University of Groningen

Organic reactivity in mixed aqueous solventsBlokzijl, Wilfried

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:1991

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Blokzijl, W. (1991). Organic reactivity in mixed aqueous solvents: a link between kinetics andthermodynamics. s.n.

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 22-05-2021

5. Alkyl substinrent fleets. The importance of solvation

Alkyl Substituent Effects on the Neutral Hydrolysis of 1-Acyl-(3-substituted)-1,2,4-triazoles in Highly Aqueous Media.

The Importance of Solvation.

As shown in Chapters 3 and 4, non-covalent interactions between chemically inert cosolvents and reacting substrates in highly aqueous solutions can dramatically affect rate constants of chemical reactions in these media. The quantitative treatment of solvent effects in dilute aqueous media, put forward in Chapter 2, was critically tested in the previous chapters. It was shown that solvent effects are governed by the participation of the chemically inert cosolvents in the solvation shell of the reactant as well as of the activated complex. The different ways in which reactant and activated complex are solvated, causes the observed solvent effects. Careful application of additivity schemes showed that solvent effects are usually dominated by interactions of apolar, hydrophobic parts of the cosolvent. Analysis of solvent effects in dilute aqueous media was used in a retrospective way to identify the contributions of different groups in cosolvents on solvent effects. In dilute aqueous solutions, pairwise interactions predominate solvent effects, unless cosolvent molecules form microphases in the aqueous solution.

In this chapter, a quantitative study is reported of alkyl substituent effects and solvent effects on the pseudo-first-order rate constants for the neutral hydrolysis of eighteen 1-acyl-(3-substituted)-1,2,4-triazoles (la-j, 2a-b, 3a-c, 4a-b and 5) in highly aqueous solutions, containing ethanol and 1-propanol. Furthermore, kinetic medium effects and substituent effects on the water-catalysed hydrolysis are completed with the determination of rate constants for the acid-catalysed hydrolysis, solvent deuterium isotope effects for the neutral hydrolysis and spectroscopic data of the substrates.

la, R,=Me, R2=H lb, R,=Et, R2=H lc, R,=n-Pr, R2=H

0 N > C / R ~ Id, R, =i-Pr, RZ=H II /

R,-C-N I le, Rl =i-Bu, R2=H ' C ~ N lf, R,=s-Bu, R2=H

I Ig, R,=t-Bu, R2=H H

lh, R,=n-Pent, R2=H li, Rl=3-Pent, R2=H lj, Rl=Ph, R2=H

Scheme 5.1

5. All# subsbent effects. The importance of solvarion

We will examine the extent to which the variation of the molecular structure of substrates affects the solvent effects of cosolvents and associated group contributions in highly aqueous media. To this end, the variation of the structure of the cosolvents is limited. In contrast, the structure of the reactive substrate is varied. We restrict our attention to the study of substituent effects of apolar alkyl groups. Substituent effects of alkyl groups are difficult to analyse quantitativelyg. Several previous approaches are summarised in Section 5.2. The through-bond effects of alkyl groups on the reactivity of the substrates is expected to be very small compared to those of other substituents (see Section 5.2). The consequences of systematic variations of the alkyl substituents R, and R2 on both solvent and substituent effects, have to be explained mainly in terms of steric and solvation effects. A clear link between substituent effects and solvent effects is found. The importance is emphasised of solvation effects on the magnitude and sign of alkyl substituent effects. Interestingly, an increased hydrophobi- city of the reacting substrates enhances the reactivity in water.

5.2 Alkyl substhunt efeects. Cumnt views

Substituent effects of alkyl groups on rate constants and equilibrium constants in solution have been studied e ~ t e n s i v e l ~ - ~ ~ ~ . Usually alkyl substituent effects are analysed using Linear Free Energy Relationships (LFER). The abundance of scales of substituent constants shows a strong resemblance to the wealth of solvent polarity scales. Sometimes theoretical calculations provide the empirical scales with a physical basis252-258. Substituent effects are generally governed by (i) polar, (ii) steric and (iii) solvation effects259. In principle, polar effects can be separated into field, inductive and resonance effects. Steric effects and solvation effects are through-space effects. Field effects are transmitted either through space or through the solvent molecules (if present), in contrast to inductive and conjugative effects, which are generally transmit- ted directly through the bonds of the molecular chain. Evaluation of substituent effects of alkyl groups is a complex task. Identification of the individual contributions to the overall substituent effect is difficult and has prompted controversies in the literature.

An important question concerns the ambiguous evidence for inductive substituent effects of alkyl The first and still most frequently used scale for quantifying polar effects uses a*, as defined by the Taft-Ingold equation261.

Thus, the polar effect of the substituent R (or R') is evaluated relative to methyl by comparison of the rate constants for the base(B)- and acid(A)-catalysed hydrolysis of esters RC02R7. Based on 13C-NMR data, Fliszar et a1.262 have shown, that a' values are related to the charge distributions in the alkyl groups. Later, Levitt and widine9 defined the a, scale, mainly based on ionisation potentials for molecules in the gas- phase. This scale was used to measure inductive substituent effects. In fact, the a, scale is directly correlated to the u* scale. Substituent effects of alkyl groups were

5. Alkyf substituent fleets. The importance of solvation

shown to depend on the structure and the electrical characteristics of the molecule. Levitt and W i d i ~ ~ g ~ ' ~ rationalised the magnitude and sign of the alkyl substituent constants by (i) charge delocalisation, (ii) through-the-bond and (iii) electric field models. In all models, the inductive effect has been attributed to the polarisation of heteroatornic bonds, caused by differences in ele~trone~ativiq". Alkyl groups were treated as electron donating substituents. Following this approach, alkyl substituent effects have been frequently correlated with the electronegativity of the alkyl group, expressed in xRm. Houk et alez3 have criticised the interpretation of correlations of ionisation potentials in terms of alkyl inductive effects and prefered explanations in terms of dominant hyperconjugative effects. In the gas-phase, alkyl groups are able to stabilise adjacent charges, either negative or positive. Taftm has explained this effect, induced by a neighbouring charge, in terms of the polarisability of alkyl groups, expressed in a substituent constant P.

Recently, Hansonm has expressed not only polar and inductive substituent con- stants, (a* and a,, respectively), but also the group electronegativities (x,), and the polarisability (P) of alkyl substituents in terms of connectivity characteristics. Essential- ly, the number of the carbon atoms and the pattern of their bonding determine the magnitude of alkyl substituent constants. Both a* and a, were shown to be linear functions of the electronegativity of the alkyl groups. Probably, the polarisibility has a hyperconjugative element.

Notwithstanding the experimental evidence cited above, the existence of inductive effects of alkyl substituents has been questioned by several a ~ t h o r s ~ ~ ~ - % ~ . In addition, the significance of a' as a measure for polar substituent effects of alkyl groups has been frequently disputed. For example, inductive effects of alkyl groups are hardly manifested in reactivity. Physical manifestations of alleged inductive substituent effects of alkyl groups are mainly found in NMR data, ionisation potentials and thermodyna- mic parameters. Generally, in order to obtain a reliable polar or inductive substituent constant, many sets of kinetic data are used. The controversy about the existence of inductive effects of alkyl groups and the significance of polar alkyl substituents constants is mainly caused by the fact that (i) a* and a, are much smaller for alkyl groups than for other substituents, (ii) many more data are available for alkyl groups than for other groups which leads to a divergence of the averaged substituent constant and (iii) the localised field and/or inductive effect of alkyl groups is very small. Consequently, substituent constants for alkyl groups are inevitably flawed with large errors. ~ i t c h i e ~ , ~ e ~ a ? and Chartonx5 have even argued that the small differen- ces between a* of alkyl groups are a result of artefacts and that differences in inductive effects of alkyl groups, expressed in a,, do not exist at all. These authors claim that the Taft a* constants for alkyl groups probably measure steric effects.

A few attempts have been made to separate and quantify steric effects of alkyl groups. In fact, it was again Taft, who was the first to define a steric substituent constant, E,, based on Equation 5-2261.

Thus, the steric effect of substituent R is evaluated relative to methyl by measuring the rate constants for the acid-catalysed hydrolysis of esters RCOOEt. Subsequently,

5. AIkyl substituent effects. The importance of solvation

Taft analysed the substituent effects of alkyl groups in terms of multiple parameter equations, of the form given in Equation 5-3, in which both polar and steric effects are incorporated.

log k = a + p,E, + p,a, 5-3

DeTar et a1.266 showed that E, is correlated with both a* and a,, which makes a joint correlation with E, and either a* or a, of diminished significance. Conflicting claims exist about steric constants, and alternative steric substituent constants, such as E,. 268,

E,C 269, and 0"' have been introduced to replace the E, scale. In addition, C h a r t ~ n ~ ~ ' successfully analysed the steric contribution of a w l substituents in terms of a branching equation.

The contribution of solvation effects to substituent effects has always been treated as a The general attitude towards the contribution of solvation effects to the overall substituent effects of alkyl groups has been characterised by pragrna- tism. Solvation effects are assumed to be effectively the same for different substrates. Alternatively, it has been assumed that they tend to parallel steric effects. In either case it was thought possible to obtain, at least, relative values of steric effects. The validity of this assumption is not borne out by theoretical or experimental evidence. Recent1 , Charton reported attempts to quantify the role of solvation in substituent 7 effects2 '. In this chapter, the importance of solvation will be analysed for the overall substituent effect of alkyl groups on a simple hydrolysis reaction.

5.3 Solvent effects and substituent gects on the hydrdysir I-acyl-(3-sUbs~d)-1,2,4- triazohs

Theoretical background. In water-rich media, the pH-independent hydrolysis of l-acyl- (3-substituted)-1,2,4-triazoles proceeds via a general-base catalysed rocess, in which P the water molecules act as a nucleophile and a general base19 '%, respectively; Scheme 5-2.

Scheme 5-2

86

5. AIkyl substiruetat fleets. The importance of solvation

Depending on the effectiveness of acid- and base-catalysed hydrolysis, the rate constants me pH-independent in a particular pH range (ca.3-6). However, this range is critically determined by the substituents R, and R, in the substrate. The acid- catalysed hydrolysis shows the characteristics of specific-acid catalysis and proceeds via reversible protonation at N-4 in the triazole ring, followed by rate-determining attack of water at the carbonyl moiev3(Scheme 5-3).

Scheme 5-3

For the neutral hydrolysis, the reaction medium consists of water, m, and m, mol kg-' of reactant and activated complex, respectively, a small concentration of HCl in order to prevent base catalysis, and m, mol kg-' of a cosolvent C (ethanol or l-propa- nol). In all experiments, the substrate concentration is very small (ca.10" mol kg-'). Product analyses revealed only minor amounts of products formed by alcoholysis (see Experimental Section). Therefore, solvent effects are a consequence of the interaction of reactant and activated complex with the added cosolvent molecule. Previously, we derived Equation 2-32 , which relates the pseudo-first-order rate constant for solvoly- sis reactions in dilute mixed solvents to the rate constant in the pure solvent. This equation can be applied to describe the solvent effect of ethanol and 1-propanol on the neutral hydrolysis of compounds 1-5. In this chapter we use the formalism introduced in Chapter 3. Kinetic data are quantitatively described by

Herein, the factor [CG,-CG,,] is defined as G(C), where G, and GSi represent the pairwise Gibbs energy interaction parameters of groups i in the cosolvent with reactant and activated complex, respectively. G(C) can be subdivided into group contributions G(i), following a quasi-SWAG approach (see Section 3.3). In this study, solvent effects of ethanol and 1-propanol are expressed as G(Et0H) and G(Pr0H). In chapter 3 it was shown that the group contribution of the CH groups and the OH group of monohydric alcohols can be determined from a comparison of the solvent effect of ethanol and propanol. The solvent effects of ethanol and 1-propanol on the neutral hydrolysis of a series of 1-acyl-(3-substituted)-1,2,4-triazoles are subsequently

5. AIhyl substintent effects. The importance of solvation

Table 5-1. Neutral and Acid-Catalysed Hydrolysis of la-j. Rate Constants and Solvent Deuterium Isotope Effects at 25°C.

l a methyl l b ethyl l c n-propyl Id i-propyl l e i-butyl If S-butyl l g t-butyl l h n-pentyl l i 3-pentyl l i vhenvl 203 9.4 2.62

'Rate constant for neutral hydrolysis in water containing ca.10~ m01.k~-' of HC1. k a t e constant for neutral hydrolysis in aqueous solution, containing 5 mol kg-' of 2-propanol. '%ate constant for acid- catalysed hydrolysis. d ~ o r neutral hydrolysis.

Table 5-2. Neutral and Acid-Catalysed Hydrolysis of 1-Acyl-(3-substituted)-1,2,4- triazoles. Rate constants and Solvent Deuterium Isoto~e Effects at 25OC.

l a methyl H 216 20 3.00 2a methyl t-butyl 59.7 56 3.06 2b methyl C1 692 2.92 Ib ethyl H 290 29 3.13 3a ethyl methyl 132 67 3.19 3b ethyl t-butyl 82.8 80 3.15 3c ethyl phenyl 212 9.5 3.24 l g t-butyl H 341 68 3.09 4a t-butyl methyl 168 213 3.04 4b t-butyl t-butyl 106 241 C

lj phenyl H 203 9.4 2.62 5 phenyl phenyl 127 2.8 2.95

aRate constant for neutral hydrolysis. b ~ a t e constant for acid-catalysed hydrolysis. CBecause of the high sensitivity for acid catalysis, an accurate value of the SDIE for the neutral hydrolysis is difficult to obtain.

5. Alkyl substituent effects. The importance of solvation

Table 53. Spectroscopic Data for 1-Acyl-(3-substituted)-1,2,4-triazoles.

13c chemical shift,' Rl R2 vc=c,,a UV 1-

b 89 I'pm

cm-' nm C=O C3 C5

l a methyl H 1754 218 167.9 152.8 143.1 2a methyl t-butyl 1749 226 173.6 168.2 143.2 2b methyl C1 1765 225 l b ethyl H 1752 221 171.4 152.6 143.2 3a ethyl methyl 1747 226 171.3 162.6 143.5 3b ethyl t-butyl 1749 226 173.4 171.7 143.2 3c ethyl phenyl 1746 258,270d 171.7 163.0 143.8 l c n-propyl H 1751 217 Id i-propyl H 1751 218 174.5 152.8 143.5 l e i-butyl H 1750 218 If s-butyl H 1750 219 lg t-butyl H 1735 220 175.1 152.1 145.0 4a t-butyl methyl 1729 227 175.1 162.0 145.4 4b t-butyl t-butyl 1726 229 175.3 172.7 145.0 l h n-pentyl H 1748 219 l i 3-pentyl H 1748 219 173.5 152.6 143.2 lj phenyl H 1716 250 164.2 152.8 145.7 5 phenyl phenyl 1706 273 164.3 163.8 146.3

aIn CC14 b ~ n water. 'In CDCl,. d~avelength for monitoring the kinetics of the hydrolysis.

If R, is an alkyl group, the solvent deuterium isotope effect (SDIE) increases with increasing size of the alkyl substituents. When R, is an alkyl group, the SDIE is less sensitive to the size of the substituents. It is general1 assumed that hydrophobic effects are more pronounced in D20 than in Hz& The significant difference between the SDIE for compounds le and compounds If and l g indicates, however, that interpretation of these SDIE's is extremely difficult.

Substituent effects on spectroscopic parameters. Carbonyl stretching wavenumbers, wavelengths of UV maxima and 1 3 ~ - ~ ~ ~ chemical shifts for the carbonyl carbon and the triazole carbon atoms C3 and C5, are collected in Table 5-3. The carbonyl absorption is only slightly dependent on the nature of the alkyl substituents R, and R,. Only for substrates in which R, is a t-butyl group, or in which R, and/or R2 are phenyl groups, does the C=O frequency deviate markedly. The 13C chemical shift of the carbonyl carbon is also sensitive to variation of the alkyl substituents R, and R,. Essentially, introduction of alkyl moieties causes a downfield shift. The chemical shift of the C3 carbon changes drastically when the hydrogen on C3 is substituted by an alkyl group. This pattern is not unexpected. The chemical shift of the C5 carbon is, however, almost indifferent to substituent effects.

5. Alkyl substituent effects. The importance of solvation

Remarkable, therefore, is the small but significant change in the chemical shift of the C5 carbon in the substrates in which R, is a t-butyl group, or phenyl group. UV spectra are hardly sensitive to changes of the alkyl substituents. Extension of the T- electron delocalisation by the introduction of phenyl groups induces significant shifts of the W maxima.

The mutual dependence of substituent effects and solvent effects. In Figures 5-1 and 5-2, ln[k(mc)/k(mc=O)] is plotted as a function of the molality of ethanol and 1- propanol, respectively. Here, k is the pseudo-first-order rate constant for neutral hydrolysis of compounds la-lj. Both ethanol and 1-propanol induce a significant decrease of the reaction rate constant. Similar plots can be made for the solvent effect of ethanol and 1-propanol on the neutral hydrolysis of substrates 2-5. All plots show perfect linearity. As shown in Tables 5-4 and 5-5, all solvent effects are dominated by the negative G(C).

0 0.5 1 .O 1.5 -1 m,. mol.kg

Figure 5-1. Plots of -In[k(mc)/k(mc=O) vs molality of ethanol for the neutral hydrolysis of 1-acyl-1,2,4-triazoles (R1COTrR2, R2=H) at 2S°C; Rl=Me, 0 ;R,=Et, ;R,=i- Prop, A ;Rl=n-Prop, V ;R,=Ph, ;R,=i-But, ;Rl=t-But, A ;R,=3-Pent, 0 .

5. Alkyl substituent effects. The importance of solvation

Figure 5-2. See legend to Figure 5-1, with cosolvent 1-propanol instead of ethanol.

Generally, the reduced activity of water, due to the presence of cosolvents, contributes only moderately to the overall rate effect. The negative G(C) is predominantly caused by the rate decreasing contribution of the CH groups, expressed by the negative value of G(CH) (see Tables 5-4 and 5-5). This pattern is consistent with a loss of hydropho- bic character of the substrate during the activation process.

G(Et0H) and G(Pr0H) depend critically on the nature of the substrate. It is striking that not only the alkyl group R,, but also the alkyl group R, which is quite far removed from the actual reaction centre, exerts a pronounced influence on the observed solvent effects. This means that we have to account for differences in the

5. AIkyl substituent Meets. IRe importance of solvation

Gibbs energy of pairwise interactions of the cosolvents with the substituents in the reactant and in the activated complex.

An important result of the strikingly different solvent effect of apolar cosolvents on the rate of neutral hydrolysis of related compounds is shown in Table 5-1. Here, the rate constant for neutral hydrolysis of compounds la-j is given, as determined in the presence of 5 mol kg-' of 2-propanol. The sequence, observed for the reactivity of the substrates in pure water, is completely changed.

Table 5-4. Solvent Effects of Ethanol and 1-Propanol on the Neutral Hydrolysis of la- j at 25OC. Application of a Quasi-SWAG Approach.

R~ G(EtOH), G(PrOH), G(CH), G(OH), J kg mor J kg rn01'~ J kg rn01-~ J kg mol"

l a methyl -52 (2) -97 (2) -22 (2) 59 lb ethyl -103 (2) -158 (3) -28 (3) 37 l c n-propyl -107 (1) -182 (3) -38 (2) 82 Id i-propyl -155 (2) -237 (3) -41 (3) 50 le i-butyl -133 (2) -226 (3) -47 (3) 102 lg t-butyl -185 (1) -289 (2) -52 (2) 75 l i 3-pentyl -202 (2) -324 (5) -61 (4) 103 lj phenyl -83 (2) -172 (3) -45 (3) 142

Table 5-5. Solvent Effects of Ethanol and 1-Propanol on the Neutral Hydrolysis of 1- Acyl-(3-substituted)-1,2,4-triazoles at 25OC. Application of a Quasi-SWAG Approach.

l a methyl 2a methyl l b ethyl 3a ethyl 3b ethyl 3c ethyl lg t-butyl 4a t-butyl 4b t-butyl l j phenyl 5 phenyl

H t-butyl H methyl t-b~tyl phenyl H methyl t-buvl H phenyl -

5. Alkyl substituent effeccrs. The importance of solvation

5.4 A link between alkyl subsfhent effects and solvent effects

As shown in Chapter 3, the solvent effect of monohydric alcohols is attributed to the participation of the cosolvent in the solvation shell of the reactant as well as of the activated complex. The magnitude and sign of the observed solvent effect directly reflect the relative loss or gain of hydrophobicity of the substrate during the activation process. The kinetic data show that the loss of hydrophobicity of related substrates 1- 5, undergoing neutral hydrolysis, depends critically on the nature of substituents. Clearly, the solvation of the substituent in the initial state of the reaction, is quite different from the solvation in the transition state of the reaction. A quantitative analysis of solvent effects in terms of a quasi-SWAG approach quantifies this differen- ce in terms of G(C), G(CH) and G(0H).

It is remarkable that G(CH), obtained for different substrates, shows a perfect correlation with the hydrophobicity of the substituent. To illustrate this fact, G(CH) is plotted as a function of Rekker's hydrophobic fragmental constants274 (Cfi) of the alkyl substituent R, (see Figure 5-3). A similar dependence, though less pronounced, can be obtained with respect to G(CH) and the hydrophobicity of the substituent R,. In Figure 5-4 we have constructed a plot, using as the horizental axis the value of Cfi for R, and as vertical axis the value of Cfi for R,. The contribution of the CH groups to the overall solvent effect of ethanol and 1-propanol, expressed as G(CH), is indicated for the particular substrates. In the lower left-hand comer, the most polar substrates are localised, whereas the most apolar substrates are found in the upper right-hand corner.

0 I I 1 I

0 0.5 1.0 1 .S 2.0 2.5 3 .O

I f i

Figure 53. Plot of -G(C) vs the sum of Rekker's hydrophobic fragmental constant of R,. The substrates are the 1-acyl-1,&4-triazoles (R,COTr);R,=Me, 0 ;R,=Et, ;R, =i-Prop, A ;R, =n-Prop, ;R,=Ph, V ;R, =i-But, rn ;R, =t-But, ;R,=IPent, A .

5. AlkyI substituent effects. The importance of solvatwn

If. R,

Figure 5-4. Diagram showing the sum of the Rekker's hydrophobic fragmental constants for R, and R2 on the horizontal and vertical axis, respectively. Substrates are 1-acyl-(3-substituted)-1,2,4-triazoles (R,COTrR2). The numbers, given near the symbols are the solvent effects of the apolar CH groups on the rate constant for neutral hydrolysis of the substrates at 25"C, expresses as G(CH):la, 0 ;lb, ;lc, A ;Id, a ;le, A ;lg, ;li, 4 ;lj, V ;2a, r ;3a, 0 ;3b, 4 ;3c, D ;4a, 4 ;4b, 0 ;5, b .

It appears that the loss of hydrophobic surface of the substrate during the activation process is strongly dependent on a combination of (i) the size of alkyl substituents R1 and Ra (ii) the position of the alkyl substituent with respect to the reaction centre and (iii) the overall hydrophobicity of the substrate. The effect of alkyl groups appears to be synergic. Therefore, substrates with an overall similar hydropho- bicity can exhibit a remarkably different behaviour towards solvent effects (compare, for example, compounds 2a and 4a). For substrates with a comparable hydrophobicity and a comparable positioning of the substituents, still subtle differences in solvent

5. Alkyl subsrituent @em. lke importance of solvation

effects of apolar cosolvents are observed. The solvent effect of ethanol and l-propa- no1 on the neutral hydrolysis of substrates l c and Id, and of l e and l g are significantly different. The loss of hydrophobicity during the activation process of substrates, in which the alkyl substituent R, is branched at the /3 carbon, is smaller than for substrates in which the alkyl group is branched at the a carbon. One can speculate whether this is a result of an increase in the distance to the reactive centre.

Clearly, the introduction of alkyl substituents destabilises the reactant with respect to the activated complex. Consequently, the substrate is more sensitive towards hydrolysis. Addition of an apolar cosolvent stabilises the reactant with respect to the activated complex and thereby reduces the reactivity of the substrate. Therefore, the presence of apolar cosolvents neutralises or even reverses the contribution of solvation to the overall substituent effect of alkyl groups. This proposal is confirmed experimentally in Table 5-1, where the presence of 5 mol kg-' of 2-propanol is shown to completely reverse the substituent effect of the alkyl groups. Interestingly, the pK, of RCOOH in water also increases in the series methyl, ethyl, i-propyl and r-butyl, which has been a major point of discussion with respect to alkyl substituent effects266. The trend is understandable in the light of the solvation contribution to the overall alkyl substituent effect.

5.5 The molecuIar origin of alkyl substbent effects

Introduction of alkyl substituents leads, in the absence of polar or steric effects, to a decrease of the Gibbs energy of activation for reactions in water or highly aqueous solutions. A prerequisite is, that the substrate loses apolar character during the activation process. The loss of hydrophobic surface of compounds, dissolved in water, is, in terms of Gibbs energy, a favorable process. Inspection of the substituent effects of alkyl groups, summarised in Tables 5-1 and 5-2, shows that alkyl substituent effects on rates of neutral and acid-catalysed hydrolysis of compounds 1-5 are not solely a result of solvent effects. In addition, steric effects and, possibly, polar effects of alkyl groups, though the contribution of the latter will be very small, have to be taken into account. These contributions are responsible for the observations that (i) the kinetic and spectroscopic behaviour of substrates in which R, is a phenyl or a t-butyl group deviates from the kinetic and spectroscopic behaviour of the other substrates studied, (ii) the effect of R2 substituents on the rate constants for water and acid-catalysed hydrolysis is opposite and (iii) the difference between substituent effects of substitu- ents R, is significant if the alkyl groups have a similar h drophobicity . B Following suggestions, made by Pinkus et aL2" 6, who studied the carbonyl stretching frequencies and dipole moments of a series of ketones and esters, the abnormally low stretching frequencies of compounds in which R, is t-butyl are most likely the result of an out-of-plane twisting of the t-butyl group due to steric interfe- rence with the triazole ring. The remarkable chemical shift of the C5 carbon in the ring, observed for these compounds, supports this explanation. This steric interference is absent for the other alkyl groups. Recent calculations277 have indeed confirmed that the triazole ring and the C=O bond are not coplanar if the R, group is either a t- butyl group, or a phenyl group.

5. Alkyl substiiuent effects. The importance of solvation

Table 5-6. p&-Values of substituted 1,2,4-Triazoles and 1,2,4-Triazolium Ions in Water at 20°C.

1,2,4-Triazole Derivative p c p h b

a1,2,4-Triamle. bl,2,4-~riazolium ion.

In Table 5-6, the pK, is listed for a series of substituted triazoles and triazolium ions. According to Kroger et al.278, the pK, correlates satisfactorily with a,,,. As shown by the pK, of the triazolium ions, protonation of the triazole ring is facilitated by introduction of an alkyl group on C3. This fact explains the increased sensitivity of the acyltriazoles towards acid-catalysed hydrolysis, when alkyl substituents are introduced on the C3 position. The importance of solvation for this substituent effect is difficult to assess. As shown by the p& of the triazoles, the leaving ability of the triazole ring is reduced by introduction of alkyl substituents on C3. This might explain the decrea- sed rate constant for neutral hydrolysis upon introduction of alkyl groups on C3. The molecular origin of the alkyl substituent effect remains obscure.

The abnormal behaviour of substrates in which phenyl groups are present is due to the possibility of extensive charge delocalisation. The pK, of the 3-phenyl-1,2,4- triazolium ion is very low (Table 5-6), which explains the extremely low sensitivity towards acid-catalysed hydrolysis.

The difference between the substituent effects of isomeric alkyl groups is largely attributed to steric effects and polar effects. Molecular models show that only branching at the /? carbon as well as on the y carbon of R, leads to considerable shielding of the carbonyl carbon, whereas this effect is absent for alkyl groups branched at the a carbon. Therefore, attack of a nucleophilic agent is significantly hindered. Confirmation of this fact by application of a branching equation does not prove unambiguously that only steric effects are responsible for the observed substitu- ent effects. It has been argued that branching at the a carbon leads to a reduced possibility for hyperconjugationm, which might also contribute to the observed substituent effect.

5.6 Solvophbic acceleration and s u b s h n t effects

The present study shows that a quantitative treatment of solvent effects on simple hydrolysis reactions in highly aqueous reaction media in terms of a quasi-SWAG approach, offers a useful basis with which to assess the contribution of the solvent to alkyl substituent effects on reactivity in water-rich binary solvents. The important

5. Alkyl substituent effects. The Theportance of solvation

conclusion is that steric and polar substituent effects are strongly modulated by the solvation of the reactant and the activated complex. The relative extent of substituent effects can be changed dramatically and in some cases substituent effects can even be reversed by changing the solvent composition. In terms of a Hammett-type analysis this means that (i) the solvation effect is expressed in the magnitude of the dependen- ce of the measured quantity on the substituent and (ii) any correlations with substitu- ent constants is largely governed by the dominant contributions of steric and solvation effects. This fact prompts three important conclusions:

(0

(ii)

In aqueous media the determination of substituent constants for alkyl substitu- ents that measure purely steric and/or polar effects is impossible. Substituent constants for alkyl groups, or hydrophobic substituents in general, obtained for reactions in either water or highly aqueous solutions, are strongly determined by solvation effects.

(iii) An observed correlation of substituent effects of alkyl groups for processes in aqueous solutions with known substituent constants means that the solvation effects parallel the steric and/or polar effects of alkyl groups.

Chemical reactivity of hydrophobic reactants in water is strongly enhanced by the fact that the water "forces" the reactant to reduce its hydrophobic surface during the activation process. Tentatively, this is a consequence of easy fluctuations of the hydrogen-bonded structure of water together with the ability of the activated complex to adapt itself to the aqueous environment. In the absence of steric and polar effects, increasing the hydrophobicity of the reactant by increasing the size of the alkyl substituents leads to increased reactivity in aqueous solution. The contribution of solvation to the overall substituent effect of hydrophobic groups can therefore be called solvophobic or hydrophobic acceleration.

5.7 l3qerimental section

Materials. Ethanol (p.a.), 1-propanol (p.a.) and 2-propanol were supplied by Merck and were used without further purification. Demineralised water was distilled in an all-quartz distillation unit. All solutions were made up by weight and contained 4x10" mol dm" of HCl (to suppress catalysis by hydroxide ions) for the measurements of rate constants for neutral hydrolysis and appropriate concentrations of HCl for the measurement of rate constants for the acid-catalysed hydrolysis. Solvent deuterium isotope effects were measured in D,O solutions that contained 4 x 1 ~ ' mol dm-3 DCl. Generally, the pH range in which the actual reaction rate constant for hydrolysis is independent of the pH, is very small for those compounds that undergo very effective acid-catalysed hydrolysis. Therefore, measurements were performed between pH 4 and pH 4.5. The pH of the binary mixtures was always carefully checked before and after the reaction using a Corning 130 pH-meter. In case of compound 4b no reliable SDIE could be determined because of the extreme sensitivity towards acid-catalysis.

The 1-acyl-(3-substituted)-1,2,4-triazoles la-j, 2b and 5 have been synthesised as reported previously1%. The new substrates were prepared from the corresponding acyl

5. AIkyl substinrent effects. The importance of solvatwn

chloride and 3-substituted 1,2,4-triazole, according to a standard pr~cedure"~. Solid 1- acyl-(3-substituted)-124-triazoles were recrystalised twice from n-hexane and liquid substrates were distilled in vacuo. The 3-t-butyl-1,2,4-triazole, 3-methyl-1,2,4-triazole, and 3-phenyl-1,2,4-triazole were prepared with use of standard procedures. NMR spectra were recorded on a Varian VXR-300 instrument with TMS as an internal standard.

l-Methanoy1-3-S-butyl-lJ,4-tri8u)le (2a): bp 100-10l°C (1 mm Hg); 'H-NMR (CDCI,) 8 1.34 (s,9H), 2.64 (s,3H), 8.75 (s,lH) ppm; ',C-NMR (CDC1,) S 21.99 (p), 28.78 (p), 32.82 (q), 143.15 (q), 173.63 (q) ppm.

1-Ethanoyl-3-methyl-l,2,4-triamle (3a): mp 71-73OC; 'H-NMR (CDCI,) S 1.25 (t73H), 2.38 (s,3H), 3.10 (q,2H), 8.81 (s,lH) ppm; 13C-NMR (CDCI,) S 7.66 (p), 13.73 (p), 28.01 (s), 143.46 (t), 162.58 (q), 171.29 (q) ppm.

1-Ethanoyl3-5-butyl-1,2,4-triazole (3b): bp 75-77°C; 'H-NMR (CDCI,) 6 1.22 (t,3H), 1.32 (s,9H), 3.05 (q,2H), 8.75 (s,lH) ppm; 13C-~MR (CDCI,) S 7.65 (p), 27.96 (p), 128.73 (p), 132.81 (q), 143.23 (t), 171.67 (q), 173.41 (q) ppm.

l-Ethanoyl3-phenyl-l,2,4-triazole (3c): mp 60-62OC; 'H-NMR (CDCI,) S 1.33 (s,3H), 3.18 (q,2H), 7.45 (m,2H), 8.92 (s,lH) ppm; ',C-NMR (CDCI,) S 7.77 (p), 28.11 (s), 126.79, 128.56, 129.37, 130.2, 143.84 (t), 163.46 (q). 171.70 (q) ppm.

l~-Butanoyl-3-rnethy1-1,2,4-tri8~)le (43): bp 50-51°C (0.7 mm Hg); 'H-NMR (CDCI,) S 1.38 (s,9H), 2.34 (s,3H), 8.72 (s,lH) ppm; 13C-NMR (CDCI,) S 13.83 (p), 26.68 (p), 41.08 (q), 145.37 (t), 161.99 (q), 175.14 (q) ppm.

l~-Butanoyl-3t-buty1-1,2,4triamle (4b): bp 180-182°C (8 mm Hg); 'H-NMR (CDCI,) 6 1.30 (s,9H), 1.40 (s,9H), 8.70 (s,lH) ppm; 13C-NM~ (CDCI,) S 26.71 (p), 28.75 (p), 32.70 (q), 41.06 (q), 145.01 (t), 172.66 (t), 172.66 (q), 175.29 (q) ppm.

Product analysis. The reaction products of the solvolysis of the conpounds la, lb, lg, lj, 4a and 5 were analysed quantitatively. Hereto, reactions were performed in the presence of 0.5, 1.0 and 1.5 mol kg-' of ethanol and 1-propanol, respectively. The substrate concentration in these experiments was always about 5x10" mol dm-3, the pH was between 4 and 4.5. The pH was checked before and after the reaction. After completion of the reaction, the products of the reaction were analysed by gas chromatography (Hewlett-Packard 5890 instrument, equipped with a 15 m wide-bore fused silica column), and, if necessary, by GC-MS (Ribermag R-10-10c) with the authentic triazoles, acids and esters as reference materials. The relative amount of alcoholysis was determined by calibration. In every case, traces of ethyl and propyl ester could be observed. Independent experiments showed that esters were not formed by esterification of the acid formed after hydrolysis. The yield of the esters depends linearly on the concentration of the alcohol. Although slight differences were found between the amount of ester for the different substrates studied, the amount of ethyl ester formed at 1.5 mol kg-' ethanol never exceeded 3+1%, and the amount of propyl ester was even smaller, that is 2*1%. Kinetic analysis therefore shows that the occurrence of alcoholysis does not hamper our quantitative analysis of solvent effects.

Kinetic Measurements. The pseudo-first-order rate constants were determined by following the change of absorbance at appropriate wavelengths; see Table 5-3. About 3-5pL of a concentrated stock solution of the substrate in acetonitrile (ca. 5x10-' mol

5. Alkyl substituent effects. The importance of solvation

dm3) was added to the reaction medium (ca. 2.5 cm3) in a quartz UV cell (1 cm) that was placed in a thermostated cell compartment of a spectrophotometer (Perkin Elmer 15, or a Perkin Elmer 12), both equipped with a data station. Care was taken to avoid inhomogeneous reaction mixtures in view of the low solubility of the apolar substrates. Therefore, initial concentrations of the very apolar substrates were kept as low as possible. For compound 4b some solubility problems troubled the kinetic analysis. In this case, a delay time was applied after the injection of the stock solution before collection of the data points. In addition, the solution was vigorously stirred with an external microstirrer. The reactions were followed for about 10 half-lives, and excellent pseudo-first-order kinetics were observed in all cases. For every kinetic run, about 100-300 datapoints were collected. Rate constants were calculated using a fitting program as well as by applying the end-value approach. Rate constants, at each molality of cosolvent, were determined at least three times, and were reproducible to within 1%. For the calculation of G(C) from data obtained at, at least, six molalities, a least-squares procedure was used, and the line was forced to go through (0,O). The second-order rate constants for the acid-catalysed hydrolysis were calculated by a least-squares analysis from pseudo-first-order rate constants obtained at six different pH values.