Solvent effects on stereoselectivity: more than just an environment

Gianfranco Cainelli,* Paola Galletti and Daria Giacomini*

Received 2nd June 2008

First published as an Advance Article on the web 12th February 2009

DOI: 10.1039/b802815j

Stereoselectivity is a major topic in organic synthesis. Intensive investigations into the role of

solvents on diastereo- and enantioselective reactions, as well as temperature-dependent

measurements of diastereomeric and enantiomeric ratios, have shed light on the existence of

dynamic solvation effects. In this tutorial review, several examples of non-linear Eyring plots in

stereoselective nucleophilic additions, cycloadditions, photochemical and enzymatic reactions are

reported. Experimental data and spectroscopic analyses obtained in aliphatic and aromatic

hydrocarbons, halohydrocarbons, ethers and mixtures lead to the formulation of a hypothesis on

the inversion temperature phenomenon as being due to an equilibrium between distinct

solute–solvent clusters, which are the real reactive species in solution.

Introduction

From the early studies on asymmetric induction by Fischer up

to the excellent stereoselectivity obtained in the last two

decades by means of asymmetric organo- and metal-catalysis,

asymmetric organic synthesis is, nowadays, a main topic of

organic chemistry.1,2

Stereoselectivity is defined in a chemical reaction as the

preferential formation of one stereoisomer over another.3

The stereoselective control of a reaction is generally discussed

in terms of the geometry of reagents, reagent–catalyst

complexes and activated complexes. The effects of solvent on

stereoselectivity have been described by organic chemists, and

in particular several examples of solvent-dependent face selec-

tivity have been discussed. However, a proper rationalization

of these effects is far from being in sight. As an example, the

two most common qualitative models to rationalize the

diastereoselectivity in nucleophilic additions to a-chiralcarbonyl compounds, the Cram and Felkin-Ahn models,4

have two main limitations: (i) the reaction is considered to

occur in a vacuum, i.e. in the absence of any solvent, whereas

most reactions take place in a condensed liquid phase, and

(ii) each carbonyl compound has the same fixed conformation

and the attack comes from the less hindered direction. Thus,

these models deal only with the steric and electronic features of

activated complexes. In other words, only enthalpic differences

Fig. 1 Stereoselectivity as the ratio between the kinetic constants of

two competitive processes.

Department of Chemistry ‘‘G.Ciamician’’, University of Bologna,Via Selmi 2, 40126 Bologna, Italy. E-mail: daria.giacomini@unibo.it;Fax: +39 051 2099456; Tel: +39 051 2099528

Paola Galletti, Gianfranco Cainelli and Daria Giacomini

Gianfranco Cainelli was born in Trento in 1932, became Dipl. Ing.in 1954 and Doctor der Technischen Wissenschaften at the ETHZurich working in the laboratory of Professor Oskar Jeger in1958. After two years as a postdoctoral fellow with Professor O.Jeger, he moved to the Politecnico of Milan as an Assistant ofProfessor A. Quilico. In 1968, he joined the Faculty of Pharmacyof the University of Bari as a full Professor of chemistry of naturalproducts. He has been Professor of organic chemistry at theUniversity of Bologna since 1971. His main research interestscover the synthesis of natural products.Paola Galletti was born in Bologna, Italy in 1969. She is aresearcher in organic chemistry at the University of Bologna, fromwhere she graduated in chemistry (1994) and received her PhD(1999). Her research interests are in the field of biocatalysis inorganic solvents and the synthesis of biologically-active compounds.

Daria Giacomini was born in SanMarino (R. S. M.) in 1958, graduated in chemistry in 1982 and obtained a PhD in chemistry fromthe University of Bologna in 1987. She is currently Associate Professor in organic chemistry at the University of Bologna. Herresearch interests cover stereoselectivity in the synthesis of biologically-active compounds.

990 | Chem. Soc. Rev., 2009, 38, 990–1001 This journal is �c The Royal Society of Chemistry 2009

TUTORIAL REVIEW www.rsc.org/csr | Chemical Society Reviews

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are mainly considered, whereas differential enthalpy and

differential entropy both contribute to the Gibbs energy.

For the formation of products in a stereoselective process, at

least two distinct reaction pathways are possible: starting from

the reagents A and B, two stereoisomers C or D are obtained

(Fig. 1). The aim of the preparative chemist is to achieve a

stronger differentiation between the two reaction paths to yield

only one isomer in a high selectivity.

The stereoselectivity of a process is essentially a kinetic

phenomenon, quantitatively expressed by the ratio of the

kinetic constants that result from all the steps necessary to

convert the reagents into the two stereoisomers.3

This very important relationship is not often exploited

by synthetic chemists, but it highlights the possibility of

controlling the stereoselectivity by changing the reaction

conditions that directly influence those rate constants, such

as the reaction solvent and temperature.5

Temperature dependence analyses reveal solvent

effects

In recent years, the observation of temperature effects in

connection with the Eyring theory has been used to gain a

better understanding of the factors influencing the stereo-

chemical outcome of various reactions. In particular, studies

of enantio- and diastereoselective reactions by varying the

reaction temperature have shed light on solvent effects and

stereoselectivity.6

An analysis of the logarithmic values of stereoselectivity

as a function of reciprocal temperature results in the linear

relationship in the equation reported in Fig. 2, known as

the modified Eyring equation,7 where ln(k/k0) is the natural

logarithm of stereoselectivity, and k and k0 are the overall rate

constants of the reactions leading to the two stereoisomers.

According to Eyring theory, when this relationship is

plotted, the slope corresponds to the difference in the overall

activation enthalpies (DDHa) and the intercept represents the

difference in the overall activation entropies (DDSa) (Fig. 2).

The influence of the solvent on stereoselectivity can be

considered as a macroscopic effect related to solute–solvent

interactions at the molecular level. These interactions differ-

ently affect the reaction paths leading to the two stereoisomers

by changing the activation parameters and therefore the

stereoselectivity. The solvent effect can be so significant that

it can switch the stereoselectivity from enthalpy control (where

DDSa E 0) to entropy control (where DDHa E 0). As an

example, we observed such an effect on the facial diastereo-

selectivity of an aldol condensation under kinetic control.8

The reaction between lithium tert-butyl acetate and

2-phenylpropanal was studied in THF and n-hexane at

different temperatures, thus obtaining different syn and anti

aldol ratios. Data were analyzed according to the Eyring

equation, and values of DDHa and DDSa were obtained from

the slopes and intercepts of the linear plots of ln (syn/anti) vs. 1/T

(Fig. 3). In THF, DDSa was very small and only DDHa

determined the prevalence of the anti isomer. In contrast, in

n-hexane, where the enthalpy contribution was almost zero,

DDSa determined the diastereomeric ratio.

The differential entropy of activation (DDSa) reflects the

entropic difference between two diastereomeric activated

complexes, and it could depend on a different number of

microstates modulated by the reaction solvent. For enantio-

or diastereoselective reactions where small DDHas occur,

DDSa can be the determinant factor. Recent examples that

show constant selectivity with the variation of reaction tem-

perature have been reported in the literature by Inoue et al.9

and Gil et al.10 as ‘‘entropy-driven’’ processes.

It is difficult to rationalize solvation phenomena and to

discern the solvent effects on facial diastereoselectivity, but

some hypotheses could be considered. Accepting the effect of

solvents on conformational equilibria, two cases can be ratio-

nalised: (i) the solvent could enthalpically favour and

entropically disfavour an isomer whenever the solute–solvent

interactions are high in strength and/or in number, thus

stabilizing conformers with the lowest intramolecular steric

interactions; (ii) the solvent could entropically favour and

enthalpically disfavour an isomer whenever the solute–solvent

interactions are mild or low in number, which results in

the solvation being less ordered, thus making the system

conformationally less rigid.

It therefore appears clear that any theoretical model for the

analysis of stereochemical concerns completely looses its

predictive value by ignoring solvent effects.

Temperature-dependent studies of stereoselectivity often give

non-linear Eyring plots. Extreme values of ln(k/k0) vs. 1/TFig. 2 Stereoselectivity and thermodynamic parameters: a graphic

representation of the Eyring equation.

Fig. 3 Linear Eyring plots of the syn/anti diastereomeric ratios

obtained in an aldol reaction.

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in the form of maxima and minima have been observed.

Fig. 4 reports an example by Collin et al. from the current

literature.11

The knowledge and understanding of such non-linear

behaviour is important for the optimization of selectivities,

especially the apex in the plot, which contains the most useful

information since, as in the example of Fig. 4, it represents the

point with the maximum available selectivity.

Non-linear Eyring plots consist of two distinct linear trends,

intersecting at a point which is identified as the so-called

inversion temperature (Tinv). This phenomenon was

thoroughly reviewed in 1991 by Scharf et al.,12 and it has been

observed quite frequently for different selective processes.

Pracejus and Tille first described a non-linear trend of

enantioselectivity in an asymmetric addition of alcohols to a

ketene catalyzed by chiral amines,13 and non-linear Eyring

plots have been observed in a large number of completely

different reactions: catalytic hydrogenations, photochemical

reactions like the Paterno–Buchi reaction, the Sharpless

dihydroxylation, Diels–Alder cycloadditions and several

addition reactions.14 Very recently, interesting examples of

non-linear Eyring plots in an enantioselective cycloaddition

have been reported by Buono et al.15

Fig. 5 and Fig. 6 show two recent examples of stereo-

selective Paterno–Buchi reactions with maxima16 or minima17

in their corresponding Eyring plots, respectively.

The phenomenon of inversion temperature and, more

importantly, its significance is a matter of debate.

In Scharf et al.’s studies, the observed inversion temperature

was explained by a reaction pathway with at least two stereo-

selective steps in the reaction mechanism that were differently

Fig. 4 A non-linear Eyring plot in an enantioselective Michael

addition (from: I. Reboule, R. Gil and J. Collin, Enantioselective

Conjugate Addition of Aromatic Amines to N-Alkenoyloxazolidinones

Catalyzed by Iodido(binaphtholato)samarium, Eur. J. Org. Chem.,

2008, 532–539. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.

Reproduced with permission of Wiley).

Fig. 5 Non-linear Eyring plots in a regioselective cycloaddition

reaction (from: X.-M. Hei, Q.-H. Song, X.-B. Li, W.-J. Tang, H.-B.

Wang and Q.-X. Guo, Origin of a Large Temperature Dependence of

Regioselectivity Observed for [2 + 2] Photocycloaddition (Paterno–

Buchi Reaction) of 1,3-Dimethylthymine with Benzophenone and Its

Derivatives: Conformational Property of the Intermediary Triplet 1,4-

Diradicals, J. Org. Chem., 2005, 70, 2522. Reproduced with permis-

sion of the American Chemical Society).

Fig. 6 Non-linear Eyring plots in a diastereoselective cycloaddition

reaction (from: M. Abe, M. Terazawa, K. Nozaki, A. Masuyama and

T. Hayashia, Notable temperature effect on the stereoselectivity in

the photochemical [2 + 2] cycloaddition reaction (Paterno–Buchi

reaction) of 2,3-dihydrofuran-3-ol derivatives with benzophenone,

Tetrahedron Lett., 2006, 47, 2527. Reproduced with the permission

of Elsevier).

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affected by temperature. The Tinv was explained by the

existence of two levels of selectivity, and a change in the

dominance of activation enthalpy differences and activation

entropy differences occurring at different levels of selection in

different temperature domains. In this approach, the abrupt

change in stereoselectivity at the Tinv is due to a change of the

rate-determining stereoselective step.12

For Ridd et al., a sudden change in the dominance of

selection levels is unlikely. Their interpretation of the non-

linear behaviour is based on changes of the rate-determining

steps from one level of selection to the other, but only in one of

the two temperature domains is a single selection step really

rate-determining, while the remaining region may be viewed as

representing a transitional regime, in which none of the single

steps in the mechanism is rate-determining.18

Heller et al. have shown that Scharf and Ridd’s two

arguments are in fact not contradictory. Both interpretations

are possible within defined limits and by considering a

temperature-dependent change in the relative concentration

of two intermediates, which then leads to selective product

formation.19

Following Ridd et al.’s hypothesis, Gypser and Norrby

considered the non-linear relative rate plots in terms of their

absolute rate behaviour.20 They highlighted the ‘‘transition

region width’’ and ‘‘inversion temperature’’ as important

features in their interpretation of the relative rate plots of

the corresponding absolute rate plots. Their theoretical efforts

showed that inversion points for relative rates are physically

significant if the inversion temperatures for the absolute rates

are identical. If the inversion points for the absolute rates

differ, they have no physical meaning.

We have extensively studied the diastereofacial selectivity of

a-hydroxy aldehydes and silylimines, and have observed

non-linear Eyring plots in many cases. Based on experimental

data, we proposed a different interpretation of the inversion

temperature that mainly depends on solvation:

Tinv could constitute a transition temperature between two

different solute–solvent clusters, which act as distinct supra-

molecules with different thermodynamic properties, reactivity

and therefore stereoselectivity.21

Our proposal on the solvent-dependent nature of Tinv is

based upon two main lines of evidence obtained in a detailed

study on the diastereoselective addition of n-BuLi to

2-phenylpropanal and O-(TBS)-mandelic aldehyde in a series

of linear hydrocarbons:

(i) each aldehyde–solvent couple generates a characteristic

inversion temperature.

(ii) for each aldehyde, Tinv depends on the chain length of

the solvent.22

Measurements of the diastereomeric ratio of n-BuLi

addition to 2-phenylpropanal in a homologous series of linear

hydrocarbons showed some striking regularities in their

corresponding Eyring plots (Fig. 7).

The pattern is consistent with the chain length of the

solvent: the longer the hydrocarbon chain, the lower the de

and the higher the Tinv. In all cases, Tinv constitutes a break

point, leading to two sets of activation parameters, one for

T 4 Tinv and one for T o Tinv. At low temperatures,

the slopes of the regression lines (enthalpy contribution)

flatten; the differential entropy therefore modulates the stereo-

selectivity, and the effect of solvent chain length on face

selectivity is due to an entropic control. On the other hand,

Fig. 7 (a) Non-linear Eyring plots for the diastereoselective addition of n-BuLi to 2-phenylpropanal in hydrocarbons, and a correlation between

Tinv values and the melting points of the solvents. (b) Correlations between Tinv and melting point, and Tinv and the chain length of hydrocarbons

for the diastereoselective addition of n-BuLi to O-(TBS)-mandelic aldehyde in hydrocarbons.

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at T 4 Tinv, lengthening the solvent chain increases the slope,

thus increasing the enthalpic contribution to the

diastereomeric ratio.

All efforts to correlate inversion temperatures with classical

solvent parameters, such as relative permittivity and

viscosity,23 have failed. Interestingly, we found a good corre-

lation between Tinv values and hydrocarbon melting points.

This correlation was confirmed, even in the case of O-(TBS)-

mandelic aldehyde, upon addition of n-BuLi, where Tinv

correlates better when considering the odd and even series of

linear hydrocarbons (Fig. 7(b)). A plot of the inversion

temperature vs. the number of solvent carbon atoms exhibits

the same alternating feature as that of the hydrocarbon

melting points. It is known that even- and odd-numbered

linear hydrocarbons differ in their crystalline packing, and

this fact causes the melting point alternation.24 A similar

alternation has been observed for the Tinv values obtained

with 2-phenylpropanal and O-(TBS)-mandelic aldehyde,

suggesting a relationship with the phase modification that

occurs upon melting.

An innovative explanation can be then formulated: Tinv

could constitute a sort of transition between two ‘phases’

which, in the case of solutions, could be represented by two

distinct solute–solvent clusters (Fig. 8). At a temperature

higher than Tinv, one solute–solvent cluster is present in

solution, generating a linear Eyring plot; at a temperature

lower than Tinv, another solvation cluster is present, generat-

ing a second linear plot. Thus in a non-linear Eyring plot, the

Tinv results from the intersection of the two linear plots is

generated by two independent supramolecular species that are

in equilibrium at Tinv. These two dynamic solvation clusters

behave like two different molecules, with different thermo-

dynamic parameters and therefore different stereoselectivities.

In this hypothesis, Tinv represents the interconversion

temperature between two supramolecules, and does not imply

any change in the rate-determining step or in the reaction

mechanism.

In a given experiment, in the explorable T range, if two

solvent–solute clusters were present, only one Tinv could be

observed. However, there are Eyring plots with two Tinv values

and thus three solvation supramolecules are present in the

range. We observed this phenomenon when n-BuLi was

added to O-(TBS)-mandelic aldehyde in n-hexane.22 Our

interpretation of the solvation-dependent nature of Tinv fits

well, even in those cases of non-linear Eyring plots with

multiple Tinv values, as well as in some other unusual temp-

erature behaviours, like that observed in the diastereoselective

allylation of the O-(TBS)-N-triisopropylsilylimine of lactal

(Fig. 9). This imine showed a reversal of diastereoselectivity

with temperature, going from 97% of the anti isomer at

�90 1C to 65% of the syn isomer at 60 1C. Moreover, in the

temperature range �40 to �46 1C, we have an abrupt jump in

diastereoselectivity.25

This interruption marks two linear trends, one at a higher T

and one at a lower T, with quite similar slopes but different

intercepts, meaning that the jump is derived exclusively from a

change in DDSa. This break in the Eyring plot can be readily

explained in terms of the interconversion of solute–solvent

clusters, such as at the inversion temperature, and, in our

opinion, it can be effectively considered a proper Tinv.

To strengthen the solvation hypothesis on Tinv, we reported

a study on the diastereofacial selectivity of EtMgBr addition

to (2S)-O-(tert-butyldimethylsilyl)lactal. Analysis of the

temperature dependence of the diastereomeric ratio gave

non-linear Eyring plots with peculiar Tinv values for each

solvent (Fig. 10).26

We observed that solute–solvent interactions govern a

diastereomeric switch from the anti to the syn isomer upon

changing from THF to an anisole solvent system. In THF, the

temperature scarcely affects the diastereofacial selectivity over

a wide T range until Tinv, after which the diastereomeric ratio

(dr) rapidly decreases; the flattest part of the plot, and con-

sequently the steady diastereomeric excess, is derived from a

small value of DDHa, and thus the good diastereoselectivity

can be entirely attributed to an entropic effect. Diethylether

and di-n-pentylether have parallel Eyring plots at T 4 Tinv,

whereas branched ethers run almost parallel in all T ranges:

this means that only DDSa contributes to differentiate the

diastereomeric ratio between the reaction solvents. In spite of

difficulties in modelling entropy, our results clearly demon-

strate how deep its influence on diastereofacial selectivity

can be.Fig. 8 Tinv in an Eyring plot as the interconversion temperature

between two solute–solvent clusters.

Fig. 9 The Eyring plot for the diastereoselective addition toO-(TBS)-

imine of (2S)-lactal in THF.

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There has been remarkable progress in the development of

electronic theories of molecules in solution in the last two

decades,27–29 but efficient and accurate treatment of solvation

remains a problem in molecular modelling, despite its prime

importance. Molecular clusters are nowadays the preferred

models to study both the energetics and dynamics of molecules

in a tailored molecular environment,30,31 and in this context

we developed the idea of the dynamic solvation cluster nature

of the inversion temperature.

It is difficult to formulate a detailed microscopic model for

solvation cluster interconversion at Tinv and, where the experi-

mental structural information in solution is missing, one can

rely solely on hypotheses. The interconversion of solvation

clusters at Tinv could involve an internal rearrangement of

the solvation cluster, or a solvent shell reorganization with

transfer of solvent molecules from the solute–solvent cluster to

the medium.

The experimental results now available strongly suggest that

for all molecules in solution, even in the presence of weak

solvation forces such as in hydrocarbons, the active chemical

species is not the bare molecule but molecule–solvent clusters,

whose structure and reactivity depend on the temperature; the

inversion temperature reveals effects on the stereoselectivity by

distinct solvation clusters.

Spectroscopic evidence for solvation cluster theory

on Tinv

To support our interpretative model of inversion temperature,

we considered spectroscopic techniques. We started with 13C

NMR spectroscopy because chemical shifts are affected by

intermolecular interactions with the solvent. We recorded 13C

NMR spectra of some aldehydes in d8-THF or d14-n-hexane at

several temperature values and noted an evolution of the

CQO chemical shift(s) with temperature.32 After full assign-

ment, all spectra showed a unique set of signals in the

temperature range explored, which ensured the presence of a

population-weighted average of rapidly interconverting

conformers. Fig. 12 reports dCQO vs. T for (S)-O-(TBS)-lactal

in deuterated THF and n-hexane. In both solvents, the

carbonyl chemical shift decreased upon warming. This carbonyl

shielding could be interpreted as a loss of electron density:

upon raising the temperature, a looser solvation may be

envisaged. Upon switching from THF to n-hexane, a shift of

Dd = 4 was observed for the CQO signal: the ether solvent

enhances the shielding thanks to a higher electron density on

the carbonyl group than the hydrocarbon. Moreover, on

closer inspection, it could be recognized that both plots were

composed of two linear segments, intersecting at a tempera-

ture that we named TNMR (Fig. 11). The data for dCQO vs. T

were analyzed by a linear least-squares fitting, and a residual

analysis was applied to evaluate the number of linear trends

and the value of the intersecting temperature (TNMR). More

specifically, the complete {dCQOi, Ti} data set was first esti-

mated by fitting a single regression line. The data pair corres-

ponding to the largest absolute value residual was used to

partition the data set into left and right subsets. The two

groups of points were then separately fitted with a least-

squares straight line. For the n-hexane solution, TNMR

occurred at �68 1C, whereas this figure was 0 1C in THF.

These TNMR numerical values are close to the inversion

temperatures of the diastereoselective nucleophilic addition to

(S)-O-(TBS)-lactal: with n-BuLi in THF, Tinv = +1 1C, with

tBuLi in n-hexane, Tinv = �81 1C, respectively.32

We found equivalence between TNMR and Tinv values

several times; for instance, in the Diels–Alder reaction in

toluene (Fig. 12; Tinv = �61 1C, TNMR = �62 1C).

Fig. 10 Non-linear Eyring plots of the diastereomeric ratios in the diastereoselective addition of EtMgBr to O-(TBS)-lactal in a series of ethers.

Fig. 11 Non-linear plots of 13CQO chemical shift vs. temperature for

O-(TBS)-lactal in deuterated solvents.

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From all of the collected data, TNMR and Tinv emerge as two

independent experimental observations related to a specific

solute–solvent couple, thus reinforcing our hypothesis on the

solvation-dependent nature of Tinv.

More recently, variable temperature NMR measurements

were coupled with the circular dichroism (CD) and ultraviolet

(UV) spectra of solutions of chiral aldehydes in the absence of

any reaction.33

UV-vis absorption and CD are two techniques also affected

by solute–solvent interactions, CD being generally the more

sensitive. In collaboration with Spada et al.,33 we evaluated the

UV and CD spectra of a-chiral aldehydes in n-decane and

n-dodecane solution upon changing the temperature, and

compared the results with 13C NMR variable temperature

analyses and the observed Tinv values of diastereoselective

reactions. As an example, in Fig. 13, ellipticity and absorbance

at selected wavelengths for (S)-O-(TBS)-lactal in n-dodecane,

and CQO chemical shift, were plotted against T. All the plots

presented break points, denoting a change of slope. It is worth

noting that all break temperatures (named TUV, TCD and

TNMR) matched well with Tinv, within experimental error,

being obtained from the diastereoselective addition of n-BuLi

to (S)-O-(TBS)-lactal in n-dodecane.

Small differences in numerical values could be accounted for

by the fact that TNMR, TCD and TUV refer to temperature-

dependent changes in solvation of the reactant in the ground

state, whereas the Tinv refers to the effect of that solvation

change on the differential activation energy (DDGa) of the two

diastereomeric reaction paths. Moreover, TNMR was detected

in a deuterated solvent (d26-n-dodecane). Thus, TNMR, TCD,

Fig. 12 Non-linear Eyring plots in a diastereoselective Diels–Alder cycloaddition.

Fig. 13 Temperature-dependent data for O-(TBS)-lactal in n-dodecane: (a) 13C NMR chemical shift of CQO, (b) CD ellipticity, (c) anti/syn ratio

upon n-BuLi addition and (d) UV absorbance.

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TUV and Tinv are effectively independent experimental results

of the same phenomenon that is directly linked to the aldehyde–

solvent pair. TNMR, TCD and TUV reveal the presence of an

equilibrium between two aldehyde–solvent clusters, which

exist in specific temperature domains, and Tinv reveals the

equilibrium between the clusters, which has important effects

on the stereoselectivity.

Solvation modelling and the inversion temperature

The phenomenon of inversion temperature and its experi-

mentally-observed dependence on the substrate–solvent pair

is not easy to rationalize intuitively, nor to be predicted using

quantum modelling, not only in the traditional ‘‘one molecule

in a vacuum approach’’, but also using fixed conformation

continuum or discrete models with a few explicit solvent

molecules to account for the solvent effect. Indeed, on the

one hand, important differences in inversion temperature are

found in different linear alkanes with essentially the same

relative permittivity, but on the other, the good conforma-

tional sampling in an equilibrium-condensed phase that would

be necessary to undertake this task is, from a computational

point of view, beyond the current capability of quantum

chemical calculations.

In collaboration with Zannoni et al., we have tried to

predict the p-facial selectivity of solvation with an atomistic

simulation.34 Using molecular dynamics simulations, we

compared the facial solvation of (R)-2-phenylpropanal in

n-pentane and n-octane at various temperatures with the

diastereoselectivity data for the n-BuLi addition to (R)-2-

phenylpropanal, which gave non-linear Eyring plots with

peculiar inversion temperatures (Fig. 14).

Extensive molecular dynamics computer simulations for

(R)-2-phenylpropanal in n-pentane and n-octane were

performed with the aim of examining the distribution of

solvent molecules around the solute and the properties of

the chiral solute in the explicit medium. It was found that

the close presence of a chiral center determined different

average solvent densities on the two faces of the p-bond and

that the density depends on the solvent. From this point of

view, n-pentane and n-octane showed remarkable differences,

which were likely to affect the diastereoselectivity of a nucleo-

philic reaction if we think of the solvent density as a measure

of the accessibility of a face. The higher diastereoselectivity

reported in n-pentane can be rationalized as a higher accessi-

bility of the face that leads to the anti product.

As this concept is not sufficient in itself to explain the

presence of an inversion temperature, we then focused on a

physical property of the solute: the conformationally-averaged

molecular chiral index G0S, which can be determined from the

simulation data.34 We found that ln G0S exhibits a non-linear

temperature dependence in both solvents, with break tempera-

tures, TCI (Fig. 15), that are in good agreement with the

experimental Tinv values (n-pentane: TCI = �50 1C and

Tinv = �69 1C, n-octane: TCI = 1 1C and Tinv = 15 1C;

Fig. 14).

We believe that this MD simulation could lead to a viable

approach to predict Tinv values and other subtle solvent effects

in a number of stereoselective reactions.

The effects of solvent mixtures on stereoselectivity

and Tinv

The development and design of industrial processes requires

the selection of the most adequate solvent to increase the

productivity, reduce waste and improve the whole product

cycle, according to the demand for sustainable and environmentallyFig. 14 Eyring plots of diastereoselective addition to (R)-2-phenyl-

propanal.

Fig. 15 A snapshot of the united atom n-pentane molecules partially

or totally contained in the first solvation sphere around the carbonyl

carbon (n-pentane, 180 K). Molecular chiral index G0S vs. T for (R)-2-

phenylpropanal obtained from MD simulations in hydrocarbons

(from: R. Berardi, G. Cainelli, P. Galletti, D. Giacomini, A. Gualandi,

L. Muccioli and C. Zannoni, Can the p-Facial Selectivity of Solvation

Be Predicted by Atomistic Simulation?, J. Am. Chem. Soc., 2005, 127,

10699. Reproduced with permission of the American Chemical

Society).

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friendly technologies. The use of mixed solvents is almost

ubiquitous, ranging from petrochemical to pharmaceutical

industries. It appears interesting then to evaluate the impact

of solvent mixtures on stereoselectivity and Tinv.

We have investigated the effect on diastereoselectivity of

solvent mixtures with respect to pure solvents in the addition

of n-BuLi to 2-phenylpropanal (Fig. 16).35

In binary mixtures of hydrocarbons, Tinv was still observed

but it was generally higher than that obtained in pure solvents.

This result suggests that solvation clusters with a mix of

solvents could be thermodynamically more stable than those

occurring in the corresponding pure solvents, so that their

interconversion requires more energy. It is interesting to note

that in a ternary mixture composed of n-pentane, n-hexane

and n-decane in a 1 : 1 : 1 molar ratio, Tinv disappeared, and

the diastereoselectivity was slightly higher than that obtained

in each individual pure solvent. Since at high T the DDHa is

lower than in pure solvents, the higher selectivity reached in

ternary mixtures is due to a larger DDSa contribution.

Studying the correlation of Tinv with the n-hexane/n-decane

molar fraction, it was observed that the greatest change in Tinv

occurred at the extremities of the graph close to the pure

solvents, whereas over a large mole fraction range, Tinv was

relatively unaffected by the composition of the mixture

(Fig. 17). The consistency of Tinv could be due to the presence

of two solvation clusters with microstructures independent of

the composition of the bulk solvent. This is quite interesting

because hydrocarbons, which should exert only weak and

non-specific interactions with a neutral dipolar solute, could

reveal more structured solvation shells than is currently

believed. Interpolation of the experimental data allowed us

to evaluate the molecular composition of the solvation shell,

which was a ratio of 5 : 2 n-hexane/n-decane per mole of

2-phenylpropanal.

The study on solvent mixtures was extended to mixtures of

n-hexane and 5 mol% of a tertiary amine. We examined the

role of several amines as co-solvents in the addition of n-BuLi

to 2-phenylpropanal and (S)-O-(TBS)-lactal, which have been

revealed to have strong effects on diastereofacial selectivity

(Fig. 18).36 The presence of such trialkylamines in n-hexane

substantially enhanced the preferential formation of the anti

isomer for 2-phenylpropanal across the T range, allowing an

increased diastereoselectivity with respect to that in pure

n-hexane or pure THF.

The possibility to improve diastereofacial selectivity by

adding a tertiary amine as a co-solvent to a hydrocarbon is

quite an interesting result in view of the potential synthetic and

industrial applications, and for the possible replacement

of THF as a solvent in organometallic synthesis with its

associated cost and safety issues.

The presence of Tinv values in Eyring plots, which differ

when changing the amine, confirm the direct involvement of

solute–solvent clusters, which are subject to temperature-

dependent reorganization phenomena. The mixture with

Et3N presented Tinv as a jump, as in the case of the allylation

of lactalimine (cf. Fig. 9). Moreover, Tinv values in n-hexane/

amine mixtures occur at higher values than in pure n-hexane,

Fig. 16 Eyring plots for diastereoselective addition to 2-phenylpropanal in pure solvents and solvent mixtures.

Fig. 17 The Tinv dependence on solvent composition for the addition

of n-BuLi to 2-phenylpropanal.

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as in the case of binary mixture n-hexane/n-decane (Fig. 16),

thus indicating the greater stability of solvation clusters in

mixtures.

The addition of n-Bu3N as a co-solvent changed the

temperature dependence, even for the diastereoselective

addition of (cyanomethyl)lithium to 2-phenylpropanal

(Fig. 19).37 In this case, we observed an opposite temperature

behaviour in the diastereomeric ratio for reactions in n-hexane

vs. n-hexane/n-Bu3N and methylcyclohexane. We have

already observed opposite concavities for the Eyring plots of

cyclic vs. linear hydrocarbons in the addition of n-BuLi to

2-phenylpropanal.21

The change in concavity is derived from a change in the

slope of one of the two linear parts of the plot, and hence it

depends on a change in the enthalpic contribution to the

stereoselectivity. However, this quite interesting aspect de-

serves deeper investigation, and dedicated MD simulations

could disclose differences in microscopic solvation that may

account for this linear vs. cyclic solvent effect.38

The inversion temperature in enzymatic reactions

Over the past few years, the use of enzymes in organic

synthesis has become increasingly important due to the basic

discovery that enzymatic reactions can occur in organic

solvents as well as in aqueous media. Indeed, enzymatic

selectivity is remarkably dependent on the organic solvent,

and many attempts have been made to explain this influence.39

However, less attention has been paid to the effect of

temperature on enzymatic selectivity.

We have reported an example of inversion temperature and

the corresponding TNMR found in the enzymatic resolution of

a b-lactam by Penicillin-G Acilase (Fig. 20). It is interesting to

note that the highest enantioselectivity can be achieved at

higher temperatures, whereas at lower temperatures, the

stereoselectivity is less dependent on T, thus revealing once

more a control by DDSa.

On the basis of our interpretation, the presence of a Tinv,

indicates the presence of two dynamic substrate–solvent

Fig. 18 Eyring plots of the diastereoselective addition of n-BuLi to 2-phenylpropanal in n-hexane and tertiary amines 5% mixtures.

Fig. 19 Eyring plots for the diastereoselective addition of (cyanomethyl)lithium to 2-phenylpropanal in n-hexane, methylcyclohexane and

n-Bu3N 5% mixtures.

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clusters, which affect the thermodynamic parameters and

therefore the enantioselectivity, even of enzymatic reactions.40

As in the case of diastereoselective processes, the nature of

these solvation clusters and their behavior with temperature

should not depend on the reaction but mainly on the

solute–solvent pair. To verify this hypothesis, we compared

the enantioselectivity behaviour with temperature of the

enzymatic (bio-catalyst) and a non-enzymatic (chemo-catalyst)

acylation reactions of some racemic and meso alcohols.41 We

selected lipases as bio-catalysts and chiral proline-based

diamines as chemo-catalysts. We then examined the Eyring

plots of enantioselectivity obtained with the chemo- and

bio-catalysts in the same reaction solvent. Fig. 21 reports an

example with 2-phenylpropanol in THF.

All three plots present Tinv values, and the numerical values

for the bio- and the chemo-catalyzed reactions are fairly

similar. This result confirms the dependence of Tinv on

solute–solvent clustering phenomena and not on the reaction

considered, even in the case of enzymatic reactions.

We then confirmed the solute–solvent clustering phenomena

with variable temperature 13C NMR spectroscopy. Fig. 21

shows plots of selected chemical shifts of 2-phenylpropanal in

d8-THF vs. absolute temperature. More than one carbon atom

showed non-linear behaviour with very similar TNMR values.

A direct comparison showed a close correspondence between

Tinv obtained from the bio- and chemo-catalyzed reactions in

THF, and the TNMR values.

As already discussed, Tinv and TNMR are independent

experimental observations of the same phenomenon of solva-

tion clustering. The results obtained therefore confirm that the

Tinv is quite a general phenomenon that is independent of the

particular reaction system, including the nature of the catalyst,

i.e., enzyme or chiral diamine, but tightly related to the nature

of the substrate–solvent pair.

Nakamura et al. observed that lipases recognize not only the

structure of the substrate, but also that of the solvent, assum-

ing that a solvent influences enzymatic reactions as a molecule

rather than as a bulk medium.42 Klibanov and co-workers

Fig. 20 Non-linear Eyring plots of enzymatic enantioselectivity (E) in the resolution of a racemic azetidinone and its corresponding TNMR.

Fig. 21 The Eyring plot for the enantioselective acetylation of

2-phenylpropanol with lipase and chiral diamines, and the chemical

shifts for selected carbons in 2-phenylpropanol vs. temperature in

deuterated THF.

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have stated that the solvent dependence of enzymatic prochiral

selectivity can be attributed primarily to changes in the relative

solvation modes of the substrate in the transition state.43 Our

interpretation is not in contrast with these observations, but

our comparative studies have confirmed that solute–solvent

clusters and their temperature-dependent dynamics have a

fundamental influence on stereoselectivity in chemical, as well

as in enzymatic, reactions.

Concluding remarks

Our interest in the stereoselectivity of chemical and enzymatic

reactions challenged us to investigate solvation effects. Given

the enormous interest in improving diastereo- and enantio-

selectivity, particularly in the synthesis of biologically-active

compounds, our results focus attention on a set of important

topics and open questions:

� Temperature-dependent studies on stereoselective reac-

tions can reveal dynamic solvent effects, with the presence of

the inversion temperature phenomenon.

� For all reactions in solution, the reactive species is not the

bare solute molecule but a solute–solvent cluster whose struc-

ture and reactivity depends on temperature.

� Any theoretical model for the analysis of stereoselective

processes completely looses its predictive value by ignoring

solvent effects.

� Entropy could be an important parameter in determining

stereoselectivity, even though it is generally ignored in models

of asymmetric induction; in some cases, it can be the unique

cause of the observed selectivity.

� Stereoselectivity can be improved by using mixtures of

solvents or co-solvents, essentially because of an entropic

control.

Acknowledgements

We are grateful to Prof. Spada and Prof. Zannoni for their

fruitful collaboration. We thank Dr Francesca Paradisi for

helpful discussions and comments. We thank our graduate and

postdoctoral co-workers, whose names are cited in the references,

for their valuable contribution to the work of our group. We are

also grateful to MIUR for supporting this research.

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