Harrison, Melody K.

Setliff, Frank L.

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Journal of the Arkansas Academy of ScienceVolume 54 Article 202000Hammett Correlations of the Amide ProtonChemical Shift in a Series of1-Tosyl-3-(4-substituted phenyl)ureasFrank L. SetliffUniversity of Arkansas at Little RockMelody K. HarrisonUniversity of Arkansas at Little RockFollow this and additional works at: http://scholarworks.uark.edu/jaasPart of the Organic Chemistry CommonsThis article is available for use under the Creative Commons license: Attribution-NoDerivatives 4.0 International (CC BY-ND 4.0). Users are able toread, download, copy, print, distribute, search, link to the full texts of these articles, or use them for any other lawful purpose, without asking priorpermission from the publisher or the author.This Article is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Journal of the Arkansas Academyof Science by an authorized editor of ScholarWorks@UARK. For more information, please contact scholar@uark.edu.Recommended CitationSetliff, Frank L. and Harrison, Melody K. (2000) "Hammett Correlations of the Amide Proton Chemical Shift in a Series of1-Tosyl-3-(4-substituted phenyl)ureas," Journal of the Arkansas Academy of Science: Vol. 54 , Article 20.Available at: http://scholarworks.uark.edu/jaas/vol54/iss1/20117Hammeti l^orrelations of the Amide JProton C^hemiccil Shitt in a, oeriesof l-Tosyl-3-(4-substituted phenyl)ureasFrank L.Setliff* and Melody K.HarrisonDepartment of ChemistryUniversity of Arkansas at Little RockLittle Rock, AR 72204""Corresponding AuthorAlthough direct insulin administration is the primarystrategy for the management of diabetes, certain agents havebeen found to stimulate the production ofinsulin in the pan-creas and, therefore, offer an alternative managementoption. Notable among these hypoglycemic agents are thesulfonylureas l-tosyl-3-butylurea (tolbutamide) and 1-tosyl-3-(N-piperidyl)urea (Gilman, 1985). Aryl sulfonyl ureashave also received attention as potential anticancer agents.Howbert and coworkers prepared and studied 143 suchcompounds, several of which were l-tosyl-3-(substitutedphenyl)ureas (Howbert et al., 1990). The l-tosyl-4-chlorophenyl derivative was found to have antitumor activ-ity. A closely related compound, l-(5-indanesulfonyl)-3-(4-chlorophenyl)urea, proved sufficiently active to warrantlarge scale production for clinical trials by EliLillyCo. andwas assigned the generic name sulofenur.Because of the medicinal importance of tosylureas andour previous studies of aryl substituent effects on the amidelinkage of benzamides (Setliff et al., 1995), nicotinamides(Setliff et al., 1992) and p-toluenesulfonamides (Setliff andSpradlin, 2000), we undertook the present investigation ofthe l-tosyl-3-(4-substituted phenyl)urea system. As in ourprevious work, we prepared a series of compounds with avariety of substituents (G) in the 4-phenyl position, obtainedtheir lHNMR spectra in DMSO, and attempted to corre-late the amide proton chemical shifts with the standardHammett substituent constants (oq ) ( Exner, 1988). Unlikeprevious amide systems investigated, the presenttosylarylurea system has two amide protons to be moni-tored, namely the anilide proton (on the nitrogen bonded tothe benzene ring) and the sulfonamide proton (between thesulfonyl and carbonyl groups).The series of l-tosyl-3- (substituted phenyl) ureas (Table1) were synthesized by the reaction of tosyl isocyanate(Aldrich) with the appropriate substituted aniline in drychloroform (Fig. 1).Table 1. Experimental data for the l-tosyl-3 -(4-substitutedphenyl)ureasCpd. # G % Yield M.P. (°C)1 H 81.4 170.5-171.52 CH3 99.2 152-1533 F Quant. 172-1734 OCH3 71.9 157-1585 Cl 90.3 176-176.56 CF3 72.4 189-1907 COCH3 82.2 182-182.58 CN'87.8 196-1979 NO2 91.1 245-247 d.10 4-Br-3-CH3 86.0 185-18611 3-CI-4-OCH3 Quant. 174-175The experimental preparation of the ureas was carriedout as follows: All substituted anilines were distilled orrecrystallized prior to use. The mass of the 4-substituted ani-line needed to react exactly with0.40mL (0.516 g) of the iso-cyanate was calculated for each reaction. This quantity ofamine was dissolved in dry chloroform (2.0 mL)(8.0 mLrequired for 4-nitroaniline), and 0.40 mL tosyl isocyanatewas then added quickly by syringe. In most cases anexothermic reaction occurred, and a solid began to form ina matter of seconds. The resulting suspension was stirredunder gentle reflux for 15 min. When instantaneous precip-itation did not occur, the clear solution was heated underreflux for one hour and then cooled or evaporated to isolatethe product. The crude tosylureas were washed on the vac-uum filter with cold chloroform and then recrystallized fromethanol- water (the 4-nitro derivative required benzene).Experimental data are summarized in Table 1. All com-pounds have been prepared previously (Howbert et al.1990) by a slightly different procedure, some in lower yield.Fig. 1. Preparation of the l-tosyl-3 (4-substituted phenyl)ureasJournal of the Arkansas Academy of Science, Vol.54, 2000117Journal of the Arkansas Academy of Science, Vol. 54 [2000], Art. 20Published by Arkansas Academy of Science, 2000>?»»•?>118Melting points of our compounds were in good agreementwith those reported by Howbert's group. Our compoundswere further characterized by IR and *H NMR analysis.The infrared spectra of all compounds (KBr disks; NicoletMagna FT-IR spectrophotometer) exhibited the expectedabsorbtions for the anilide and sulfonamide NHstretch, thesulfonyl O=S=O symmetrical and unsymmetrical stretches,and the anilide carbonyl stretch. The proton spectra of allcompounds (Bruker AC-F 200 MHz instrument, DMSO^;as solvent withTMS as internal standard) exhibited, inaddi-tion to the anilide and sulfonamide proton signals (Table 2),all other expected resonances with the expected multiplici-ties and integration.Table 2.Proton chemical shift data and Hammett substituentconstantsSulfonamide AnilideCpd. # 5NH (ppm) 8NH (ppm) Gq1 10.65 8.82 02 10.67 8.71 -0.143 10.75 8.89 0.064 10.59 8.65 -0.285 10.79 9.00 0.226 11.01 9.28 0.537 11.05 9.24 0.478 11.10 9.37 0.719 11.15 9.56 0.8110 10.78 8.89 0.16*11 10.73 8.83 10.10**additive valueAs shown in Fig. 2, good linear correlation of the amidechemical shifts (S^h) with the standard Hammett sub-stituent constants (gq) was obtained. The correlation equa-tions with their correlation coefficients areanilide proton 8NH-0.82 oG + 8.84 r2 = 0.99sulfonamide proton 8NH=0.55 CTq + 10.72 r2 =0.96The better correlation of the anilide shifts can be ascribed tothe fact that this proton is closer to the G substituent, andelectronic effects can act more proportionately.Analysis of the two equations provides additional infor-mation. The positive slopes (Hammett p value) indicate thatthe chemical shifts are sensitive to electron withdrawinggroups (a standard values > 0). As G becomes more elec-tron withdrawing the acidity of the amide proton increases,permitting more efficient hydrogen bonding of the hydro-gen with DMSO solvent, thus resulting in a farther down-field shift. The more positive anilide slope indicates theeffect of G on the anilide proton is greater than its effect onthe sulfonamide proton. This is easily explained in terms ofthe closer proximity of G to the former where the shortrange inductive and resonance effects can operate more effi-ciently. The magnitude of the Y intercept is a reflection ofFig. 2. Correlation of amide proton chemical shifts withHammett substituent constantsthe relative acidity of the two protons. Therefore, the sul-fonamide proton (intercept 10.72) is demonstrated to bemore acidic than the anilide proton (intercept 8.84). This ispredictable inview of the former being situated between thesulfonyl and carbonyl groups.Inorder to test for additivity of the electronic effects oftwo susbstituents upon the chemical shifts, we prepared twol-tosyl-3-(3,4-diubstituted aryl)ureas, namely the 4-bromo-3-methyl derivative (cpd 10, Table 2) and the 3-chloro-4-methoxy compound (cpd 11, Table 2). For compound 10,the numerical sum of the a values for 4-bromo (0.22) and 3-methyl (-0.06) when substituted into the respective correla-tion equations predicts a 8NH value of 8.97 ppm for theanilide proton and 10.80 ppm for the sulfonamide proton.The experimental values obtained were 8.89 and 10.78ppm, both within 1% of the calculated values. Similarly, forcompound 11, the numerical sum of the G values for 4-methoxy (-0.28) and 3-chloro (0.37), when inserted into theequations, yielded a predicted chemical shift of 8.91 ppm forthe anilide proton and 10.77 ppm for the sulfonamide pro-ton. The respective experimental values were 8.83 and10.73 ppm. Again, calculated and observed values werewithin 1%. These results suggest strongly that the electroniceffects on the proton chemical shift of both urea amide pro-tons are additive.In summary, we conclude that the acidity/hydrogenbonding ability of both urea protons can be controlled bythe nature of the substituent in the 4-position inaccordanceJournal of the Arkansas Academy of Science, Vol. 54, 2000.1118Journal of the Arkansas Academy of Science, Vol. 54 [2000], Art. 20http://scholarworks.uark.edu/jaas/vol54/iss1/20;??»»?119with Hammett theory, and that the effects of substituents inthe 3-and 4-position operate in an additive fashion.Although all data were obtained in DMSO solvent, extrap-olation of these data to aqueous systems could prove usefulinprediction of hypoglycemic activity and/or developmentofsynthetic strategies for the preparation of sulfonyl ureas asfurther candidates for antitumor therapy.Acknowledgments.—The authors gratefully acknowl-edge Dr. TitoViswanathan for helping with the database lit-erature search and Mr. Kirk Babb for assisting with theNMR spectra acquisition.Literature CitedExner, O. 1988. Correlation analysis of chemical data,pp 133-135. Plenum Press, New York, 275 pp.Gilman, A. G. 1985. Oral hypoglycemic agents, pp 1504-1507 in The pharmaceutical basics of therapeutics, 7"1ed. (L. S. Goodman, ed.) MacMillan, New York, 1839pp.Howbert, J. J., C. S. Grossman, T. A. Crowell, B. J.Rieder, R. W. Harper, K. E. Kramer, E. V. Tao, J.Aikins,G. A.Poore, S.M.Rinzel, G. B.Grindey, W.N.Shaw, and G. C. Todd. 1990. Novel agents effectiveagainst solid tumors: the diarylsulfonylureas. Synthesis,activities, and analysis of quantitative structure activityrelationships. J. Med. Chem. 33: 2393-2407.Setliff, F. L., N. G. Soman, J. Z. Caldwell and D. L.Rogers. 1992. Hammett correlations in the proton nmrspectra of some N-aryldihalonicotinamides. Proc. ARAcad. Sci. 46: 72-74.Setliff, F. L., N. G. Soman, and A. D. Toland. 1993.Determination of Hammett pyridine 3-aza and 4-azareplacement constants by 'HNMRspectroscopy. Proc.AR Acad. Sci. 47: 107-109.Setliff, F. L., N. G. Soman, and A. A Toland. 1995.Hammett correlations of amide proton chemical shifts.J. Chem. Ed. 72: 362-363.Setliff, F. L.,and T. K. Spradlin. 2000. Hammett correla-tions of the sulfonamide proton chemical shift ina seriesof N-(4-substituted aryl)-p-toluenesulfonamides. J. ARAcad. Sci. 54:102-105.Journal of the Arkansas Academy of Science, Vol. 54, 2000119Journal of the Arkansas Academy of Science, Vol. 54 [2000], Art. 20Published by Arkansas Academy of Science, 2000

Hammett Correlations of the Amide Proton Chemical Shift in a Series of 1-Tosyl-3-(4-substituted phenyl)ureas

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Journal of the Arkansas Academy of Science Volume 54 Article 20 2000 Hammett Correlations of the Amide Proton Chemical Shift in a Series of 1-Tosyl-3-(4-substituted phenyl)ureas Frank L. Setliff University of Arkansas at Little Rock Melody K. Harrison University of Arkansas at Little Rock Follow this and additional works at: https://scholarworks.uark.edu/jaas  Part of the Organic Chemistry Commons Recommended Citation Setliff, Frank L. and Harrison, Melody K. (2000) "Hammett Correlations of the Amide Proton Chemical Shift in a Series of 1-Tosyl-3-(4-substituted phenyl)ureas," Journal of the Arkansas Academy of Science: Vol. 54 , Article 20. Available at: https://scholarworks.uark.edu/jaas/vol54/iss1/20 This article is available for use under the Creative Commons license: Attribution-NoDerivatives 4.0 International (CC BY-ND 4.0). Users are able to read, download, copy, print, distribute, search, link to the full texts of these articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author. This Article is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Journal of the Arkansas Academy of Science by an authorized editor of ScholarWorks@UARK. For more information, please contact scholar@uark.edu. 117Hammeti l^orrelations of the Amide JProton C^hemiccil Shitt in a, oeriesof l-Tosyl-3-(4-substituted phenyl)ureasFrank L.Setliff* and Melody K.HarrisonDepartment of ChemistryUniversity of Arkansas at Little RockLittle Rock, AR 72204""Corresponding AuthorAlthough direct insulin administration is the primarystrategy for the management of diabetes, certain agents havebeen found to stimulate the production ofinsulin in the pan-creas and, therefore, offer an alternative managementoption. Notable among these hypoglycemic agents are thesulfonylureas l-tosyl-3-butylurea (tolbutamide) and 1-tosyl-3-(N-piperidyl)urea (Gilman, 1985). Aryl sulfonyl ureashave also received attention as potential anticancer agents.Howbert and coworkers prepared and studied 143 suchcompounds, several of which were l-tosyl-3-(substitutedphenyl)ureas (Howbert et al., 1990). The l-tosyl-4-chlorophenyl derivative was found to have antitumor activ-ity. A closely related compound, l-(5-indanesulfonyl)-3-(4-chlorophenyl)urea, proved sufficiently active to warrantlarge scale production for clinical trials by EliLillyCo. andwas assigned the generic name sulofenur.Because of the medicinal importance of tosylureas andour previous studies of aryl substituent effects on the amidelinkage of benzamides (Setliff et al., 1995), nicotinamides(Setliff et al., 1992) and p-toluenesulfonamides (Setliff andSpradlin, 2000), we undertook the present investigation ofthe l-tosyl-3-(4-substituted phenyl)urea system. As in ourprevious work, we prepared a series of compounds with avariety of substituents (G) in the 4-phenyl position, obtainedtheir lHNMR spectra in DMSO, and attempted to corre-late the amide proton chemical shifts with the standardHammett substituent constants (oq ) ( Exner, 1988). Unlikeprevious amide systems investigated, the presenttosylarylurea system has two amide protons to be moni-tored, namely the anilide proton (on the nitrogen bonded tothe benzene ring) and the sulfonamide proton (between thesulfonyl and carbonyl groups).The series of l-tosyl-3- (substituted phenyl) ureas (Table1) were synthesized by the reaction of tosyl isocyanate(Aldrich) with the appropriate substituted aniline in drychloroform (Fig. 1).Table 1. Experimental data for the l-tosyl-3 -(4-substitutedphenyl)ureasCpd. # G % Yield M.P. (°C)1 H 81.4 170.5-171.52 CH3 99.2 152-1533 F Quant. 172-1734 OCH3 71.9 157-1585 Cl 90.3 176-176.56 CF3 72.4 189-1907 COCH3 82.2 182-182.58 CN'87.8 196-1979 NO2 91.1 245-247 d.10 4-Br-3-CH3 86.0 185-18611 3-CI-4-OCH3 Quant. 174-175The experimental preparation of the ureas was carriedout as follows: All substituted anilines were distilled orrecrystallized prior to use. The mass of the 4-substituted ani-line needed to react exactly with0.40mL (0.516 g) of the iso-cyanate was calculated for each reaction. This quantity ofamine was dissolved in dry chloroform (2.0 mL)(8.0 mLrequired for 4-nitroaniline), and 0.40 mL tosyl isocyanatewas then added quickly by syringe. In most cases anexothermic reaction occurred, and a solid began to form ina matter of seconds. The resulting suspension was stirredunder gentle reflux for 15 min. When instantaneous precip-itation did not occur, the clear solution was heated underreflux for one hour and then cooled or evaporated to isolatethe product. The crude tosylureas were washed on the vac-uum filter with cold chloroform and then recrystallized fromethanol- water (the 4-nitro derivative required benzene).Experimental data are summarized in Table 1. All com-pounds have been prepared previously (Howbert et al.1990) by a slightly different procedure, some in lower yield.Fig. 1. Preparation of the l-tosyl-3 (4-substituted phenyl)ureasJournal of the Arkansas Academy of Science, Vol.54, 2000117Journal of the Arkansas Academy of Science, Vol. 54 [2000], Art. 20Published by Arkansas Academy of Science, 2000>?»»•?>118Melting points of our compounds were in good agreementwith those reported by Howbert's group. Our compoundswere further characterized by IR and *H NMR analysis.The infrared spectra of all compounds (KBr disks; NicoletMagna FT-IR spectrophotometer) exhibited the expectedabsorbtions for the anilide and sulfonamide NHstretch, thesulfonyl O=S=O symmetrical and unsymmetrical stretches,and the anilide carbonyl stretch. The proton spectra of allcompounds (Bruker AC-F 200 MHz instrument, DMSO^;as solvent withTMS as internal standard) exhibited, inaddi-tion to the anilide and sulfonamide proton signals (Table 2),all other expected resonances with the expected multiplici-ties and integration.Table 2.Proton chemical shift data and Hammett substituentconstantsSulfonamide AnilideCpd. # 5NH (ppm) 8NH (ppm) Gq1 10.65 8.82 02 10.67 8.71 -0.143 10.75 8.89 0.064 10.59 8.65 -0.285 10.79 9.00 0.226 11.01 9.28 0.537 11.05 9.24 0.478 11.10 9.37 0.719 11.15 9.56 0.8110 10.78 8.89 0.16*11 10.73 8.83 10.10**additive valueAs shown in Fig. 2, good linear correlation of the amidechemical shifts (S^h) with the standard Hammett sub-stituent constants (gq) was obtained. The correlation equa-tions with their correlation coefficients areanilide proton 8NH-0.82 oG + 8.84 r2 = 0.99sulfonamide proton 8NH=0.55 CTq + 10.72 r2 =0.96The better correlation of the anilide shifts can be ascribed tothe fact that this proton is closer to the G substituent, andelectronic effects can act more proportionately.Analysis of the two equations provides additional infor-mation. The positive slopes (Hammett p value) indicate thatthe chemical shifts are sensitive to electron withdrawinggroups (a standard values > 0). As G becomes more elec-tron withdrawing the acidity of the amide proton increases,permitting more efficient hydrogen bonding of the hydro-gen with DMSO solvent, thus resulting in a farther down-field shift. The more positive anilide slope indicates theeffect of G on the anilide proton is greater than its effect onthe sulfonamide proton. This is easily explained in terms ofthe closer proximity of G to the former where the shortrange inductive and resonance effects can operate more effi-ciently. The magnitude of the Y intercept is a reflection ofFig. 2. Correlation of amide proton chemical shifts withHammett substituent constantsthe relative acidity of the two protons. Therefore, the sul-fonamide proton (intercept 10.72) is demonstrated to bemore acidic than the anilide proton (intercept 8.84). This ispredictable inview of the former being situated between thesulfonyl and carbonyl groups.Inorder to test for additivity of the electronic effects oftwo susbstituents upon the chemical shifts, we prepared twol-tosyl-3-(3,4-diubstituted aryl)ureas, namely the 4-bromo-3-methyl derivative (cpd 10, Table 2) and the 3-chloro-4-methoxy compound (cpd 11, Table 2). For compound 10,the numerical sum of the a values for 4-bromo (0.22) and 3-methyl (-0.06) when substituted into the respective correla-tion equations predicts a 8NH value of 8.97 ppm for theanilide proton and 10.80 ppm for the sulfonamide proton.The experimental values obtained were 8.89 and 10.78ppm, both within 1% of the calculated values. Similarly, forcompound 11, the numerical sum of the G values for 4-methoxy (-0.28) and 3-chloro (0.37), when inserted into theequations, yielded a predicted chemical shift of 8.91 ppm forthe anilide proton and 10.77 ppm for the sulfonamide pro-ton. The respective experimental values were 8.83 and10.73 ppm. Again, calculated and observed values werewithin 1%. These results suggest strongly that the electroniceffects on the proton chemical shift of both urea amide pro-tons are additive.In summary, we conclude that the acidity/hydrogenbonding ability of both urea protons can be controlled bythe nature of the substituent in the 4-position inaccordanceJournal of the Arkansas Academy of Science, Vol. 54, 2000.1118Journal of the Arkansas Academy of Science, Vol. 54 [2000], Art. 20https://scholarworks.uark.edu/jaas/vol54/iss1/20;??»»?119with Hammett theory, and that the effects of substituents inthe 3-and 4-position operate in an additive fashion.Although all data were obtained in DMSO solvent, extrap-olation of these data to aqueous systems could prove usefulinprediction of hypoglycemic activity and/or developmentofsynthetic strategies for the preparation of sulfonyl ureas asfurther candidates for antitumor therapy.Acknowledgments.—The authors gratefully acknowl-edge Dr. TitoViswanathan for helping with the database lit-erature search and Mr. Kirk Babb for assisting with theNMR spectra acquisition.Literature CitedExner, O. 1988. Correlation analysis of chemical data,pp 133-135. Plenum Press, New York, 275 pp.Gilman, A. G. 1985. Oral hypoglycemic agents, pp 1504-1507 in The pharmaceutical basics of therapeutics, 7"1ed. (L. S. Goodman, ed.) MacMillan, New York, 1839pp.Howbert, J. J., C. S. Grossman, T. A. Crowell, B. J.Rieder, R. W. Harper, K. E. Kramer, E. V. Tao, J.Aikins,G. A.Poore, S.M.Rinzel, G. B.Grindey, W.N.Shaw, and G. C. Todd. 1990. Novel agents effectiveagainst solid tumors: the diarylsulfonylureas. Synthesis,activities, and analysis of quantitative structure activityrelationships. J. Med. Chem. 33: 2393-2407.Setliff, F. L., N. G. Soman, J. Z. Caldwell and D. L.Rogers. 1992. Hammett correlations in the proton nmrspectra of some N-aryldihalonicotinamides. Proc. ARAcad. Sci. 46: 72-74.Setliff, F. L., N. G. Soman, and A. D. Toland. 1993.Determination of Hammett pyridine 3-aza and 4-azareplacement constants by 'HNMRspectroscopy. Proc.AR Acad. Sci. 47: 107-109.Setliff, F. L., N. G. Soman, and A. A Toland. 1995.Hammett correlations of amide proton chemical shifts.J. Chem. Ed. 72: 362-363.Setliff, F. L.,and T. K. Spradlin. 2000. Hammett correla-tions of the sulfonamide proton chemical shift ina seriesof N-(4-substituted aryl)-p-toluenesulfonamides. J. ARAcad. Sci. 54:102-105.Journal of the Arkansas Academy of Science, Vol. 54, 2000119Journal of the Arkansas Academy of Science, Vol. 54 [2000], Art. 20Published by Arkansas Academy of Science, 2000

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Hammett Correlations of the Amide Proton Chemical Shift in a Series of 1-Tosyl-3-(4-substituted phenyl)ureas

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