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Organic reactivity in mixed aqueous solventsBlokzijl, Wilfried

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I . Introduction Solvent gects on organic reactions in aqueous mirtwes

CHAPTER 1

Solvent Effects on Organic Reactions in Aqueous Mixtures. An Introduction

2.1 Solvent effects in chemistry

2.1.1 Some words about the hirtorical background

Reactivity of molecules and ions in solution is largely dictated by the solvent. Compa- rison of rate constants in the gas-phase and in solution shows that differences of 10" are not uncommon1. In 1862, Berthelot and PCan de Saint-Gilles were the first to notice the considerable influence of the reaction medium on the rates of homogene- ous chemical reactions2. In 1890, Menschutkin performed the first detailed study of the reaction of trialkylamines with haloalkanes in twenty-three different solvents and stated that "solvents are by no means inert in chemical reactions and can greatly influence the course of themN3. Since then many papers have appeared in which more or less dramatic solvent effects are reported on a large variety of chemical processes. Changing the solvent can, in extreme cases4, lead to rate variations in the order of lo9. Not only chemical reactions, but also chemical equilibria are sensitive to the solvent. This was shown by ClaisenS and wislicenus6, who were, in 1896, among the first authors to draw attention to the considerable solvent effect on keto-en01 tautomeric equilibria. The fact that the solvent can seriously affect spectroscopic properties of molecules in solution was demonstrated by ~ u n d t ' in 1878. During the past century, solvent effects have also been reported on a number of other chemical phenomena, such as aggregation8, complexation9, ionisationlo, conformation" and isomerisation12. Solvent effects on chemical reactivity have received close attention. A long-lived goal of chemists at large has been to establish methods and to provide tools to understand and predict solvent effects on chemical reactions. Ultimately, this knowledge should enable chemists to choose in a rational way a suitable solvent for a particular chemical transformation.

1.1.2 W a r ; menstruum univer~ale?'~

According to ancient Greek philosophy every solution was called "water" and all liquids, able to dissolve compounds were classified as "divine water". Water was in fact the first liquid to be considered a solvent. Many publications and textbooks claim that water is in every aspect a unique solvent and liquid. Water certainly is the most extensively studied liquid. Properties, models and theories have been discussed in detai114-16. Although living organisms depend in a unique way on water as a solvent for biochemical transformations, synthetic organic chemists do not particularly like water

1. Introduction Solvent effects on organic reactions in aqueous mixtures

Table 1-1: Summary of organic reactions performed in homogeneous and heterogene- ous aqueous media.

Reaction References

Intermolecular Diels-Alder reactions

Intramolecular Diels-Alder reactions

Claisen rearrangements 18f,g

Aldol reactions of silyl-en01 ethers 19c

Benzoin condensation 17e

Reduction of alkyl halides with tinhydride 17f

Allylation of carbonyl compounds using zinc 22a,b, 29

as a solvent for chemical reactions. This "hydrophobic" attitude stems largely from the fact that water is far from a "Menstruum Universale" for organic compounds. Moreover, water is often highly reactive towards many organic reagents. Nevertheless, the past decade has witnessed a remarkable reappraisal of water as a solvent for organic reaction^'^-^^. This change in attitude is partly due to the pioneering work of res slow"", who, in 1980, reported intriguing solvent effects of water on notoriously solvent-insensitive Diels-Alder reactions. This discovery inspired others to search for other organic reactions that could benefit likewise from water as a solvent. In addition, the need for solvents that can satisfy the high requirements of current environmental legislation, makes water an interesting choice as a solvent for organic reactions. In Table 1-1 a collection of organic reactions is surnrnarised that are not traditionally performed in water, but were found to benefit from the presence of water as a solvent. The molecular origin of these remarkable and sometimes even spectacular solvent effects in aqueous solution remains unclear.

1.2 A survey of approaches to the analysh of solvent effect^^'-^^

Solvent effects on chemical processes are usually studied in comparison to reactivity in a reference solvent. In some cases comparison is made with gas-phase reactivity. Generally, analysis of solvent effects has been based on an equilibrium solvation model. However, for some organic reactions the reaction rates can be very high and examples are known for which non-equilibrium or dynamic solvation models have to be used to account for reactivity in solution. Consequently, sophisticated theoretical models have been developed. In the past, quantitative and qualitative approaches for the analysis of solvent effects have been developed almost simultaneously.

1. Introduction Solvent effects on organic reactiom in aqueous mixtures

Qualitative descriptions of solvent effects. Almost all qualitative treatments of solvent effects are based on the simple solvation model, developed by Hughes and Ingold in 1935, for explaining solvent effects on substitution and elimination reactionsB. The model considers mainly the change of electrical interactions between solvent and reacting species during the activation process. Solvents are thus classified according to their ability to solvate ions and molecules. A serious shortcoming of this approach is the fact that the solvent is considered as a continuum without defined structure and that specific solvent-solute interactions are completely neglected. In addition, changes in the structure of solvents as a result of changes in solvation during the activation process are neglected. Also entropic contributions to solvent effects are not incorpora- ted into this model. Especially in highly structured solvents such as water, entropic contributions to solvent effects can be significant. Notwithstanding the weak points of these qualitative models, these approaches are simple and are readily applied; they are still very popular in practical chemistry.

Quantitative descriptions of solvent effects. The starting point of most quantitative approaches for the interpretation of solvent effects is based on transition state theory (TST). A general quantitative description of solvent effects is given in Equation 1-1,

in which

A pi,= pic(S) - P ~ H ) and

where ApIsO and ApACO are the transfer standard chemical potentials of the initial state and the activated complex, respectively, for transfer from the reference solvent R to solvent S. The rate constants, found in solvents S and R are k and k,, respectively. The success of any quantitative method in describing solvent effects is determined by the accuracy with which the Gibbs energies of solvation can be calculated. A detailed knowledge of solvent-solute interactions is essential for this goal. The wide range of possible solute-solvent interactions, the actual structure of the solvent, the characteris- tics of the reacting molecules and the activated complex make enormous demands on the theory. (Semi)quantitative approaches can be subdivided into four major catego- ries:

(i) Correlations with physical properties of the solvent. (ii) Correlations with empirical solvent parameters. (iii) Analysis incorporating solubility andfor transfer parameters. (iv) Theoretical treatment of solute-solvent interactions.

In separate sections, these approaches will be briefly outlined and critically discussed.

1. Introduction Solvent pffects on organic reactions in aqueous rnirtures

1.2.1 Correlations with physical properties of the solvent

Solvents can be classified according to many physical properties. Some of these have been used for the correlation of solvent effects. Frequently, the justification for these correlations is found in some theoretical model. Most popular are correlations with the relative permittivity, E, of the solvent. Solvent effects are often related to functions like [(~;l)/(&,+l)] or I/&,. The theoretical basis for these correlations has been given by Eyring, Kirkwood, Laidler and ~andskroene?"'. Another well-known method, developed by Scatchard and Hildebrand, is based on the energy of evaporati- on of a solvent per unit of volume, the cohesive pressure or cohesive energy density, c or aH2 384. Related to this approach are correlations with the internal pressure of the solvent42, -rr. These methods are mainly used to analyse solvent effects on reactions between neutral molecules. Koppel and palm4' emphasised the importance of the polarisability of the solvent, which can be expressed by a function of the refractive index of the solvent, [(n2-1)]/[p2+l)]. In this light, also correlations with the polarisa- bility parameter P are known4 744. Finally, correlations with the viscosity of the solvent have been used to explain solvent effects on diffusion-controlled reactions45746.

Correlations of solvent effects with these solvent parameters are often surprisingly good. The inherent weakness of the method is that the parameters measure macro- scopic properties. Specific solute-solvent interactions that occur on a microscopic scale are completely neglected. The structural changes of the solvent, accompanying the activation process, are also neglected. Correlations with physical properties of the solvent are mainly associated with enthalpic contributions to the overall solvent effect, which makes the method less suitable for reactions in highly structured solvents such as water.

1.2.2 Correlations with empirical and semi-empirical solvent parameters

The ability of a solvent to solvate molecules or ions, sometimes rather ambiguously described as the solvent polarity, is difficult to express in terms of physical solvent parameters. This problem forced chemists to search for empirical or semi-empirical scales of solvent polarity. The list of solvent polarity scales is long and lengthens every yea?'. The scales are based on linear solvent energy relationships (LSER) and use solvent effects on properly selected model processes. In the literature, correlations involving solvent polarity parameters are frequently encountered. Some polarity scales have found a wider application in the analysis of solvent effects and will be described briefly below.

Most popular polarity scales are based on spectroscopic properties. Spectroscopic data describing solvent effects on UVIVIS transitions of a large number of solvato- chromic dyes resulted in a long list of solvatochromic polarity parameters4'. One of the oldest parameters, introduced by ~ o s o w e r ~ ' . ~ ~ in 1958, the Z-value, is still frequently used. Dimroth and ~eichhardt~ '~ ' reported probably the best known and most frequently used solvent polarity parameter, the q 3 0 ) value. The standard probe molecule is a pyridinium-N-phenoxide betaine dye (I), which has a T-T' absorption band with intramolecular charge-transfer characteristics.

I. Introduction Solvent effects on organic reactions in aqueous miaures

This parameter can be determined in many solvents and is very solvent sensitive. Another series of parameters, based on spectroscopic transitions was introduced by Kamlet, Taft and Abraham and is related to specific properties of the s o l ~ e n t ~ ~ . ~ ~ . The a-scale measures the hydrogen bond donor acidity of the solvent, the p-scale the hydrogen bond acceptor basicity of the solvent and the T*-scale the polarisability or dipolarity of the solvent. The a-scale and the p-scale are based on a solvatochromic comparison method, using solvatochromic shifts of 6nitroaniline and N,N-diethyl-4- nitroaniline. Similarly, the T-scale is based on electronic T-T* transitions of seven nitroaromatics. The Acceptor Number (AN), introduced by Gutmanns4, is based on the relative 3 1 ~ - ~ ~ ~ chemical shift values of triethylphosphane oxide related to those of the 1:l adduct Et,PO-SbC15. The scale classifies the solvent according to Lewis acidity or the Electron Pair Acceptor property of the solvent.

A few solvent polarity scales have been related to chemical equilibria. The Donor Number (DN) measures the Lewis basicity of the solvent'0JS~s6. SbCls was used as a reference compound. The parameter is defined by the enthalpy associated with the adduct formation between antimony pentachloride and Electron Pair Donor solvents.

The oldest polarity scales find their origin in kinetic measurements. A famous example is the ionising power, as defined by Winstein and ~runwald '~ and expressed in the solvent Y-scale. This scale has been developed on the basis of the rate constant for the SN1 solvolysis of t-butylchloride in different solvents. Later, this approach was modified by winstein*', ~ e n t l e g ~ ' ~ ' , and others6' in order to extend the procedure to correlations of solvent effects on reactions involving borderline or even pure S,2 mechanisms.

Finally, a large number of polarity scales are based upon solubility data6', transfer parameters6z63, partition coefficient^^^>^' and chromatographic These parameters quantify the phobicity or philicity of a selected compound for the solvent. In physical organic applications the Hansch value^^*^^ as well as the S,-value, recently introduced by brah ham^', are frequently encountered. Both parameters measure the solvophobicity of apolar molecules for different solvents. Some empirical parameters based on partition coefficients, solubility, and Gibbs energies of transfer are mainly used in industrial and engineering applications.

I . Introduction Solvent effects on organic reactions in aqueous mixtures

The inherent weakness of these methods is that the solvent polarity scale is based on a selected process and is therefore not universal. Obviously, only satisfactory correlations can be expected for solvent effects on processes closely related to those used to define the polarity scale. In addition, it is not always clear which of the many types of solute-solvent interactions is expressed by a certain parameter. By careful selection of the model process or by sophisticated comparison methods5z5396&70, some polarity scales have been given a relatively well-defined physical meaning. These methods are based on the fact that some classes of compounds interact with the solvent via a predominant and well-defined mode of interaction. A detailed interpreta- tion of solvent effects in terms of specific interactions based on polarity scales is, however, extremely difficult. The choice of a suitable solvent polarity scale to correlate solvent effects on a new process is often simply pragmatic. A practical limitation is that solvent polarity parameters often cannot be measured in all solvents.

It has become clear that no single solvent parameter can account for the complex nature of solvent effects on different chemical processes. To circumvent this problem, multiparameter approaches have been advocated. Koppel and palm7', and later Kamlet, Taft and brah ham" and others71772 developed sophisticated multiparameter equations, incorporating two to four empirical, semi-empirical or physical solvent parameters. Selection of a set of independent solvent parameters that incorporates all possible contributions to the overall solute-solvent interaction is rather arbitrary. Every single parameter measures a combination of distinct contributions to the overall solute-solvent interaction for which both the identity and magnitude are not properly defined. An interpretation of the results of a linear regression analysis is difficult and often highly speculative. From a more practical point of view, in particular for predictive applications, the use of linear regression analysis is seriously limited by the fact that for a proper calculation many datapoints are required. Finally, the theoretical background of LSER's and its application as a tool to analyse or even predict kinetic parameters for new chemical transformations, has been seriously criticised7'. Discussi- on of the fundamental aspects of LSER's is interesting and often philo~ophical~~.

1.2.3 Analysh of solvent effects using solubility and transfer parameters

Measurement of transfer parameters and solubilities to analyse solvent effects is directly linked to the general Equation 1-1. Many techniques are available to measure the standard chemical potentials and partial molar enthalpies and entropies of transfer of compounds from one solvent to the ~ t h e r ~ ' - ~ ~ . Transfer parameters can be used (i) to develop a solvent polarity scale or (ii) to determine the change in standard Gibbs energy, enthalpy and/or entropy for the transfer of reactants for a particular process. In the latter case, solvent effects can sometimes be analysed in terms of initial state and transition state effects7'. In fact, measurement of transfer parameters is the only way in which solvent effects can be analysed in terms of initial and transition state effects. In some cases, initial state and transition state effects have been subsequently analysed in terms of solvent polarity scales72.

In recent and interesting fundamental studies of reactivity in the gas phase, reactants, present in the gas phase, are stepwise "solvated" by a. limited and accurately

1. Introduction Solvent effects on organic reactions in aqueous mirtures

known number of solvent molecules. The reactivity of these molecules in clusters is monitored as a function of the number of solvent molecules present, and shows that even a small number of solvent molecules can bring about a large change in reactivi- ty77-79. Even with a limited number of solvent molecules, reactivity in the gas-phase starts to resemble the reactivity in the condensed phase.

1.2.4 Theoretical treatments of solute-solvent interactions in rehation to solvent effeca

The past fifteen years have shown an impressive number of sophisticated theoretical studies concerned with reactivity in the condensed phase. However, an unambiguous and universal theory of the liquid state still does not exist. This fact strongly hampers the theoretical treatment of reactivity in solutions. Early theoretical approaches were mainly based on models of Kirkwood and O n ~ a g e P ~ ' ~ .

The first simulations of reactivity in solution appeared in the late sixties. The accessibility of large computers and suitable quantum mechanical methods resulted in a whole new area of theoretical studies of solvent effects. The first ab initio calculati- ons of solvent effects were based on reactive com ounds, "solvated by a few solvent molecules; the so-called super-molecule approachr2. These ab initio approaches are still in the early stages of developments3. Other methods use quantum mechanical approaches to calculate the reaction trajectories in the gas-phase, which are subse- quently transfered into a box of solvent molecules84986. Molecular dynamics is used for allowing reacting systems to equilibrate with the solvent along the total reaction path. Until recently only rather simple and elementary processes, like the substitution reaction of chloromethane with chloride ion, have been studied in detail. Strikingly, reactivity in water has received most attention.

Many theoretical studies are focused on non-equilibrium solvation. Conventional transition state theory is shown to be unsuitable for the treatment of solvent effects in these casess4. Among the topics which can be studied using modern computers are (i) the time-scale of the reaction dynamics, (ii) the extent and importance of energy flow from solvent to reactants and (iii) the involvement of the solvent dynamics in the activation process. Recent calculation^^^ of the solvent effect on a S,Zprocess in water show that water undergoes a substantial reorganisation well before the change in the charge distribution of the reactants. This reorganisation appears to be crucial for the overall reaction.

The development of theoretical models to calculate solvent effects is, however, still in its infancy. Most methods do not take account of mechanistic changes that might be induced by the solvent. The chemical processes, treated by theoretical models, are necessarily still simple and elementary. Consequently, the results do not yet attract the interest of experimental chemists. Unfortunately, the complexity of the methods still creates a considerable gap between experimentalists and theoreticians. It is striking that theoretical approaches of solvent effects do not appear in recent reviews and textbooks on solvent effects in chemist$"32972. Apparently, reading theoretical papers gives experimentalists, dealing with solvent effects, a genuine feeling of dissatisfaction, which makes them turn to their familiar solvent polarity scales.

1. Introduction. Solvent effects on organic reactions in aqueous mi-s

1.3 Interactions and reactivity in water and in m h d aqueous solvents

Organic reactivity in water and in mixed aqueous solvents is determined by interacti- ons of water and cosolvents or cosolutes* with the reactant(s) and the activated com- p l e ~ ~ ~ ~ ~ ~ . Water-solute interactions reflect the fact that water molecules are small, moderately polarisable and able to form a highly structured hydrogen bonded network. Induced dipole-induced dipole interactions of water with solutes are small, but the dipole moment of water does enable significant dipole-induced dipole and dipole-dipole interactions with solutes. Obviously, an important contribution to the overall solute-solvent interactions in water is hydrogen bonding. Finally, the interacti- on of water with charged solutes is very strong.

Hydrophobicity and hydrophobic hydration play an important role in the solvation of reactants and activated complex in water and in mixed aqueous solvents. Hydro- phobic effects are characterised by intriguing thermodynamic properties and are the result of a combination of water-solute and water-water interactions. Traditionally, hydrophobicity and hydrophobic hydration are considered to be a consequence of the preference of water for interaction with other water molecules over interaction with hydrophobic (i.e. apolar) solutes. In a study of solvent effects on reactions in aqueous reaction media, a discussion of hydrophobicity and hydrophobic hydration is essential. Recent views on these hydrophobic effects will be discussed in more detail in Section 1.4.

Interactions of reactant(s) and activated complex with cosolvent or cosolute molecules in aqueous solutions involve all forms of dipolar interactions mentioned above, but are strongly mediated by water. The thermodynamics of these interactions strongly depend on the concentration of the solute molecules. In addition, hydropho- bic interactions play a significant role in intermolecular interactions between solutes in aqueous media. The interactions between hydrophobic compounds or hydrophobic moieties in aqueous media is thermodynamically very complex, and some recent ideas about hydrophobic interactions will be also outlined in Section 1.4.

1.4 Hydrophobic effects; &finitions and the state of the ad9-''

Hydrophobic effects; definition. Disagreements exist in the literature concerning the definition of "hydrophobicity", "hydrophobic effects", "hydrophobic hydration" and "hydrophobic interactions". The terms are strongly .related and some are practically synonymous. Many different definitions for these terms can be encountered in the literatures98. In order to prevent unnecessary ambiguities, a definition of these hydrophobic terms will be given below.

The term "hydrophobic effects" describes all phenomena related to the dissolution of non-polar solutes in aqueous media and is, as such, a quite general term. The term "hydrophobicity" is ambiguous and many different interpretations are found in the

The definition of organic, irreactive compounds in aqueous media as cosolutes or cosolvents is ambiguous. Following thermodynamic formalism, the term "cosolute" is more appropriate in dilute aqueous media, whereas in binary aqueous mixtures the term "cosolvent" is prefered.

1. Introduction. Solvent effects on organic reactions in aqueous r n h r e s

literature. The extent of "hydrophobicity" can be expressed in an experimentally accessible parameter measuring the solubility of apolar substances in waterg9. This parameter involves (a) the breaking of the solute-solute interactions and (b) refilling of the vacancy in the apolar medium, (c) creation of a cavity in the aqueous medium, (d) onset of solute-water interactions and (e) rearrangement of the water molecules surrounding the solute. Alternatively, "hydrophobicity" can be expressed in terms of a transfer process of an apolar compound from an apolar solvent to water. In this case, process (a) is replaced by breaking of the solute-solvent interactions.

The poor interactions between water and apolar solutes make the small but significant solubility of completely apolar compounds in water rather unexpected. "Hydrophobic hydration" has been suggested to account for this "high" solubility of apolar compounds in water. Privalov and Gi111009'03J08~'09~111 used the term "hydration effect" to describe this phenomenon. "Hydrophobic hydration" can be defined as the combination of process (c), (d) and (e).

The term "hydrophobic interaction" seems to express the discomfort of chemists in dealing with non-covalent interactions between apolar molecules in aqueous solution that appear to be predominantly entropic in origin. It is necessary to make a clear distinction between "bulk hydrophobic interactions" and "pairwise hydrophobic interaction^"'^^^^^^. Unfortunately, this distinction is seldomly recognised in discussions about hydrophobic interactions. "Bulk hydrophobic interaction" describes the tendency of apolar molecules or moieties to form solvent unseparated clusters and can be conveniently described as the reverse of process (a)-(e). "Pairwise hydrophobic interaction" refers to the potential of average force between two hydrophobic solutes in water, expressed in G(R), the gradient of which determines the force, necessary to bring the two solutes S from an infinite distance to a distance R, as expressed in Equation 1-292.

In this equation, Uss(R) is the solute-solute interaction potential, or the work required to bring about the same process in vacuum. G~'(R) is the contribution of water to the process in aqueous solution. This term is difficult to quantify and sometimes refered to as hydrophobic interactiong2. The contribution of water to the process of "bulk hydrophobic interactions" is even more difficult to establish experimentally. The terms "hydrophobic hydration" and "hydrophobic interactions" are poorly defined in the literature and the lack of a proper definition has resulted in discussions with a strongly semantic f l a v o ~ r ' ~ ~ ~ ' ~ ~ .

Hydrophobic effects; the state of the art. The classical description of hydrophobic hydration, as put forward by Frank and Evanslo4 in 1945 is still very popular. This "iceberg model" was later quantified by Nemethy and ~cheraga"' and Frank and wedo6. In 1959, hydrophobic interactions were introduced in a famous paper by ~auzrnann~~' . These four papers set the stage for later studies on hydrophobic effects. Figure 1-1 shows the almost exponential increase of papers on hydrophobic effects during the past 25 years. It is impossible to review in this thesis all theories and ideas

I . Introduction. Solvent fleets on organic reactions in aqueous m a r e s

about hydrophobic effects which have been presented in the literature during the last decades. Emphasis will therefore be put on some novel and interesting developments. Recently, the study of hydrophobic effects began to prompt a reconsideration of elder t h e ~ r i e s ' ~ ~ ~ ' ~ ~ ~ ~ ~ ' . An important reason for this development is the accessibility of large computers and sophisticated models which have allowed detailed theoretical studies of hydrophobic effects. Also experimental and theoretical studies of protein folding gave a new impulse to the discussion about hydrophobic effects. "New views on hydropho- bic effects" have been put forward that seriously contrast with classical descriptions112 l19. In this introducto~y chapter as well as in Chapter 8 new views on hydrophobic effects will be compared to the classical theories on hydrophobic effects.

Hydrophobic effects are characterised by a number of remarkable features. The most important feature of hydrophobicity, as expressed in the chemical potential of transfer of a hydrophobic, apolar compound from an apolar phase to water, is the unusual and large heat capacity ~hange"~*"~.

number of t i t l e s

year

Figure 1-1: Number of titles of research papers, containing the word "hydrophobic" as a function of the year.

I . Introduction Solvent effects on organic reactions in aqueous mixtures

Consequently, partial molar enthalpies and entropies of transfer are highly tempera- ture dependent.

The thermodynamic parameters, measuring the process of both pairwise and bulk hydrophobic interactions, are also shown to be strongly temperature dependenta. Privalov et a1.'00~103~108911' reported methods to determine the thermodynamic quantities of hydrophobic hydration, which are very difficult to measure experimentally, and showed that hydrophobic hydration is characterised by a similar temperature depen- dence of enthalpy and entropy terms.

The classical model of hydrophobic effects is mainly based on phenomena observed near room temperature. The hydration shell, surrounding apolar molecules or moieties, is found to be highly structured, minimising the interactions between the apolar molecule or moiety and water and optimising water-water interactions. Detailed t h e o r e t i ~ a 1 ~ " ~ ~ " ~ ~ and computer simulation studies'22-'" confirmed that the structure of the hydrogen bonded network of water is significantly altered in the first solvation shell surrounding apolar molecules or moieties. The transfer of apolar molecules from an apolar solvent to water is, at temperatures near 25"C, characteri- sed by a positive standard Gibbs energy of transfer, a slightly negative enthalpy and a large negative entropy of transfer*. For a broader temperature range, the thermo- dynamic parameters of transfer exhibit very characteristic values at two important temperatures. At a temperature TH, which is near room temperature, the enthalpy of transfer is nearly zero, whereas the entropy is strongly negative. At a temperature Ts, which is near 160°C, the entropy of transfer is zero, and the enthalpy is highly positi- ve"'. Apparently, the structure forming capacity of water is lost at these high temperatures. The strong changes of AH0 and TASO as a function of temperature are shown in Figure 1-2. The standard Gibbs energy of transfer, as indicated in Figure 1-2, can be described by Equation 1-386~100~'01~'M~10808111.

1 A GwO = AH* - A Cp[(Ts- ;T) + T

In this equation, AH*, given by AC,(Ts-T,), corresponds to the enthalpy of transfer of an apolar compound from the apolar liquid phase to water at T, and appears to resemble the enthalpy of evaporation of the liquid, apolar solute. The second term on the right, which is always negative, contributes favourably to the standard Gibbs energy of transfer, and is strongly temperature dependent. This term can be identified as due to hydrophobic hydration. Hydrophobic hydration apparently leads to a decrease in the Gibbs energy of transfer. Both the enthalpy and entropy of hydropho- bic hydration are strongly temperature dependent, but appear to be strongly compen- sating, leading to a small, but favourable overall Gibbs energy of transfer. At 160°C it is definitely the unfavourable enthalpy of transfer AH*, which causes the large and positive Gibbs energy of transfer of the apolar solutes from an apolar phase to water. This unfavourable term has to be attributed to the disruption of London dispersion interactions between the apolar solute molecules in the pure apolar, liquid state. At room temperature, however, the loss of entropy determines the unfavourable Gibbs energy of transfer. The loss of entropy, associated with the hydrophobic hydration of the apolar molecules, is also accompanied by a similar gain of enthalpy. As a conse-

1. Introduction. Solvent effects on organic reachm in aqueous mixtures

quence, the net Gibbs energy effect, associated with hydrophobic hydration, is very small. In summary, the enthalpy and entropy of hydrophobic hydration strongly moderate the enthalpy and entropy of transfer of apolar compounds from an apolar phase to water, but hydrophobicity is caused by the enthalpically unfavourable disruption of London dispersion interactions between the apolar solutes in the apolar phase which are not restored by solute-water interactions. In fact, structural reorgani- sation of water around the apolar compounds decreases the propensity for London dispersion interactions between the apolar solutes, and therefore increases the solubility. This leads to the statement that the solubility of apolar molecules in water is surprisingly large.

2 5 0 3 0 0 350 4 0 0 450

T I K

Figure 1-2: Standard Gibbs energy, partial molar enthalpy and entropy of transfer for the transfer of an apolar liquid from its liquid state to water as a function of the temperature. For simplicity, the temperature dependence of the heat capacity change is neglected. Taken from ref. 108.

1. Introduction Solvent effects on organic reactions in aqueous rnirlures

This "new view on hydrophobicity" is mainly based on thermodynamic considera- tions. Recently, Lee has developed a model which accounts for the low solubility of apolar compounds in water based on scaled particle theory as developed by Pierotti and ~inanoglu'~- '~. In this model the importance of the exceptionally small molecular volume of water for the low solubility of apolar molecules in water is stressed. Linked to this approach are studies in which the formation of a cavity in water is theoretically modeled in order to gain more insight into the energetics of this process, which appears to be entropically highly ~nfavourable'~'. The basic idea behind these models is that a large number of small solvent molecules is restricted with respect to their rotational freedom due to the presence in the solvation shell of an apolar solute.

The interaction of hydrophobic solutes in aqueous media is accompanied by the overlap and merging of hydrophobic hydration shells. Near room temperature the destructive overlap is accompanied by a gain of entropy and a loss of enthalpy. However, the change of enthalpy and entropy, associated with this overlap term is strongly temperature dependent. Based on the thermodynamic parameters of transfer of apolar compounds from an apolar phase to water, Privalov and others have concluded that hydrophobic interactions are, like the hydrophobicity, determined by enthalpically favourable London dispersion interactions between the apolar solu- tes'O1*ll'. This is almost certainly the case for bulk hydrophobic interactions, which lead to clusters of different size and morphology in the aqueous solution. The onset of bulk hydrophobic interactions is often characterised by a critical concentration of the solute, at which the formation of independent hydrophobic hydration shells, sufficient- ly effective to prevent association, has become impossible.

For pabvise hydrophobic interactions the problem is more complex. There has been a tremendous growth in the application of empirical and ab initio intermolecular potentials to model hydration processes. Recently, a host of papers has appeared in which hydrophobic interactions are modeled extensively, using very sophisticated theoretical models describing average potential forces between solutes in aqueous solution. Studies by Chandler, Rossky, Karplus, Pettit and have revealed the existence of two clearly distinct configurations, which are separated by a Gibbs energy bamer. These configurations are identified as (i) two apolar molecules, separated by water and (ii) two apolar molecules in direct contact. The height of the bamer and the relative importance of both configurations is not yet clear. Hydropho- bic interactions have also been studied by theoretical analyses of the second virial coefficients that appear in concentration expansion series describing thermodynamic properties of aqueous solutions143. Second virial coefficients are experimental quanti- ties. Model descriptions, which have been developed by Friedman and ~ r i shnan '~ '~ '~~ and later by Franks'46, S ~ h e r a g a l ~ ~ ' ~ ~ , Ben Nairn" and others14', were used to interpret these quantities in more detail. In Chapters 2 and 3, some results of these theoretical approaches of aqueous solutions will be discussed in more detail.

Nearly all recent theoretical studies of solvent-averaged forces between solutes in water and some ab initio studies do agree that water decreases the attractive forces between apolar solutes, compared to the interactions present in the gas-phase. Notwithstanding the fact that not all theoretical models agree on this particular point, most studies indicate a preference for solvent separated pairwise hydrophobic interactions. However, the height of the barriers between contact and solvent separated configurations remains unclear. The size of the solute appears to determine

1. Introduction Solvent effects on organic reactions in aqueous rniriwes

the height of the bamer. Recently, it has been shown that long-range attractive forces are present between large apolar surfaces148. The molecular origin of these hydration forces is also unclear.

1.5 The need for a quantitative description of solvent egects in mixed (aqueous) solve&. Incenlives fir this study

In Section 1.2 it has been shown that simple quantitative models to analyse solvent effects in pure solvents which are based on empirical solvent polarity parameters, lack general applicability. Moreover, the molecular basis of solvent effects remains unclear because of the undefined physical significance of these polarity scales. Macroscopic solvent parameters, derived from physical properties of the solvent give an unrealistic picture of the reaction medium as a continuum without specific structure. Specific interactions between solvent and reacting species, as well as the importance of the structure of the solvent, are neglected. More sophisticated, theoretical approaches to analyse solvent effects in pure solvents are either inaccessible or difficult to use for practical problems.

Many chemical reactions are performed in mixtures of solvents. Particularly solvent mixtures of water and an organic cosolvent are very popular. Quantitative descriptions of solvent effects in mixtures of solvents are even more complicated than those in the pure solvents. It is, for example, an impossible task to determine solvent polarity parameters in every mixture of solvents. Very often therefore, the assumption has been made that these solvent parameters depend linearly on the composition of the mixture. Obviously, the occurence and consequences of preferential solvation are not taken into account. The even more pronounced complexity of specific solute- solvent interactions is also fully neglected.

Patterns of organic reactivity in mixed aqueous solutions are particularly interes- ting. Kinetic data for reactions in water and in mixed aqueous solvents are often intriguing and their interpretation is a real challenge. The study of organic reactivity in water and in aqueous solutions has become more interesting since water has been shown to induce high reaction rate constants as well as high selectivities for a number of organic reactions, both homogeneous and heterogeneous (see Table 1-1). The low solubility of organic reagents can be overcome by addition of organic cosolvents. The consequences of addition of cosolvents for reactivity and selectivity of reactions in water are unknown. A quantitative study of solvent effects on a series of organic reactions in water and in mixed aqueous solvents, based on a general theory for quantitative analysis of solvent effects in mixed solvents, would offer insight into the molecular basis of rate effects on organic reactions in aqueous media. This knowledge should enable organic chemists to select organic reactions, which can benefit from mixed aqueous solvents with a suitable composition with respect to solubility, reactivi- ty and selectivity, in a rational way. However, it is remarkable that no valid quantitati- ve model exists for the analysis of solvent effects on reactions in mixed solvents.

I . Introduction Solvent effects on manic r e a c h in aquew~s mirtwes

1.6 A h of this st&

The general aim of this study was to develop and test a new, simple, but general theoretical model for the quantitative analysis of solvent effects in mixed solvents. An important objective was to draw together transition state, theory and thermodynamic formalism to describe thermodynamic properties of solutions. Following this approach, three important demands, made with respect to a novel theoretical model for the analysis of solvent effects in mixed solvents, can be met.

(i) Kinetic medium effects in mixed solvents can be expressed in terms of thermo- dynamic parameters.

(ii) These thermodynamic parameters can be determined by experimental techni- ques other than kinetic measurements.

(iii) The theoretical model enables a quantitative analysis of observed solvent effects leading to further insight into the solute-solvent interactions which govern solvent effects in mixed solvents.

A major incentive for the development of a new theoretical model for the quantitative analysis of solvent effects on reactions in mixed solvents has been its possible application to study solvent effects on reactions in mixed aqueous media. In fact, this application would involve a rigorous test for the new approach. The second aim of this study was, therefore, to critically appraise the developed theory by studying the kinetics of, first, simple first-order processes and, later, of bimolecular reactions and equilibria, in mixed aqueous solvents. The general strategy involved systematic variation of the nature of the mixed aqueous solvent (i) by varying of the composition of the mixed solvent and (ii) by varying the structure of the cosolvent(s). In addition, different reaction types have been studied and the structure of the reacting molecules has also been changed by changing substituents. The consequences for a quantitative analysis of the observed solvent effects, based on the novel theoretical model, have been examined. Concomittantly, the variation of the structure of the reactants provides an opportunity for a detailed quantitative study of the contribution of solvation effects to the overall substituent effects of alkyl groups on chemical reactivity in mixed aqueous solvents. A challenging goal was found in the application of the developed theory to elucidate the role of water, and eventually of the apolar cosol- vents, in the spectacular rate enhancements of some organic reactions in aqueous media.

1.7 Survey of the contents of thk thesis

Chapter 1 contains a general introduction in the field of qualitative and quantitative methods for the analysis of solvent effects. After a brief historical overview, emphasis is placed on recent methods to analyse solvent effects. In this context conventional methods are critically discussed. The second part of the chapter is devoted to a description of water and mixed aqueous solvents as reaction media. Attention is focussed on intermolecular interactions in aqueous solvents. Hydrophobic effects are

1. Introduction Solvent effects on organic reactions in aqueous mirrures

clearly defined and recent theories on hydrophobic effects are discussed. Finally, the incentives and aims of the study are summarised.

A general theoretical model for the analysis of solvent effects in mixed solvents is reported in Chapter 2. In this chapter, kinetic theory and thermodynamic formalism to describe thermodynamic properties of solutions are drawn together. This leads to theoretical expressions which relate solvent effects in mixed solvents to the composi- tion of the solvent. The general model is elaborated by using two alternative thermo- dynamic descriptions of the reaction medium, dependent on the composition of the medium. Both methods are discussed in detail and are critically compared. Theoretical expressions are derived for solvent effects on a simple unimolecular reaction in mixed solvents. The expressions are modified in order to analyse solvent effects on solvolysis reactions, bimolecular processes and chemical equilibria. Furthermore, the quantitati- ve treatment for the analysis of solvent effects on Gibbs energies of activation is extended to a quantitative analysis of enthalpies and entropies of activation in mixed solvents. A general feature of all theoretical expressions derived is that they describe the dependence of reactivity on the composition of the reaction medium in terms of interactions of the (co)solvent(s) with the reactants and activated complex, respective- ly. These expressions form the basis of the second part of the thesis, and will be used frequently.

In Chapter 3, solvent effects are described on the neutral hydrolysis of l-benzoyl- 3-phenyl-1,2,4-triazole in mixed aqueous solvents that contain monohydric and polyhy- dric alcohols. In the introduction, the vast amount of literature on solute-solute interactions in dilute aqueous solutions is briefly reviewed and some important features are discussed. The new theoretical model, as developed in Chapter 2, is critically tested by analysing the solvent effects of 24 different mono- and polyhydric alcohols on the rates of hydrolysis. The theoretical expression was found to describe the experimental data very well. Particular attention has been paid to the applicability of group additivity approaches for the analysis of solute-solute interactions. It was observed that addivity schemes are only valid under strict conditions and deviation from additivity is discussed in detail. In addition, the effect of urea on solvent effects in mixed aqueous solvents was investigated. Urea reduces the solvent effects of apolar cosolvents, whereas urea itself does not induce a significant solvent effect at all. Solvent effects are expressed in terms of Gibbs energy parameters, describing solute- solute interactions in aqueous solutions, and the results are compared with literature data for the analysis of solute-solute interaction in aqueous media. Emphasis has been placed on the participation of the cosolvent in the solvation shell of the reactant and the activated complex, accompanied by hydration shell overlap.

In the first part of Chapter 4, solvent effects on the Gibbs energy, the isobaric enthalpy and entropy of activation of the neutral hydrolysis of p-methoxyphenyl dichloroacetate in mixed aqueous solvents containing urea and alkyl-substituted ureas, are quantitatively analysed. The theoretica1 model, developed in Chapter 2, is shown to describe the dependence of the activation parameters on the composition of the reaction medium. However, higher-order enthalpic and entropic interaction terms are more important for the description of solute-solute interactions in dilute aqueous solutions than higher order Gibbs energetic interaction terms. The origin of this phenomenon is discussed in detail in terms of hydrophobic effects. In the second part of Chapter 4, the theory is successfully applied in the quantitative analysis of solvent

1. Introduction Solvent EfJects on organic r e a c h in aqueous m h s

effects on the Diels-Alder reaction of methyl vinyl ketone with cyclopentadiene, the keto-en01 equilibrium of 2,epentanedione and the intramolecular Diels-Alder reaction of N-alkyl-N-furfurylmaleamic acid in mixed aqueous solvents.

A thorough study of the medium effect of ethanol and 1-propanol on the neutral hydrolysis of 18 different l-acyl-3-alkyl-1,~4-triazoles is reported in Chapter 5. The dependence of the solvent effect on the alkyl groups in the substrate was examined in detail. The solvent effects depend critically on the substituent. This implies that the substituent effects of alkyl groups are significantly affected by the composition of the solvent. In the introduction conventional quantitative methods for analysing, under- standing and predicting alkyl substituent effects in terms of substituent constants are outlined and discussed. The results show that substituent effects of all@ groups on reactions in aqueous media are strongly governed by solvation effects. It is argued that efforts to describe steric, polar and inductive effects of alkyl substituents either include a substantial contribution of solvation effects or are completely useless. The contribu- tion of solvation to the substituent effect of alkyl groups on reaction rates of reactions in aqueous media is explained in terms of "hydrophobic acceleration".

The main theme of Chapters 6 and 7 is the analysis of solvent effects on Diels- Alder reactions in mixed aqueous solvents, containing monohydric alcohols across the whole mole fraction range. The applicability is tested of the theoretical expression, derived in Chapter 2, for a quantitative anaIysis of solvent effects in binary solvents.

Chapter 6 contains a quantitative study of solvent effects on the rate constants and isobaric activation parameters for bimolecular Diels-Alder reactions of cyclopent- adiene with alkyl vinyl ketones as well as with 5-substituted-1,4-naphthoquinones in mixed aqueous solvents. In addition, standard Gibbs energies of transfer of the reactants, activated complex and products of the Diels-Alder reaction of alkyl vinyl ketones and cyclopentadiene from 1-propanol to aqueous solutions of 1-propanol have been determined and analysed.

Chapter 7 describes the synthesis and the intramolecular Diels-Alder reaction of four N-alkyl-N-furfurylmaleamic acids. The intramolecular Diels-Alder process undergoes a spectacular rate increase in aqueous reaction media. The solvent effects appear to be very similar to solvent effects on the bimolecular process. Emphasis is placed on solvent effects on the stereochemistry of the intramolecular cyclisation.

The solvent effects, reported in Chapters 6 and 7, are satisfactorily described by the derived theoretical expressions. The spectacular rate effects of water on Diels- Alder reactions are largely preserved in highly aqueous reaction media. Preferential solvation of the reactants appears to diminish the rate effect of water in the presence of higher concentrations of cosolvent molecules. The spectacular rate accelerations are ascribed to the apparent decrease of the hydrophobic surface of the apolar reactants during the activation process. This "hydrophobic acceleration" is a result of "enforced hydrophobic interaction" of the reactants during the activation process. The possibility of induction of a more polar activated complex in highly aqueous media is tentatively suggested.

Chapter 8 evaluates the applicability, merits and shortcomings of the proposed theoretical treatment of solvent effects in mixed aqueous solvents. In this thesis, the dependence of solvent effects on reactivity of apolar organic reactants in water on the concentration of cosolvents, has been mainly explained in terms of bulk and pairwise hydrophobic interactions. Based on the quantitative analyses of these solvent effects a

1. Introduction Solvent effects on organic reactions in aqueous mixtwes

novel model is introduced for the description of hydrophobicity and hydrophobic interactions. This model accounts for the most characteristic properties of hydropho- bic effects. Finally, the use of water as a solvent for organic reactions is critically discussed. It is shown that organic reactions can benefit from water as a solvent due to the fact that reactive, hydrophobic species in water and highly aqueous media tend to minimise their hydrophobic exposure to water of the hydrophobic groups during the activation process. Reaction types are suggested which might be accelerated in aqueous solutions.

A major part of the work described in this thesis either has already been publis- hed or will be published in the near f u t ~ r e ' ~ ~ - ~ ~ ~ .