Issue in Honor of Prof. Domenico Spinelli ARKIVOC 2002 (xi)

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1 Anlysis of substituent effects in the rections of some 2-L-3-nitro-5-X-thiophenes with niline in benzene. A new interprettion of the element effect Giovnni Consiglio,* Vincenzo Frenn, b Susnn Guernelli, nd Gbriell Mcluso b Diprtimento di Chimic rgnic A. Mngini, Vi Sn Donto 15, I Bologn, Itli b Diprtimento di Chimic rgnic E. Pternò, Vile delle Scienze, Prco d rlens II, I Plermo, Itli E-mil: giro@kiser.lm.unibo.it Dedicted to Professor Domenico Spinelli on his 70 th birthdy (received 16 ct 02; ccepted 07 Dec 02; published on the web 15 Dec 02) Abstrct The kinetic constnts for the title rections hve been mesured in benzene, t 25 ºC, t vrious niline concentrtions. In spite of the low k B /k 0 rtios, the rections re inferred to be genuinely bse-ctlyzed. The susceptibility constnts estimted for the vrious steps of the rection mechnism(s) hve llowed to mke cler the limits of the so-clled element effect criterion. Keywords: S N Ar rections, thiophenes, bse ctlysis, element effect Introduction The S N Ar rections of nitro-ctivted thiophenes with primry nd secondry mines cn be ctlyzed by the nucleophile. 1 By pplying the stedy-stte pproximtion in the intermedite in the ddition elimintion mechnism 2 shown in the Scheme, one obtins eq. (1) X S 1-4 N N 2 N 2 2 k 1 L + 2C 6 H 5 NH 2 + L k -1 X S NH X S NHC 6 H 5 2 C 6 H 5 B k IH 3 5 k 2 1: L = Br, 2: L = Cl, 3: L = C 6 H 5, 4: L = C 6 H 4 N 2 -p Scheme 1 X = H, Br, CNH 2, C 2 Me, CMe, S 2 Me, CN, N 2 ISSN Pge 104

2 k A = (k 1 k 2 + k 1 k 3 B [B])/(k -1 + k 2 + k 3 B [B]) eq. (1) where k A represents the pprent second-order kinetic constnt. According to eq. (1), when (k 2 + k 3 B [B])» k -1 or k -1 > k 2 nd k 2» k 3 B [B], no bse ctlysis is observed. Aprt from some rre exceptions where the coefficient k 3 B is very smll, for exmple becuse of steric hindrnce, the insensitivity to bse concentrtion generlly indictes tht the overll rte is controlled by the ddition step, i.e., k A = k 1. When (k 2 + k 3 B [B]) «k -1 the kinetic constnt increses linerly with incresing bse concentrtion, following eq. (2) k A = k 1 k 2 k -1 + k 1 k 3 B [B] k -1 eq. (2) When k 2 «k -1 nd k -1 k 3 B [B], k A vries in curviliner fshion s function of [B], obeying to eq. (1). The ctlysis lw observed depends on the nture of the romtic substrte, the mine, the nucleofugl group, the bse, nd the solvent used. 1 Results nd Discussion The pprent second-order kinetic constnts, k A, for rections of compounds (1 4) with niline in benzene, t vrious nucleophile concentrtions, re listed in Tbles 1-4. Exmintion of the kinetic dt shows tht for ech substrte k A increses linerly with incresing nucleophile concentrtion. A lest-squres tretment of dt ccording to eq. (3) k A = k 0 + k B [B] eq. (3) gve the results reported in Tbles 5 8. With reference to the Scheme nd eq. (1), the fct tht the pprent second-order kinetic constnts re described correctly by eq. (3) would imply the condition k -1» (k 2 + k 3 B [B]) where B represents the mine nucleophile. In fct, in this hypothesis, eq. (3) is equivlent to eq. (2) Thus the k B /k 0 shown in Tbles 5 8 would represent the k 3 B /k 2 rtios. Since the clculted k B /k 0 vlues rnge between 2.4 nd 6.9, ccording to Bunnett nd Grst 3 they hve to be nlyzed very cutiously. If the ccelertion observed, expressed quntittively by eq. (3) were not due to bse ctlysis but to some effects of uncler origin, the k 0 prmeter should correspond to k 1. ISSN Pge 105

3 According to this identifiction, this specific rte constnt increses with incresing electronwithdrwing power of the substituent present in the thiophene ring, with the leving group being equl (Tbles 5 8), s expected on the grounds of the electronic substituent effects on the ctivtion energy for the formtion of the rection intermedite. In fct, the k B prmeter lso increses in the sme wy nd, moreover, there is n excellent liner correltion between log k B nd the corresponding log k 0 vlues (Tble 9). Since it is difficult to give n ppeling interprettion of this rigorously quntittive dependence on the substituent effects of the phenomenon mesured by k B nd,, effects due to the medium polrity, 4 we must conclude tht in this cse genuine bse ctlysis is involved. The reltively low k B 3 /k 2 rtios certinly depend on the poor bsicity of niline nd then on its poor ctlytic efficiency. Plots of log k B or log k 0 vlues versus σ - substituent constnts 5 show excellent liner correltions (Tble 10). Since k B = k 1 k 3 k -1 [B], k0 = k 1 k 2 k -1 nd log k = ρσ - + c the slopes of the stright lines obtined correspond, for ech leving group, respectively, to ρ 1 +ρ 3 B ρ -1 nd ρ 1 +ρ 2 ρ -1. In the k -1 step tht is, in the decomposition of rection intermedite into strting compounds one observes both the breking of the intrmoleculr hydrogen bonding between the nilinium proton nd the 3-nitro group nd the breking of the bond between nucleophilic nitrogen nd romtic crbon tom s exemplified in 6. δ - N X S H NHC 6 H L 5 6 δ + An electron-withdrwing substituent present in the thiophene ring fvors, with respect to hydrogen, breking of the first bond nd hinders tht of the second one. f course, the more importnt effect is tht on the crbon nitrogen bond, in tht it is the degree of formtion or of breking of this bond tht controls predominntly the energy of the first trnsition stte of the ddition elimintion; thus ρ -1 should be negtive. In the k 2 step, where spontneous decomposition of the intermedite in the rection products occurs, n nilinium proton trnsfer to the leving group is concerted with the detchment of this group from the romtic crbon tom, s shown in 7. ISSN Pge 106

4 X δ - S 7 N H(1) δ + NC 6 H 5 L H(2) With increse in the electron-withdrwing power of X, the bsicity of the oxygen toms of the nitro group is reduced, nd the cidity of the H(1) nd H(2) hydrogen toms increses. As mtter of fct, the lower cidity of H(1) cused by the elimintion of H(2) is prtly counterblnced by the increse in the cidity of H(1) cused by the chnge occurring from mono-ryl-substituted mine (niline) to bi-ryl-substituted mine (N-thienyl-niline); thus, there is nerly no effect on the hydrogen bond involving the nitro group nd the H(1) hydrogen tom. n the grounds of the effect (not counterblnced) on the cidity of H(2), ρ 2 should be positive. The intrmoleculr cid ctlysis occurring through the hydrogen bonding between L nd H(2) is influenced in direct wy by the nucleofuglity of the leving group involved, s controlled by the electronic effect of the X substituent; thus ρ 2 should be negtive. It is evident tht the more importnt effect is tht on the crbon leving- group bond, in tht it is the degree of formtion or of breking of this bond tht controls, predominntly, the energy of the second trnsition stte of the ddition elimintion mechnism; thus, s whole, ρ 2 should be negtive. As fr s the k B 3 step is concerned, it is worthwhile to consider the possible ctlysis mechnisms. The removl of the cidic nilinium proton in the rection intermedite could hppen in different wys. 6 In the first mechnism the rte-determining step involves the formtion of the trnsition stte 8. X N - δ + H(1) S NC 6 H 5 L H(2) 8 δ + H 2 NC 6 H 5 With incresing electron-withdrwing power of X, the bsicity of the oxygen toms of the 3- nitro group decreses, nd the cidity of H(1) nd H(2) hydrogen toms increses. As consequence of the detchment of H(2) the cidity of H(1) decreses, with the net effect of reducing the stbiliztion of the trnsition stte owing to the intrmoleculr hydrogen bonding between the nitro group nd H(1). Thus, there is blncing between the fvorble effect of the X- substituent vrition nd the unfvorble effect on the intrmoleculr hydrogen bonding. ISSN Pge 107

5 As whole, in this ctlysis mechnism one should observe ρ B 3 ~ 0. In the SB GA mechnism 1 rpid pre-equilibrium occurs with trnsition stte like 8 where proton is trnsferred from 1-H to the mine. In this cse, t vrince with wht hppens in the k 2 step (see bove), the cidifying effect of the X substituent is complete. If this were the only fctor operting it should give ρ B 3 > 0. The subsequent step, tht is, the cid ctlysis for the leving group s elimintion by the conjugte cid of the mine [trnsition stte 9] is hmpered by the electron-withdrwing X substituents nd ρ B 3 < 0 should be observed. The effect of X on the C Ar -L bond breking should be similr to tht seen bove for the k 2 step. X δ - S 9 N H NC 6 H 5 L H δ + H 2 NC 6 H 5 The mechnism for the intermedite s decomposition by bifunctionl ctlysis involves breking of the hydrogen bond between the nilinium proton nd the nitrogen, which is concerted with the breking of the bond between the leving group nd the romtic crbon tom, s exemplified in 10. δ - N H S X L NC 6 H 5 H H NHC 6 H 5 10 δ + Also in this cse the effect of X on the cidity of the H(2) hydrogen is only prtil, wheres tht on the breking of the C Ar -L bond should be similr to tht seen bove for the SB GA mechnism. B Let us now consider the vlues of ρ 0 (= ρ 1 +ρ 2 ρ -1 ) nd of ρ B (= ρ 1 + ρ 3 ρ -1 ) for the vrious series of substrtes (Tble 11). Since the ρ 1 vlues for the rections of 2-L-3-nitro-5-X-thiophenes with niline re known 5,7,8 (Tble 11), by ssuming (ρ 1 ) benzene = (ρ 1 ) methnol it is possible to estimte the ISSN Pge 108

6 differences ρ 2 -ρ 1 nd ρ 3 B -ρ -1 for ech leving group concerned. The estimted vlues, s well s the observed ρ 3 B -ρ 2 vlues re shown in Tble 11. Both the ρ 2 -ρ -1 nd ρ 3 B -ρ -1 differences re rther smll nd suggest ρ 2 nd ρ 3 B vlues, respectively, similr to the ρ -1 vlue. n the resonble hypothesis tht ρ 1 ρ -1, the ρ 3 B -ρ -1 differences estimted llow us to exclude the ide tht the studied rections re ctlyzed through the mechnism where the rtedetermining step is the proton trnsfer [trnsition stte 8]. The trnsition sttes for the k 3 B step of the SB GA mechnism [9] nd tht for bifunctionl ctlysis [10] involve, s in the cse for the k 2 step [trnsition stte 7], the breking of the bond between crbon tom nd leving group, but only in the SB GA mechnism does the X substituent exert complete cidifying effect on the H(2) hydrogen. Since this effect opposes tht on the breking of the C Ar -L bond, the observtion of ρ 3 B -ρ 2 > 0, with the impliction tht ρ 3 B < ρ 2, represents strong indiction in fvor of the SB GA mechnism for the k 3 B step. n the hypothesis tht the rections studied re ctlyzed by this mechnism, the leving group vrition should not gretly ffect the pre-equilibrium where proton is trnsferred from 1-H to the mine. In the subsequent step [trnsition stte 9], the generl- cid ctlysis involves trnsfer of the proton of the conjugte cid of nucleophile to the leving group, concerted with its elimintion from the romtic crbon tom. Since the more bsic is the leving group, the more difficult is the breking of the C Ar L bond, nd thermodynmiclly more fvorble is the pk difference between the leving group nd cid ctlyst, it is likely tht the influence of L on the position of the trnsition stte [9] long the rection coordinte is rther smll. Similr resoning cn be given for the k 2 step nd the relevnt trnsition stte [7]. However, in this cse, the sitution could be complicted by the fct tht the bulkier leving group (for exmple, bromine s compred to chlorine) should hve more fvorble geometry for the formtion of the intrmoleculr hydrogen bonding. In conclusion, the differences ρ 3 B ρ -1 nd ρ 2 ρ -1, s function of L, should be minly determined by the effect of vrition of the leving group on the ρ -1 rection constnt. It turns out tht the prmeter k -1 is influenced by the electrophilicity of the crbon tom to which it is bonded in the rection intermedite nd tht this electrophilicity is controlled by the inductive effect of the leving group. The greter efficient electronegtivity of phenoxy- nd p- nitrophenoxy- groups cuses, with respect to the two hlogens, nd with X being equl, greter k 1 vlues nd lower k -1 vlues. Thus, the rnges of trnsition sttes for these leving groups re closer to the rectnts, with respect to the corresponding rnges for hlogen leving groups, nd consequently imply higher ρ - 1 vlues. By ssuming ρ -1 < 0, ρ 2 < 0, nd ρ 3 B < 0 (see bove), on going from L = Cl or Br to L = C 6 H 5 or C 6 H 4 N 2 -p, it is resonble tht the bsolute vlue ρ -1 increses, nd the sme holds for the ρ 3 B ρ -1 difference. For the resons given bove, the ρ 2 ρ -1 differences re more difficult to interpret. ISSN Pge 109

7 The results obtined in the present work contribute to mke cler the limits of the criterion clled the, bsence of element effect. 9 From comprison of the pprent reltive nucleofugcities of the vrious leving groups one observes tht, wheres the mobility order is lwys C 6 H 4 N 2 -p > C 6 H 5 > Cl > Br, the rectivity rnge for k B (k 0 ) vries from 26 (18) for X = N 2 to 91 (13) for X = Br. These dt would point out remrkble element effect if they referred to the breking of the C Ar L bond in the rte-determining step. From wht we hve sid bove, they refer, in contrst, to composite constnts (k 1 k 3 B /k -1, k 1 k 2 /k -1 ) nd probbly the effect of the leving group vrition on these prmeters reflects mostly on the k -1 prmeter which, indeed, pertins to the step where there is no breking of the C Ar- L bond! Tble 1. Apprent kinetic constnts for the rections of 2-bromo-3-nitro-5-X-thiophenes with niline in benzene t 25 C X = H [niline]/ M k A /dm 3 mol -1 s X = Br [niline]/ M k A /dm 3 mol -1 s X = CNH 2 [niline]/ M k A /dm 3 mol -1 s X = C 2 Me [niline]/ M k A /dm 3 mol -1 s X = CMe [niline]/ M k A /dm 3 mol -1 s X = S 2 Me [niline]/ M k A /dm 3 mol -1 s X = CN [niline]/ M k A /dm 3 mol -1 s X = N 2 [niline]/ M k A /dm 3 mol -1 s The kinetic constnts were reproducible to within ± 3 %. ISSN Pge 110

8 Tble 2. Apprent kinetic constnts for the rections of 2-chloro-3-nitro-5-X-thiophenes with niline in benzene t 25 C X = H [niline]/ M k A /dm 3 mol -1 s X = CNH 2 [niline]/ M k A /dm 3 mol -1 s X = C 2 Me [niline]/ M k A /dm 3 mol -1 s X = CMe [niline]/ M k A /dm 3 mol -1 s X = S 2 Me [niline]/ M k A /dm 3 mol -1 s X = CN [niline]/ M k A /dm 3 mol -1 s X = N 2 [niline]/ M k A /dm 3 mol -1 s The kinetic constnts were reproducible to within ± 3 %. Tble 3. Apprent kinetic constnts for the rections of 2-phenoxy-3-nitro-5-X-thiophenes with niline in benzene t 25 C X = H [niline]/ M k A /dm 3 mol -1 s X = CNH 2 [niline]/ M k A /dm 3 mol -1 s X = C 2 Me [niline]/ M k A /dm 3 mol -1 s X = CMe [niline]/ M ISSN Pge 111

9 Tble 3. Continued 10 5 k A /dm 3 mol -1 s X = S 2 Me [niline]/ M k A /dm 3 mol -1 s X = CN [niline]/ M k A /dm 3 mol -1 s X = N 2 [niline]/ M k A /dm 3 mol -1 s The kinetic constnts were reproducible to within ± 3 %. Tble 4. Apprent kinetic constnts for the rections of 2-p-nitrophenoxy-3-nitro-5-Xthiophenes with niline in benzene t 25 C X = H [niline]/ M k A /dm 3 mol -1 s X = Br [niline]/ M k A /dm 3 mol -1 s X = CNH 2 [niline]/ M k A /dm 3 mol -1 s X = C 2 Me [niline]/ M k A /dm 3 mol -1 s X = CMe [niline]/ M k A /dm 3 mol -1 s X = S 2 Me [niline]/ M k A /dm 3 mol -1 s X = CN [niline]/ M k A /dm 3 mol -1 s X = N 2 [niline]/ M ISSN Pge 112

10 Tble 4. Continued 10 3 k A /dm 3 mol -1 s The kinetic constnts were reproducible to within ± 3 %. Tble 5. Liner regression nlysis of pprent- second- order kinetic constnts, k A, for the rections of 2-bromo-3-nitro-5-X-thiophenes with niline in benzene, t 25 C, ccording to the eqution k A = k 0 + k B [B] X 10 7 (k 0 ± s 0 ) 10 7 (k B ± s B ) k B /k 0 b r n H ± ± Br 0.158± ± CNH ± ± C 2 Me 2.11± ± CMe 10.0± ± S 2 Me 13.9± ± CN 17.4± ± N 2 371±5 2460± s 0 nd s B re the stndrd devitions of the regression prmeters k 0 nd k B, respectively; r is the correltion coefficient; n is the number of experimentl points. b The mximum error of k B /k 0 rtio is estimted to be 3.9 %. Tble 6. Liner regression nlysis of pprent- second- order kinetic constnts, k A, for the rections of 2-chloro-3-nitro-5-X-thiophenes with niline in benzene, t 25 C, ccording to the eqution k A = k 0 + k B [B] X 10 7 (k 0 ± s 0 ) 10 7 (k B ± s B ) k B /k 0 b H ± ± CNH ± ± C 2 Me 2.94± ± CMe 15.0± ± S 2 Me 20.1± ± CN 16.8± ± N 2 491±9 3390± s 0 nd s B re the stndrd devitions of the regression prmeters k 0 nd k B, respectively; r is the correltion coefficient; n is the number of experimentl points. b The mximum error of k B /k 0 rtio is estimted to 3.8 %. r n ISSN Pge 113

11 Tble 7. Liner regression nlysis of pprent- second-order kinetic constnts, k A, for the rections of 2-phenoxy-3-nitro-5-X-thiophenes with niline in benzene, t 25 C, ccording to the eqution k A = k 0 + k B [B] X 10 6 (k 0 ± s 0 ) 10 6 (k B ± s B ) k B /k 0 b H ± ± CNH ± ± C 2 Me 1.44± ± CMe 4.57± ± S 2 Me 6.74± ± CN 7.97± ± N 2 131±2 646± s 0 nd s B re the stndrd devitions of the regression prmeters k 0 nd k B, respectively; r is the correltion coefficient; n is the number of experimentl points. b The mximum error of k B /k 0 rtio is estimted to 3.3 %. Tble 8. Liner regression nlysis of pprent second order kinetic constnts, k A, for the rections of 2-p-nitrophenoxy-3-nitro-5-X-thiophenes with niline in benzene, t 25 C, ccording to the eqution k A = k 0 + k B [B] X 10 5 (k 0 ± s 0 ) 10 5 (k B ± s B ) k B /k 0 b H ± ± Br 0.189± ± CNH ± ± C 2 Me 1.44± ± CMe 4.57± ± S 2 Me 6.55± ± CN 7.90± ± N 2 100±2 640± s 0 nd s B re the stndrd devitions of the regression prmeters k 0 nd k B, respectively; r is the correltion coefficient; n is the number of experimentl points. b The mximum error of k B /k 0 rtio is estimted to 4.2 %. Tble 9. Correltions by the eqution log(k B ) X = log(k 0 ) X + b L ±s b ±s b n r Br 1.07± ± Cl 1.04± ± C 6 H ± ± C 6 H 4 -N 2 -p 1.11± ± s nd s b, stndrd devitions of nd b; r, correltion coefficient; n, number of dt points. r r n n ISSN Pge 114

12 Tble 10. Susceptibility constnts nd other sttisticl dt for the rections of 2-L-3-nitro-5-Xthiophenes with niline in benzene L ρ ±s ρ i ±s i r ρ Β ±s ρβ i Β ±s iβ r n Br 3.44± ± ± ± Cl 3.20± ± ± ± C 6 H ± ± ± ± C 6 H 4 -N 2 -p 2.78± ± ± ± ρ, rection constnt; i, intercept of the regression line with the ordinte (σ = 0); r, correltion coefficient; n, number of dt points. Tble 11. Susceptibility constnts for the rections of 2-L-3-nitro-5-X-thiophenes with niline in benzene L ρ ρ Β ρ 3 - ρ 2 ρ (methnol) ρ 2 - ρ ρ 3 - ρ Br Cl C 6 H C 6 H 4 -N 2 -p Experimentl Section Synthesis nd Purifiction of Compounds. Benzene, 10 niline, 11 2-L-3-nitro-5-X-thiophenes, 12 nd N-(3-nitro-5-X-2-thienyl)nilines 11 were prepred nd/or purified s previously reported. Kinetic Mesurements. The kinetics were followed spectrophotometriclly s previously described. 13 The concentrtions used were 2.4 x 10-4 mol dm -3 for 1-4 nd those indicted in Tbles 1-4 for niline. The wvelength nd log ε vlues for UV spectrl mesurements re reported in Tble 12. ISSN Pge 115

13 Tble 12. Spectroscopic dt for 2-nilino-3-nitro-5-X-thiophenes 1-4. X λ mx (benzene)/nm log ε H Br CNH C 2 Me CMe S 2 Me CN N References 1. () Consiglio, G.; Frenn, V.; Spinelli, D. Bse Ctlysis in Aromtic Nucleophilic Substitutions: Current Views In Topics in Heterocyclic Systems. Synthesis, Rections nd Properties;. Spinelli, D.; Attnsi,. Eds; 1996; Vol. 1. (b) Arnone, C.; Consiglio, G.; Spinelli, D.; Frenn, V. J. Chem. Soc., Perkin Trns , () Bunnett, J. F.; Zhler, R. E. Chem. Rev. 1951, 49, 273. (b) Bunnett, J. F. Qurt. Rev. Chem. Soc. 1958, 12, Bunnett, J. F.; Grst, R. H. J. Am. Chem. Soc. 1965, 87, () Ross, S. D. Progr. Phys. rg. Chem. 1963, 1, 31. (b) Bmkole, T..; Hirst, J. J. Chem. Soc. (B) 1969, 848. (c) Suhr, H. Ber. Bunsenges. Phys. Chem. 1963, 67, 893. (d) Beltrme, P.; Bonomi, L.; De Re, P.; Simonett, M. Gzz. Chim. Itl. 1967, 97, 470. (e) Dnilov, N. K.; Shein, S. M. Rekts. Sposobn. rg. Soedin. 1970, 7, 476. (f) Shein, S. M.; Suchkov, L. A. Rekts. Sposobn. rg. Soedin. 1970, 7, 732. (g) Lisitsyn, U. N.; Shul chishin, V. A. J. rg. Chem. USSR 1970, 6, 313. (h) Ross, S. D. Comprehensive Chemicl Kinetics; Bmford, C. H.; Tipper, C. F. H. Eds; Elsevier: Amsterdm, 1972; Vol. 13. (i) Bernsconi, C. F.; Kufmnn, M.; Zollinger, H. Helv. Chim. Act 1966, 49, Consiglio, G.; Arnone, C.; Spinelli, D.; Noto, R.; Frenn, V. J. Chem. Soc., Perkin Trns , Spinelli, D.; Consiglio, G.; Noto, R. J. Chem. Soc., Perkin Trns , 1316 nd references therein. ISSN Pge 116

14 7. () Consiglio, G.; Frenn, V.; Guernelli, S.; Mcluso, G.; Spinelli, D. J. Chem. Res. (S) 2001, 266. (b) Consiglio, G.; Frenn, V.; Guernelli, S.; Mcluso, G.; Spinelli, D. J. Chem. Res. (M) 2001, Consiglio, G.; Frenn, V.; Guernelli, S.; Mcluso, G.; Spinelli, D. unpublished dt. 9. Spinelli, D.; Consiglio, G.; Dell Erb, C.; Novi, M. Nucleophilic Substitution of Thiophene Derivtives In The Chemistry of Heterocyclic Compounds, Vol. 44; Thiophene nd Its Derivtives, Prt Four, Gronowitz, J. Ed; Wiley & Sons, Inc.: 1991; p Vogel, A. I. Prcticl rgnic Chemistry; Longmns: London, 3 rd Edn; 1971; p Spinelli, D.; Consiglio, G.; Noto, R.; Frenn, V. J. rg. Chem. 1976, 41, Consiglio, G.; Frenn, V.; Arnone, C.; Mezzin, E.; Spinelli, D. J. Chem. Soc., Perkin Trns , 2187 nd references therein. 13. Spinelli, D.; Consiglio, G.; Noto, R. J. Heterocycl. Chem. 1977, 14, ISSN Pge 117

Organic Acids - Carboxylic Acids

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