. Khim., 19} 2232 (1974).
`
`10.
`
`12.
`
`13.
`
`14.
`
`15.
`
`TETRAZOLES.
`
`9.* ACIDmBASE PROPERTIES OF S—SUBSTITUTED TETRAZOLES
`
`V. A. Ostrovskii, G. I. Koldobskii,
`N. P. Shirokova, and V. S. Poplavskii
`
`UDC 547.796.11541.121
`
`The basicities of series of S-R-tetrazoles in aqueous solutions of sulfuric acid
`were studied by UV and PMR spectroscopy.
`The pKBH+ values of these compound
`correlate with the op substituent constants.
`The transmission factor of the
`p—phenylene ring (n' = 0.23) was calculated from the ratio of the reaction con-
`stants for protonation of substituted 5-phenyltetrazoles and S-R—tetrazoles.
`A
`linear dependence between the pKa values and the PKBH+ values of 5-substituted
`tetrazoles was established.
`
`It is known that tetrazoles and 5-substituted tetrazoles are heterocyclic N—H acids
`with moderate strength. When these compounds are dissolved in mineral acids,
`they behave
`like weak organic bases [2].
`
`P
`.\
`
`R\
`
`Ci”3
`H+
`Ctifii
`n+
`145;% ::;__ J
`1
`-—"~
`"xii/l
`\N%
`
`R.
`
`\C-TNH
`/r.n
`HNQNVN
`
`*See [1] for Communication 8.
`
`Lensovet Leningrad Technological Institute, Leningrad 198013. Translated from Khimiya
`Geterotsiklicheskikh Soedinenii, No. 4, pp. 559-562, April, 1981. Original article sub-
`mitted May 21, 1980.
`
`412
`
`0009—3122/81/1704‘0412$07‘50
`Page1 of5
`
`.
`© 1981 Plenum Publishing Corporation
`
`LUPIN EX 1038
`
`LUPIN EX 1038
`
`Page 1 of 5
`
`
`
`Although tetrazole and 5-substituted tetrazoles theoretically can exist in the form of
`l-Hr and 2—H—tautomers, it has been shown in many cases that the 1—H form is preferred.
`Thus the acidities of tetrazoles are actually estimated from the pKa values of the 1-H-
`tautomers.
`
`The protonation of tetrazoles in aqueous solutions of sulfuric and perchloric acids is
`described by the Ho acidity function.
`Since the distribution of the electron density over
`the tetrazole ring has its maximum value on the l and 4 nitrogen atoms [3],
`the addition
`of a proton may lead to the formation of two tautomers. This possibility cannot be ex-
`cluded during a study of the protonation of these compounds. Nevertheless,
`the available
`significant amount of experimental data on the basicities of tetrazoles with various struc-
`tures [2] makes it possible to assume that the protonation center is the ring 3 atom. Below
`we present new data on the effect of the nature of the substituents attached to the ring
`carbon atom on the acidities and basicities of tetrazoles and we also discuss the inter—
`
`relationship between the acidities and the basicities of these compounds.
`
`It has been previously shown that the acidities of substituted 5—phenyltetrazoles
`change only slightly, despite the wide variation in the electronic properties of the sub—
`stituents [4].
`The relatively low value of reaction constant p
`(1.27) constitutes evidence
`for the weak effect of the substituent attached to the ring carbon atom on the acidities of
`these compounds in water.
`A similar principle is observed during a study of the acidities
`of Substituted 5-phenyltetrazoles in aqueous alcohol solutions and in the dimethyl sul-
`foxide (DMSO)—water system [5].
`
`The reaction constants for the indicated solvents are, respectively, 1.52 and 1.67.
`the same time,
`the dependence of the pKa values of acidic dissociation in water on the
`At
`op substituent constants for S-R—tetrazoles (R = CH3,* H“, Br, I, CF3, and N02”) has
`the
`form
`
`pga: _ (6‘65t0,60) 5.1+ (446:0‘27),
`r=O.98, 11:6. s=o.5,
`
`It follows from this that in the acidic dissociation of substituted 5-phenyltetrazoles
`the phenyl ring isolates to a considerable extent
`the reaction center from the electronic
`effect of the substituent.
`In this case a quantitative measure of the bridging effect of the
`phenyl ring is transmission factor n' = 0.19 [9], which is calculated from the ratio of the
`reaction constants for acidic dissociation in water of substituted 5—phenyltetrazoles and
`S-R—tetrazoles.
`
`No less interesting information regarding the transmission of the electronic effects of
`substituents through the phenyl ring can evidently be obtained by a comparison of the
`basicity constants of substituted 5~phenyltetrazoles and S-thetrazoles.
`The basicities of
`substituted 5-phenyltetrazoles depend relatively little on the nature of the substituents in
`the-phenyl ring [10].
`Thus the PKBH+ values of 5*(o-methylphenyl)- and 5—(p~nitrophenyl)-
`tetrazoles are, respectively, —l.96 and-4.l9.
`The reactivity constant p = 1.80 obtained
`from the dependence of the PKBH+ values of substituted 5-phenyltetrazoles on the 0 sub—
`stituent constants also constitutes evidence for the low sensitivity of protonation to the
`effect of the substituents.
`Since data on the basicities of 5-substituted tetrazoles that
`
`contain “simple" substituents are not available, for comparison with substituted S—phenyl—
`tetrazoles we selected a series of S-R—tetrazoles,
`the protonation of which was studied in
`aqueous solutions of sulfuric acid by UV and PMR spectroscopy (Table l).
`The basicity con—
`stants of S—R-tetrazoles were calculated from the expression
`
`mi]
`10g]: me0+pKIBH+1Wh6ICISW'
`
`(1)
`
`(1) are close to unity (Table 1).
`For all of the investigated compounds slopes m in Eq.
`Consequently, it may be assumed that S-R-tetrazoles are protonated in the same way as Hammett
`bases and that the thermodynamic PKBH+ values can be obtained by division of the free term
`of Eq.
`(1) by slope m.
`The thermodynamic pKBH+ values of S-R-tetrazoles correlate with the
`op substituent constants:
`
`PKBH+= — (7.83:0350)on — (2.88:0.50),
`r=O.99, n=6, 5:040,
`
`*The pKa values were obtained by the authors for individual compounds taken from [6—8].
`
`Page 2 of 5
`
`413
`
`Page 2 of 5
`
`
`
`30
`
`4 o
`
`5 o
`70
`
`6
`
`a d
`
`9°
`
`0 10
`
`4
`
`2
`
`o
`
`;.-L__._J_._~J—.—L—_§l—_Z
`2
`4
`6
`8
`
`n
`
`pK8H+
`
`Fig. 1. Dependence of the pKa and pHBH*
`values of 5-substituted tetrazoles:
`l)
`5—methyltetrazole; Z)
`tetrazole; 3)
`5-(p—methoxyphenyl)tetrazole; 4) 5—(m-
`chlorophenyl)tetrazole; 5)
`(m-nitro-
`phenyl)tetrazole; 6) 5—(p-nitrophenyl)-
`tetrazole; 7) 5-(o-nitrophenyl)tetrazole;
`8) 5—iodotetrazole; 9) 5-bromotetrazole;
`lO) 5-trifluoromethyltetrazole; ll)
`S-nitrotetrazole.
`
`TABLE 1. Protonation of S—RrTetrazoles in Aqueous Solutions
`of H2501, at 25°C
`
`R
`
`CH3
`H
`Br
`1
`CF3
`N02
`
`M31909 0f in-
`vestigation
`(9’ mm)
`
`PMR
`PMR
`UV
`UV
`UV
`UV
`UV
`
`(200)
`(230)
`(210)
`(235)
`(240)
`
`10g {=—mHa+pK’BH+
`
`m
`
`‘DK’BIfi‘
`
`_pKBH+
`
`l
`
`r
`
`
`
`0,93i0,02
`0,86 :0,06
`0,91 i006
`088:0,05
`0,90i0,02
`1,00 i006
`0,95:0,05
`
`'1 ,83
`1,+60 0,04
`2,+28 0,12,68
`4, 72' 0,30
`5,20
`3,87i 0 20
`4,40
`6, 30+ 0,1
`7,00
`9 ,2_8 0,20
`9,26 ,
`9, 281w 0,2
`
`0,99
`0,96.
`0,99
`0,99
`0,97
`0,99
`0,99
`
`n
`
`8
`19
`7
`7
`8
`8
`8
`
`1
`
`3
`
`0,03
`0,18
`0,12
`0,10
`0,20
`0,13
`0,09
`
`TABLE 2. Protonation of Substituted Tetrazoles in Aqueous
`Solutions of H280“ at 25°C
`
`10g1=—ch+pK’DII+
`
`M69109.“ in-
`R
`vesngauon
`
`“Wren“F
`{
`(0, firm)
`I
`m
`,
`“P‘K'mf‘?
`1 -Methy1-5 -R -tetraz 0165
`0,98i0, 02
`2,941" 0,01
`0.99:004
`1,66i0,07
`O,95i0,10
`8,84i0,60
`
`H
`CH3
`N02
`
`PMR
`PMR
`UV (240)
`
`
`
`
`
`
`
`3,00
`1,68
`9,31
`
`r
`
`I
`
`n
`
`(
`
`
`
`0,99
`0,99
`0,97
`
`{
`
`
`
`s
`
`0,04
`0,08
`0,17
`
`0,06
`0,03
`
`10
`8
`7
`
`10
`8
`
`H
`N02
`
`PMR
`UV
`
`(245)
`
`2-Methyl-S-R-tetrazoles
`091 i0,08
`2,96:0,10
`0, 99$ 0,02
`8,97i0,19
`
`3,25
`9,06
`
`' 0,99
`0,99
`
`Thus it is apparent that the PKBH+ value undergoes a change of seven orders of magni—
`tude on passing from 5—methy1-
`to 5-nitrotetrazole. This circumstance may be associated
`either with a shift of the protonation center or with the electronic effect of the sub-
`stituents.
`
`including substituted
`tetrazoles with different structures,
`As we have already noted,
`5—phenyltetrazoles, undergo protonation at the nitrogen atom in the 4 position of the ring
`in aqueous solutions of mineral acids.
`The correlation of the pKBH+ values of S-R—tetrazoles
`with the Up substituent constants means that the addition of a proton to the tetrazole ring
`
`414
`
`Page 3 of 5
`
`Page 3 of 5
`
`
`
`for all of the members of the reaction series occurs at one and the same reaction center.
`
`However, on the basis of this one cannot answer the question as to which of the nitrogen
`atoms of the ring (1 or 4) is the protonation center. This information can be obtained by
`a comparison of the basicities of 5-R-tetrazoles and their 1— and 2—methyl-substituted de-
`rivatives (Table 2). All of the compounds presented in Table 2 are Hammett bases.
`It is
`apparent (Tables 1 and 2)
`that 5~methyltetrazole is a stronger base than the isomeric
`l—methyl— and 2—methyltetrazoles, while 1,5-dimethyltetrazole differs virtually not at all
`from 5—methyltetrazole.
`The basicity constants of 5—nitrotetrazole and l—methyl- and
`2-methy1—S—nitrotetrazoles are also very close to one another.
`A similar principle can be
`observed by comparing the basicities of 5—phenyltetrazole and l-methyl— and 2—methy1—5-
`phenyltetrazoles [11].
`It follows from this that the addition of a proton to 5-thetra—
`zoles, just as in the case of 5-phenyltetrazoles,
`takes place at the nitrogen atom in the
`4 position of the ring, since otherwise all l-methyl- and 2-methyl-5—R—tetrazoles should be
`stronger bases than the corresponding 5-R—substituted compounds.
`
`the reaction constants for protonation of Substituted 5-phenyl—
`On the basis of this,
`tetrazoles and S-R-tetrazoles can be used to calculate the transmission factor.
`The small
`
`transmission factor w' = 0.23 means that in the protonation, just as in acidic dissociation,
`of substituted 5-phenyltetrazoles the phenyl ring substantially insulates the reaction cen—
`ter from the electronic effect of the substituent.
`
`Thus it is evident that the effect of substituents on the acidites and basicities of
`
`5—substituted tetrazoles is manifested in the same way and that a linear dependence should
`consequently exist between the pKa and pKBH+ values of
`these compounds.
`In fact,
`this sort
`of correlation does exist
`(see Fig.
`l) and is described by the equation
`
`pKa=(078i003pK§H++(63flt02®,r=098,n:dl,s=03.
`
`,
`
`(m
`
`It should be noted that expression (2) encompasses a rather broad range of changes in the
`pKa and pKBH+ values, and this makes it possible to make a quantitative evaluation of the'
`acid—base properties of S-substituted tetrazoles with the most diverse structures.
`
`EXPERIMENTAL
`
`The tetrazole and the disubstituted tetra201es were obtained by known methods. All of
`the compounds had characteristics that were in agreement with the literature data [6—8, 12,
`13]. Aqueous buffer solutions with ionic strength u 0.01 were prepared by the method in
`[14].
`The sulfuric acid solutions were obtained by dilution of 96% H280“ (especially pure—
`grade) with twice-distilled water, while solutions with higher concentrations were prepared
`by the addition of oleum (analytical—grade).
`The concentrations were determined by poten—
`tiometric titration with a 0.1 N solution of NaOH with an accuracy of r0.l%.
`The acidity
`constants of tetrazole (pKa = 4.86 i 0.02) and 5-methyltetrazole (pKa = 5.50 i 0.01) in
`water were determined by potentiometry in a thermostatted cell (25 i 0.1°C) with a pH—lZl
`pH meter.
`The acidity constants of S—nitrotetrazole (pKa =‘—0.83i0.03)were determined
`spectrophotometrically in aqueous buffer solutions and aqueous solutions of sulfuric acid.
`During the study of the acidities and basicities of the tetrazoles the UV spectra were re—
`corded with an SF-26 spectrophotometer with a thermostatted block (25 : 0.l°C);
`the
`analytical concentrations of the tetrazoles were «11-10—5 mole/liter.
`The PMR spectra were
`recorded with a Perkin—Elmer R-12 spectrometer;
`the analytical concentrations of the tetra-
`zoles were Wl'IO—z mole/liter, and the internal standard was tetramethylammonium bromide.
`The values of the Ho and H_ acidity functions Were taken from [15, 16].
`The experimental
`data were processed by the methods presented in [4, 10}.
`
`LITERATURE CITED
`
`1.
`
`2.
`
`3.
`
`4.
`
`V. A. Ostrovskii, G. I. Koldobskii, and 1. Yu. Shirobokov, Zh. Org. Khim., 11, 146
`(1981).
`G. I. Koldobskii, V. A. Ostrovskii, and B. V. Gidaspov, Khim. Geterotsikl. Soedin.,
`No. 7, 867 (1980).
`V. A. Ostrovskii, N. S. Panina, G. I. Koldobskii, B. V. Gidaspov, and 1. Yu. Shirobokov,
`Zh. Org. Khim., 12) 844 (1979).
`V. A. Ostrovskii, G. I. Koldobskii, N. P. Shirokova, 1. Yu. Shirobokov, and B. V.
`Gidaspov, Zh. Org. Khim., 13) 1697 (1978).
`
`Page 4 of 5
`
`A15
`
`Page 4 of 5
`
`
`
`5.
`
`J. Kaczmarek, H. Smagowski, and Z. Grzonka, J. Chem. Soc., Perkin II, No. 12, 1670
`(1979).
`
`10.
`
`J. S. Mihina and R. M. Herbst, J. Org. Chem., 1:, 1082 (1950).
`6.
`E. Lieber, S. Patinkin, and H. H. Tao, J. Am. Chem. Soc., 12, 1792 (1951).
`7.
`8. W. P. Norris, J. Org. Chem., 21, 3248 (1962).
`9. Yu. A. Zhdanov and V. I. Minkin, Correlation Analysis in Organic Chemistry [in Rus-
`sian], Rostov—on—Don (1966), p. 56.
`V. N. Strel'tsova, N. P. Shirokova, G. I. Koldobskii, and B. V. Gidaspov, Zh. Org.
`Khim.,_1g, 1081 (1974).
`A. V. Moskvin, V. A. Ostrovskii, I. Yu. Shirobokov, G. I. Koldobskii, and B. V.
`Gidaspov, Zh. Org. Khim., 14, 2440 (1978).
`R. A. Henry and W. G. Finnegan, J. Am. Chem. Soc., 16. 290 (1954).
`12.
`R. A. Henry and W. G. Finnegan, J. Am. Chem. Soc., 26, 923 (1954).
`13.
`D. D. Perrin, Aust. J. Chem., 16, 572 (1963).
`14.
`15. M. I. Vinnik, USp. Khim., §§) 1922 (1966).
`16.
`R. H. Boyd, J. Am. Chem. Soc., 93; 4288 (1961).
`
`11.
`
`416
`
`Page 5 of 5
`
`Page 5 of 5
`
`