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Apolar versus Polar Solvents: A Comparison of the Strength of Some Organic Acids against Different Bases in Toluene and in Water Francesca D’Anna,† Vincenzo Frenna,† Franco Ghelfi,‡ Gabriella Macaluso,† Salvatore Marullo,† and Domenico Spinelli*,§ Dipartimento di Chimica Organica “E. Paterno`”, UniVersita` degli Studi di Palermo, Viale delle Scienze-Parco d’Orleans II, 90128 Palermo, Italy, Dipartimento di Chimica, UniVersita` degli Studi di Modena e Reggio Emilia, Organic Chemistry, Via Campi 183, 41100 Modena, Italy, and Dipartimento di Chimica “G. Ciamician”, UniVersita` degli Studi di Bologna, Via Selmi 2, 40126 Bologna, Italy ReceiVed: July 28, 2010; ReVised Manuscript ReceiVed: September 7, 2010
The constants of ion-pair formation with 3-nitroaniline (3NO2A) for eight halogenoacetic acids (HAAs, 3a-h: TFA, TCA, TBA, DFA, DCA, DBA, MCA, and MBA), and five 2,2-dichloroalkanoic acids containing 3-8 carbon atoms (HAs, 5a-e: DCPA, DCBA, DCMBA, DCVA, and DCOA) have been determined in TOL at 298.1 K. The results obtained brought to evidence for HAAs the formation of ion-pairs with two different stoichiometries (base-acid, 1:1 or 1:2), while in contrast the HAs furnish only the 1:1 pairs. The different steric and electronic requirements of HAAs and HAs seem to be responsible for such an unlikely behavior. At the same time, the acid-catalyzed MRH of the (Z)-phenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole (1) into (2,5-diphenyl-2H-1,2,3-triazol-4-yl)urea (2) in the presence of the five HAs above has been investigated in TOL at 313.1 K. Thus, in contrast with previous results in the presence of several HAAs, a unique pathway for the rearrangement has been observed, again pointing out the importance of the above effects on the initial acid/base interactions. Finally the acidic strength of TFA against seven nitroanilines (NA, 4a-g: 4NO2A, 3NO2A, 3Me4NO2A, 4Me3NO2A, 2Me3NO2A, 2NO2A, and 3,5diNO2A) characterized by a very different basicity has been measured in TOL at 298.1 K. Introduction In the course of our studies on the ring-to-ring interconversion,1 we have addressed our attention to both synthetic applications2 and mechanistic details2,3 of mononuclear rearrangements of heterocycles (MRH or Boulton-Katritzsky reactions, BKR, a typical SNi process).4 In this context, we have recently enlightened that (Z)hydrazones of 3-acyl-1,2,4-oxadiazoles decorated bearing an amino group on C-5 can rearrange into the relevant triazoles in polar solvents (e.g., in a 1:1 dioxane/water mixture, v/v) via three different reaction pathways as a function of the proton concentration. Thus, for instance, the (Z)-phenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole (1) rearranges into the relevant (2,5-diphenyl-2H-1,2,3-triazol-4-yl)urea (2) at high or at low proton concentration via a specific-acid- or a generalbase-catalyzed process, respectively, while at intermediate proton concentrations a uncatalyzed pathway prevails (Scheme 1).5 In a nonpolar solvent (e.g., toluene, TOL) in the presence of a halogenated acetic acid (e.g., trichloroacetic acid, TCA) or a base (e.g., piperidine, PIP), a general-acid- or a general-basecatalyzed path were observed, respectively.6 Because of the nonpolar character of TOL and accordingly with some results from density functional theory (DFT) calculations in the gas phase, the uncatalyzed path was not manifested.6,7 * To whom correspondence should be addressed. Phone: +390512099478. Fax: +390512099456. E-mail
[email protected]. † Universita` degli Studi di Palermo. ‡ Universita` degli Studi di Modena e Reggio Emilia. § Universita` degli Studi di Bologna.
To gain further information on the course of MRH, we have recently carried out a deep kinetic investigation of the 1 f 2 process in TOL at 313.1 K in the presence of a series of halogenated acetic acids (HAAs, 3a-h), characterized by very different acidic strengths [from monobromoacetic acid (MBA, pKa 2.90) to trifluoroacetic acid (TFA, pKa 0.23)]. In every case, we observed an upward curvilinear dependence of the reactivity versus [HAA], while the linear trends of (kA,R)/[HAA] versus [HAA], allowing the calculation of the relevant second- (kII) and third-order (kIII) rate constants according to eq 1, testify for the occurrence of catalysis-of-catalysis.6
(kA,R)/[HAA] ) (kII) + (kIII)[HAA]
(1)
We have also determined the association (ion-pair formation) constants between the HAAs employed and 4-nitroaniline (4NO2, 4a) in TOL at 298.1 K, finding the likewise involvement of either one (K2, eq 2) or two (K3, eq 3) molecules of HAA.6b K2
(HAA)2 + 4a h AA- /4a · H+ + HAA
(2)
K3
AA- /4a · H+ + HAA h AA- · · · HAA/4a · H+
(3)
Interestingly enough, both kIII/kII and K3/K2 have been found to depend on the nature of the HAA used; their values range between 9.7 and 7.9 L mol-1 and 7.6 and 1.4 L mol-1 on going from TFA to MBA, respectively, and the trends observed clearly indicate that the stronger the HAAs involved, the higher the calculated ratios.6b
10.1021/jp107058x 2010 American Chemical Society Published on Web 09/28/2010
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SCHEME 1: Schematic Representation of the Different Paths (Acid-Catalyzed, Uncatalyzed, and Base-Catalyzed) for 1 into 2 MRH
These experimental results are well in line with the prevision/ rationalization that in both cases stronger acids involve higher acid/base (HAAs/nitrogen basic centers) interactions with formation of transition states with higher charge separations “which enjoy (that is, strongly requires) the stabilizing assistance of a second molecule of HAA to give a second transition state which in turn gives” the rearrangement product (2) or the (HAA)2/4a ion-pairs (eq 3).6b Looking at the influence of the base on the above interactions, we can forecast that with the same acid, but changing the base a similar kind of effects should be observed. That is, increasing the basicity of the rearranging (Z)-arylhydrazone of 5-amino3-benzoyl-1,2,4-oxadiazole or of the base involved in the association process, the path requiring 2 mol of organic acid would increase its contribution with respect the one requiring only 1 mol. Considering these preliminary remarks we present in this paper an examination of the following acid/base interactions: (a) the association constants in TOL of 13 halogenated carboxylic acids [the previously examined series of halogenoacetic acids HAAs (TFA, TCA, TBA, DFA, DCA, DBA, MCA, and MBA, 3a-h) has been extended to five 2,2-dichloroalkanoic acids containing 3-8 carbon atoms [HAs: DCPA (5a, 2,2dichloropropanoic acid), DCBA (5b, 2,2-dichlorobutanoic acid), DCMBA (5c, 2,2-dichloro-3-methylbutanoic acid), DCVA (5d, 2,2-dichloropentanoic acid), and DCOA (5e, 2,2-dichlorooctanoic acid)] with 3-nitroaniline (3NO2A, 4b, a base stronger than the previously investigated 4a, ∆pKa 1.5)8 will be determined at 298.1 K. We would like to focus on the fact that the choice of the new investigated HAs is due to the following: the versatile synthetic interest linked to their bifunctionality and
the large steric requirements together with the moderate inductive effect of their linear or branched chains, which could cause some significant differences in reactivity with respect to HAAs (Chart 1). (b) The association constants in TOL at 298.1 K of TFA with a significant series of nitroanilines (NAs, 4a-g: 4NO2A, 3NO2A, 3Me4NO2A, 4Me3NO2A, 2Me3NO2A, 2NO2A, and 3,5diNO2A) showing different basic strength (encompassing a pKa range larger than three unities)8 will be determined at 298.1 K with the aim of understanding the influence of the basicity of the used NAs on the two kinds of acid/base interactions (Chart 1). The above-reported 2,2-dichloroalkanoic acids (and their derivatives) are valuable and versatile substrates in organic chemistry. This is due to their bifunctional structure, R-CCl2COY, which provides these molecules with a number of interesting features, such as, the easy nucleophilic acyl substitution at the carboxylic CdO,9 the smooth generation of radicals10,11 or of R-halo enolates,12 the dehydrohalogenation to R-chloroacrylic monomer,13 and the possibility of nucleophilic transformations of the Cl,Cl-acetal group.14a,b They have been also used as starting materials to build up bioactive molecules, both natural15a-c or synthetic.14 Moreover 2,2-dichloropropanoic acid (dalapon) is by itself a well-known herbicide,16a while ω-substituted 2,2-dichloroaliphatic acids appear as promising antidiabetics,16b and several of them have been used as acid catalysts in industrial processes.17 Moreover also the kinetic behavior in the MRH (a typical azole-into-azole interconversion) of the (Z)-phenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole 1 into (2,5-diphenyl-2H1,2,3-triazol-4-yl)urea 2 in TOL at 313.1 K in the presence of the above five HAs 5a-e will be examined.
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CHART 1: Structures of Alkanoic Acids and Nitroanilines Used
TABLE 1: Constants for Ion-Pair Formation with 3-Nitroaniline (4b) in TOL, pKa Values in Water of Some Halogenoacetic Acids (HAAs) and Some 2,2-Dichloroalkanoic Acids (HAs) at 298.1 K, and Second-Order Rate Constants for the Rearrangement of 1 into 2 at 313.1 K entry
HAA or HA (3a-h) or (5a-e)
K2 ( s2a (L mol-1)
K3 ( s2a (L mol-1)2
K3/K2 (L mol-1)
pKab
104(kII ( sII)a (L mol-1 s-1)
1 2 3 4 5 6 7 8 9 10 11 12 13
TFA (3a) TCA (3b) TBA (3c) DFA (3d) DCA (3e) DBA (3f) MCA (3g) MBA (3h) DCPA (5a) DCBA (5b) DCMBA (5c) DCVA (5d) DCOA (5e)
11.5 ( 0.3 6.21 ( 0.16 4.56 ( 0.07 3.74 ( 0.07 2.02 ( 0.05 1.45 ( 0.04 0.193 ( 0.008 0.159 ( 0.004 1.46 ( 0.05 1.38 ( 0.07 1.17 ( 0.06 1.05 ( 0.06 1.20 ( 0.05
219 ( 4 108 ( 2 65.0 ( 0.8 38.2 ( 0.4 18.3 ( 0.3 12.1 ( 0.2 0.639 ( 0.019 0.426 ( 0.011
19.0 17.4 14.3 10.2 9.06 8.34 3.31 2.68
0.23 0.64 0.80 1.13 1.30 1.48c 2.86 2.90 1.32d 1.34d 1.38d 1.43d NDf
345 ( 1e 104 ( 0e 45.6 ( 0.2e 41.8 ( 0.5e 8.99 ( 0.18e 5.57 ( 0.09e 0.0911 ( 0.0018e 0.0533 ( 0.0019e 3.79 ( 0.02 3.32 ( 0.01 2.35 ( 0.01 1.80 ( 0.01 2.22 ( 0.01
a
s2, s3, and sII are the standard deviations of the regression parameters of K2, K3, and kII, respectively; the correlation coefficients are always g0.9997, and the number of points range between 11 and 15. The confidence levels for the significance of regression parameters are all better than 99.9%. b Data from Brown, H.C.; Mc Daniel, D. H.; Ha¨flinger, O. In Determination of Organic Structures by Physical Methods, Vol. 1; Braude, E. A., Nachod, F. C., Eds.; Academic Press: New York, 1955; p 567, except data concerning DBA and HAs. c Serjeant, E. P.; Dempsey, B. In Ionisation Constants of Organic Acids in Aqueous Solution; IUPAC Chemical Data Series No. 23, Pergamon Press, 1979. d This work. e See ref 6b. f ND: not determined.
In conclusion, why are we collecting these data and which are the aims of this study? We think that the shifting from an acetic acid structure (a two-carbon chain) to some propanoic, butanoic, pentanoic, and octanoic ones (three/eight-carbon chains, both linear and branched) could affect the nature of the acid/base interactions, and we hope that the collected data will allow a better understanding of the effect of apolar versus polar solvents on them. Results and Discussion A. Ion-Pair Formation between HAs and 4b in TOL at 298.1 K. Following the procedures recently described,6b the association constants for the formation of the above ion-pairs have been calculated and their values are collected in Table 1. An examination of the data allows the following considerations: (a) all of the derivatives of acetic acid (HAAs: 3a-h; Table 1, lines 1-8) show the occurrence of two processes of ion-pair formation with 4b. Their absolute values are higher than those measured with 4a,6b by a factor ranging between 1.7 or 4.35 for K2 and K3 in the instance of TFA and 3.5 or 6.45 for K2 and K3 in that of MBA. Therefore the increase is especially significant in the instance of K3 well in line with the prevision that the transition state for the ion-pair formation with a stronger base causes a higher charge separation, thus increasing the necessity of assistance by a second molecule of HAAs (see above). There are some excellent (r g 0.997) relationships between K2 and K3 now measured with 4b versus the values with 4a as well as versus the relevant pKa; for example, the plots concerning K2 and K3 show slopes lower than unity (s
0.859 ( 0.007) or quasi-unitary (0.934 ( 0.018), a similar trend characterizes the plot versus pKa values (-0.692 ( 0.022 and -1.01 ( 0.03), thus indicating the occurrence of different quantitative effects on K2 and K3. (b) Interestingly enough, the five HAs 5a-e now examined (DCPA, DCBA, DCMBA, DCVA, and DCOA; see Table 1, lines 9-13), all of which contain two chlorine atoms at C-2, with linear and branched chains of 3-8 carbon atoms, give rise only to the formation of 1:1 (base-acid) ion-pairs. This behavior, different with respect to that observed with HAAs, can be related to the fact that in comparison with the similar DCA 3e (an acid again containing two chlorines linked to the C-2 of the acidic chain) one hydrogen (ES, 0.00)18 is substituted by the much more space-demanding methyl, ethyl, propyl, iso-propyl, or hexyl groups (the ES values range between -1.24, for methyl, and -1.71, for iso-propyl),18b,c which makes the formation of a 1:2 ion-pair much less favorable. The present alkyls could affect the HAs behavior also because of their moderate inductive effects (the σI values are in the range of -0.05).18a The K2 values measured for all of them (1.05-1.46 L mol-1) are of the same order of magnitude of that of DCA (2.02 L mol-1), the relevant 2,2-dichloroacetic acid, the observed moderate lessening can be again related to both the moderate inductive effects and the strong steric requirements of the alkyls. A linear plot between the acidity in TOL and in water of HAs 5a-d has been observed (s -1.34 ( 0.13, i 1.93 ( 0.18, r 0.996, n 4); its slope, significantly higher than unity, shows that structure modifications affect the acidic strength in TOL more than in water.
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D’Anna et al. Therefore, second-order kinetic constants have been calculated according to eq 4 and collected in Table 1, thus recalling the above behavior observed in the association constants determination. As a matter of fact, a simple interaction (i.e., involving only one molecule of acids, path a, Scheme 2) between HAs and the basic nitrogen of 1 with (TS)1 formation now represents the rate-determining step in the acid-catalyzed rearrangement process. We shall recall that, in contrast, in the presence of HAAs also, path b of Scheme 2 operates, with the ratedetermining formation of (TS)2 (catalysis-of-catalysis).
(kA,R)HA ) kII[HA] + i
Figure 1. Plot of 105 kA,R for the rearrangement of 1 into 2 at 313.1 K in TOL vs (O) [DCBA] or (b) [DCA].
B. On the 1 f 2 MRH in TOL in the Presence of the HAs 5a-e at 313.1 K. The observation that the dichloroalkanoic acids 5a-e containing 3-8 carbon atoms give only ion-pair adducts of 1:1 type with 4b has induced us to study the catalytic effect of the same acids in the reaction above; as a matter of fact if the absence of the 1:2 adducts in the ion-pair formation between 4b and HAs 5a-e, in contrast with what occurs with HAAs, could be related to steric and/or electronic effects, one can suppose that the same factors would affect the course of the MRH process. The apparent first-order rate constants in TOL at 313.1 K of the rearrangement of 1 in the presence of 5a-e, measured at different [HA] (within a 0.01 and 0.11 M concentration range) are collected in Table 1 of the Supporting Information. In contrast with observations recently collected in the presence of several HAAs (3a-h), a linear increase of kA,R versus [HA] indicates that a simple acid-catalyzed pathway occurs in the presence of 5a-e (for the sake of comparison in Figure 1, the different behavior observed in the MRH of 1 with DCA and DCBA as a function of the organic acid concentration is shown). Moreover with all of the examined HAs, the calculated intercepts (see eq 4) were equal to zero [ranging between (-0.08 ( 0.03) and (0.02 ( 0.02) 10-5 s-1], once more confirming the absence of an uncatalyzed pathway in these experimental conditions.7
It is noteworthy that also for HAs a good free energy relationship between the measured second-order kinetic constants for the rearrangement 1 f 2 in TOL at 313 K and the equilibrium constants of ion-pair formations can be observed. Interestingly the plot (s 2.49 ( 0.11, i -3.82 ( 0.02, r 0.996, n 6) can be extended also to DCA (of course using the “simple” K2 and kII constants). We would like to remember that we had already evidenced the importance of steric effects also in some other catalyzed MRHs in an apolar solvent. As a matter of fact the (Z)-pnitrophenylhydrazone (6) of 3-benzoyl-5-phenyl-1,2,4-oxadiazole rearranges into the relevant 4-benzoylamino-2-p-nitrophenyl1,2,3-triazole (7) in benzene in the presence of several amines. Inter alia, piperidine and di-isobutylamine (two secondary amines, a general-base-catalyzed process occurs) have been used; in the presence of the former, a “complex” third-order kinetic law occurs (catalysis-of-catalysis), while with the latter a “simple” second-order one has been observed. This has been attributed to their different steric requirements.19 C. Ion-Pair Formation between TFA and Some Nitroanilines (4a-g) in TOL at 298.1 K. On going from 4a to 4b, we have observed significant increases in the values of K2 and K3 as well as of K3/K2 ratios for the ion-pair formation with TFA, in line with prevision/rationalization on their trends as a function of the nature of the acids and bases involved. In this framework, we have enlarged our investigation to ionpair formations between TFA (a strong acid able to interact also with very feeble bases) and a series of nitroanilines (NA, 4a-g, 4NO2A, 3NO2A, 3Me4NO2A, 4Me3NO2A, 2Me3NO2A, 2NO2A, and 3,5diNO2A) characterized by a very different basic strength,8 in order to get information on the above trends as a
SCHEME 2: Proposed Course of the Reaction and Relevant Transition Statesa
a
(4)
(TS)1 and (TS)2 refer to the second- and the third-order paths, respectively.
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TABLE 2: Constants for Ion-Pair Formation with TFA of Some Nitroanilines (NA) in TOL at 298.1 K entry
NA (4a-g)
K2 ( s2a (L mol-1)
K3 ( s3a (L mol-1)
K3/K2 (L mol-1)
1 2 3 4 5 6 7
4-NO2A (4a) 3-NO2A (4b) 3-Me-4-NO2A (4c) 2-Me-3-NO2A (4d) 4-Me-3-NO2A (4e) 2-NO2A (4f) 3,5-(NO2)2A (4g)
6.63 ( 0.06 11.5 ( 0.3 7.82 ( 0.17 10.4 ( 0.3 12.7 ( 0.4 1.45 ( 0.02 0.82 ( 0.002
50.3 ( 0.6 219 ( 4 81.8 ( 0.8 178 ( 4 317 ( 6
7.59 19.0 10.5 17.0 25.0
a s2 and s3 are the standard deviations of the regression parameters of K2 and K3, respectively; the correlation coefficient are always g0.9997, and the number of points ranges between 11 and 15. The confidence levels for significance of regression parameters are all better than 99.9%.
function of the involved base. The calculated association constants are collected in Table 2. An examination of data obtained allows the following observations: (a) the calculated K2 values (see eq 2) range between 0.82 L mol-1 for the least basic NA (3,5diNO2A), and 12.7 L mol-1 for the most basic one (4Me3NO2A). Interestingly enough, neither 2NO2A nor 3,5diNO2A (the least basic NAs) give rise to the equilibrium of eq 3. (b) The calculated K3 values (see eq 3) range between 50.3 (L mol-1)2 for 4NO2A and 317 (L mol-1)2 for 4Me3NO2A. (c) The calculated K3/K2 ratios range between 7.6 L mol-1 for 4NO2A and 25 L mol-1 for 4Me3NO2A. D. Some Comments. The whole of the results appear well in line with previous data on the behavior of HAAs and HAs with 4b. In fact, the results relevant to both the thermodynamics of acid/base equilibria and the kinetics of the acid-catalyzed MRH in TOL allow one to make the considerations below on the comparison between the influence of a polar solvent (water or dioxane/water mixture) and of an apolar one (TOL) on the above processes. The most important consideration lies in the observation that polar and apolar solvents can very differently influence both the thermodynamics or the kinetics of the processes; actually, in the former instance, the reaction media can behave as “actors” able to participate in the formation of the transition state or at least able to “strongly” affect its formation.7 For example, taking into account an acid/base equilibrium between organic partners of medium/high strength in a polar solvent (that is, a solvent able to give “interactions” with cations and anions), the formation of strongly solvated and then stabilized cations and anions is observed. Thus, e.g., in the presence of water, the initially formed ion-pair (R-COO-/ Ar-NH3+) yields anion 8 and cation 9 by the action of water: both high dielectric constant and ability to behave as donor and acceptor of hydrogen bonds being important factors which help charge dispersion and stabilize the so-formed solvated ions.
In contrast, in an apolar solvent such as TOL, similar factors cannot operate and then the system looks for other favorable events. Thus, in the presence of an excess of the acid the ionpair R-COO-/Ar-NH3+ can be stabilized thanks to an interaction with a second molecule of R-COOH, giving R-COO-• · · ·
HOOC-R/Ar-NH3+ (probably as an ion-pair) and favoring the dispersion of the negative charge.20 This picture of acid/base interactions is likewise supported by all of the results collected. As a matter of fact, considering the interaction of a base with a series of acids characterized by different acidity (3a-h), we must observe that the stronger the acid, the bigger should be the partial negative charge on the carboxylate and then the higher the necessity of assistance by a second molecule of carboxylic acid. This means that increasingly higher K3/K2 ratios should be observed as a function of the strength of the acid under consideration: as a matter of fact in the interaction with 3NO2A, K3/K2 increases from 2.7 for MBA (the weakest acid examined) to 19 for TFA (the strongest acid examined). A parallel trend of the K3/K2 ratios has been observed examining the behavior of TFA with a series of different NAs. Once more, with an increase in the base strength, the partial negative charge on the carboxylate augments and the requirement of further assistance by a second molecule of carboxylic acid causes higher K3/K2 ratios: from 7.6 for 4NO2A to 25 L mol-1 for 4Me3NO2A. What happens with acids in the instance of acids which for some reason cannot interact with a second molecule of the acid itself or in the instance of a “very very” feeble base? The answer to the two above questions comes from results on the behavior of HAs with 3NO2A and of TFA with 2NO2A and with 3,5diNO2A. Interestingly enough, all of the HAs with 3NO2A in TOL gave “only” the 1:1 interaction: this behavior could be related to the different steric and electronic requirements of halogenoacetic acids 3a-h with respect to the 2,2-dichloroalkanoic acids 5a-e, which make the interaction with a second molecule of HA thermodynamically unfavorable. We would remark that in the instance of DCPA, a K2 quite similar to that of DCA has been measured (1.50 versus 2.02 L mol-1). The last comment to the experimental results concerns the very interesting behavior of TFA with 2NO2A and with 3,5diNO2A: in fact, with these two very feeble bases (K2 1.45 and 0.82 L mol-1, respectively) again only a 1:1 interaction has been evidenced. In this instance, the observed behavior must be related to the fact that the two bases are so feeble that the 1:1 interaction occurs giving rise to so low a charge separation in the resulting ion-pair that the intervention of a second TFA molecule is not necessary. Conclusions To gain information concerning the nature of acid/base interactions in apolar solvents and their effects on the thermodynamics and kinetics of some processes, we have carried out some measurements of the equilibrium constants of ion-pairs formation between 3-NO2A and some halogenated organic acids with different carbon chains [C2 (3a-h); C3, C4, C5, and C8 both linear and branched (5a-e)], and of the rate constants concerning the MRH of the (Z)-phenylhydrazone (1) of 5-amino3-benzoyl-1,2,4-oxadiazole into the relevant (2,5-diphenyl-2H1,2,3-triazol-4-yl)urea 2 in the presence of the HAs 5a-e in TOL. Moreover the behavior of TFA with seven nitroanilines in TOL has been examined. The whole of the obtained results indicates that in apolar solvents the acid/base interactions, lacking the assistance of a solvent able to strongly solvate and then stabilize the formed ions, give ion-pairs that can be stabilized by interaction with a second molecule of acid, thus giving rise to two different, successive acid/base equilibria requiring one or two molecules
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of alkanoic acid, respectively. The occurrence of the second equilibrium can be prevented because of steric and electronic effects or, in turn, when the base is very feeble. Looking at the trend of K3/K2 ratios (fast decreasing on going from the strong TFA to the weak MBA), we can suppose that also in the instance of very feeble acids only the equilibrium involving one molecule of alkanoic acid would be observed. Interestingly also the kinetic behavior concerning the 1 f 2 rearrangement well fits within the picture coming from results of the thermodynamics of ionpair formation. Finally, we think that the present results could help to shed light on the nature of the possible species involved in acid/ base equilibria in apolar solvents. As we have recently pointed out,6b up until now this topic appears not completely understood, notwithstanding the problem of the interactions between organic acids and bases in apolar solvents (first step of ion-pair formation as well as of several organic reactions) appears of very large importance: it does not refer only to the thermodynamics of ion-pair formation but also to the kinetics of a large part of processes carried on in apolar solvents (from the acid- or basecatalyzed reactions to the electrophilic and nucleophilic ones). Acknowledgment. We thank the Universities of Palermo and Bologna (funds for selected research topics) and MIURRoma (Grants PRIN 200708J9L2A_005, 20085E2LXC_004, 20085E2LXC_003, and PRIN 2008KRBX3B) for financial support. Supporting Information Available: Table of apparent firstorder rate constants for the rearrangement of 1 into 2 in toluene in the presence of some halogenated alkanoic acids at 313.1 K, experimental procedures for kinetic measurement, equilibrium constants values, and pKa determinations. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) (a) ComprehensiVe Heterocyclic Chemistry I; Rees, C. W., Katritzky, A. R., Eds.; Pergamon: NewYork, 1984. (b) ComprehensiVe Heterocyclic Chemistry II: a ReView of the Literature 1982-1995: The Structure, Reactions, Synthesis, And Uses of Heterocyclic Compounds; Rees, C. W., Katritzky, A. R., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, U.K., 2008. (c) ComprehensiVe Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C., Scriven, E., Taylor, R., Eds.; Elsevier: London, U.K., 2008. (d) van der Plas, H. C., Ring Transformations of Heterocycles; Academic Press: London, 1973; Vols. 1 and 2. (e) L’abbe`, G. J. Heterocycl. Chem. 1984, 21, 627–638. (f) Vivona, N.; Buscemi, S. Heterocycles 1992, 41, 2095–2116. (g) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds. Pergamon Press: New York, 1991. (2) (a) Ruccia, M.; Vivona, N.; Spinelli, D. AdV. Heterocycl. Chem. 1981, 29, 141–169. (b) Vivona, N.; Buscemi, S.; Frenna, V.; Cusmano, G. AdV. Heterocycl. Chem. 1993, 56, 49–154. (c) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N. J. Org. Chem. 2002, 67, 6253–6255. (d) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N.; Spinelli, D. J. Org. Chem. 2003, 68, 605–608. (e) Pace, A.; Pibiri, I.; Buscemi, S.; Vivona, N. Heterocycles 2004, 63,
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