`
`1.
`2.
`
`3.
`
`6.
`
`7.
`8.
`
`9.
`
`10.
`
`K. Monah, K. Bharamaramba, and R. V. Venkataraman, Chem. 1nd., 125 (1978).
`G. Henbachg L. Emmel, and A. Waltersdorfer, Ger. Offen 2725148; Chem. Abstr., 90,
`196956 (1979).
`.-
`S. Iwai, M. Eatano, I.
`Ischikawa, and T. Kawano, Japan Kokai Tokkyo Koho 78135981;
`Chem. Abstr., 29} 152195 (1979).
`4. W. Manchot and R. Noll, ggg, 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. Vasi1'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.,_1§, 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).
`
`12.
`
`13.
`
`14.
`
`15.
`
`TETRAZOLES.
`
`9.* ACID~BASE PROPERTIES OF 5—SUBSTITUTED TETRAZOLES
`
`V. A. Ostrovskii, G. 1. Koldobskii,
`N. P. Shirokova, and V. S. Poplavskii
`
`UDC 547.796.1:541.12l
`
`The basicities of series of 5-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—pheny1ene ring (n' = 0.23) was calculated from the ratio of the reaction con-
`stants for protonation of substituted 5-phenyltetrazoles and 5-R—tetrazo1es.
`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].
`
`H\
`CT "19
`\\ ..
`Jbfi
`.,N/
`
`+
`
`H
`
`*See [1] for Communication 8.
`
`R\
`
`+
`
`9
`
`‘\c__..N u
`C-—-NH
`\ I
`J,A W_*H$Qh
`\N/
`\N/
`
`Lensovet Leningrad Technological Institute, Leningrad 198013. Translated from Khimiya
`Geterotsiklicheskikh Soedinenii, No. 4, pp. 559-562, April, 1981. Original article sub-
`mitted May 21, 1980.
`
`412
`
`000973122/81/1704'O4l2$O7‘50
`Page1 of5
`
`© 1981 Plenum Publishing Corporation
`
`LUPIN EX1o38
`
`LUPIN EX 1038
`
`Page 1 of 5
`
`
`
`Although tetrazole and 5-substituted tetrazoles theoretically can exist in the form of
`l-H- 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 5-R—tetrazoles (R = CH3,* H“, Br, I, CF3, and N02“) has
`the
`form
`
`pKa=—{665:0fimon+(4A6:O2fl,
`r=O3&n=6s=05
`
`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 5—R-tetrazoles.
`The basicities of
`substituted 5—phenyltetrazoles depend relatively little on the nature of the substituents in
`the-phenyl ring [l0].
`Thus the pKBH+ values of 5-(o-methylphenyl)— and 5—(p-nitrophenyl)-
`tetrazoles are, respectively, -1.96 and-4.19.
`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 5-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 5—R-tetrazoles were calculated from the expression
`+
`TH
`
`log]: ”mH0+pK’BH+,wheIe1:{—[]T].
`
`(1)
`
`(1) are close to unity (Table l).
`For all of the investigated compounds slopes m in Eq.
`Consequently, it may be assumed that 5-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 5-R-tetrazoles correlate with the
`op substituent constants:
`
`pKBH+: _ (7.83:0.60)on - (2.88:O.5D),
`r=OB9,n=6,S=0AO
`
`*The pKa values were obtained by the authors for individual compounds taken from [6—8].
`
`Page2of5
`
`413
`
`Page 2 of 5
`
`
`
`30
`
`4o
`
`50
`7°
`
`6
`
`_
`191,‘
`
`9°
`
`Q10
`
`4
`
`2
`
`0
`
`.L__...L___._1__._._.L___|__._.L_;j._;
`2
`4
`5
`8»
`
`,1
`pKaH+
`
`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;
`10) 5-trifluoromethyltetrazole; ll)
`5—nitrotetrazole.
`
`TABLE 1. Protonation of 5—RrTetrazo1es in Aqueous Solutions
`of H250, at 25°C
`
`R
`
`CH3
`H
`Br
`1
`CF3
`N02
`
`Method of m—
`vestigation
`0" mm)
`
`PM-R
`PMR
`UV
`UV
`UV
`UV
`UV
`
`(200)
`(230)
`(210)
`(235)
`(240)
`
`1og,=_m,,O+pK,BH+
`
`m
`
`‘1’K'IsII+
`
`!
`
`‘F’K13H"’
`
`l
`
`r
`
`
`
`0,93i0,02
`0,86 ;*:0,06
`0,91 i0,06
`0,88:0,05
`0,90i0,02
`1,00i~0,06
`0,95i0,05
`
`1,60 -_t0,04
`2,28-_*-0,14
`4,72i0,30
`3,87:0,20
`6,30i0,14
`9,28:0,20
`9,28 i0,22
`
`1,83
`2,68
`5,20
`4,40
`7,00
`9,26 V
`
`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
`0,13
`0,12
`0,10
`0,20
`0,13
`0,09
`
`TABLE 2. Protonation of Substituted Tetrazoles in Aqueous
`Solutions of H280. at 25°C
`
`Met_h°d_°f in‘
`vesngauorl
`O‘: 317?)
`
`
`I
`
`m
`
`R
`
`1-I
`CH3
`N02
`
`H
`NO2
`
`PMR
`PMR
`UV (240)
`
`PMR
`UV
`
`(245)
`
`
`
`!
`
`r
`
`1
`
`n
`
`(
`
`
`
`0,99
`0,99
`0,97
`
`1
`
`
`
`s
`
`0,04
`0,08
`0,17
`
`0,06
`0,03
`
`10
`8
`7
`
`10
`8
`
`1OgI=~mHn+pK’DH+
`
`‘’DKBH+
`{
`‘‘l‘’K'nxr‘*
`1
`1 -Methyl -5 -R -tetraz oles
`0,98i0,02
`2,94fl:0,01
`0,99i0,04
`1,60i0,07
`0,95iO,l0
`8,84i0,60
`
`
`
`
`
`3,00
`1,58
`9,31
`
`2—Methy1-5—R-tetrazoles
`I 0.91:0,03
`2,96:O,10
`0,99i0,02
`8,97i0,19
`
`3,25
`9,06
`
`‘Q99
`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—phenyltetrazo}.es, 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 5-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~methy1tetrazo1e is a stronger base than the isomeric
`l—methy1— 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—methyl—5—nitrotetrazoles are also very close to one another.
`A similar principle can be
`observed by comparing the basicities of 5—pheny1tetrazo1e and l-methyl- and 2—methyl—5-
`phenyltetrazoles [11].
`It follows from this that the addition of a proton to 5-Rrtetra—
`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 5-R-tetrazoles can be used to calculate the transmission factor.
`The small
`
`transmission factor n‘ = 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. 1) and is described by the equation
`
`PKa=(078i00$pK§H++(&3TtQ2®,r=0B8,n=J1,S=03.
`
`,
`
`(§
`
`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 tetrazoles 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% H2804 (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 :O.l%.
`The acidity
`constants of tetrazole (pKa = 4.86 r 0.02) and 5—methyltetrazole (pKa = 5.50 i 0.01) in
`water were determined by potentiometry in a thermostatted cell (25 i O.l°C) with a pH—l2l
`pH meter.
`The acidity constants of 5—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 : O.l°C);
`the
`analytical concentrations of the tetrazoles were N1-10's mole/liter.
`The PMR spectra were
`recorded with a Perkin—Elmer R-l2 spectrometer;
`the analytical concentrations of the tetra-
`zoles were ml'l0—2 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).
`
`Page4of5
`
`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., 16, 1082 (1950).
`6.
`E. Lieber, S. Patinkin, and H. H. Tao, J. Am. Chem. Soc., 16, 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. Stre1'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., Z6, 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., 66, 1922 (1966).
`16.
`R. H. Boyd, J. Am. Chem. Soc., 66, 4288 (1961).
`
`11.
`
`416
`
`Page 5 of 5
`
`Page 5 of 5