Chemical reactivity and solution structure: on the way to a paradigm shift?

Abstract

Recent studies unveiled two unprecedented phenomena which together may induce a paradigm shift in understanding chemical reactivity in solutions which would no longer be related to molecular species. Research on chemical reactions under microfluidic conditions (and some other systems) revealed that the same compound involved in the same chemical reaction performed under slightly different conditions may exhibit a significantly altered chemical reactivity pattern (different chemical properties). This review aims at linking this discovery to another unusual finding that commonly used solutions are not homogeneous at the mesoscale suggesting that a solute, depending on concentration, solvent, temperature and the presence of other compounds including impurities, may exist in solutions as a variety of supramolecular species (supramers), which may also comprise solvent molecules, differing in size and structure, and hence physical and chemical properties.

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L. O. Kononov

Leonid Kononov is currently a Leading Researcher at N.K. Kochetkov Laboratory of Carbohydrate Chemistry of N.D. Zelinsky Institute of Organic Chemistry (Russian Academy of Sciences, Moscow, Russia). Degrees: MSc (Chemistry) in 1983 (M.V. Lomonosov Moscow State University, Moscow, USSR), PhD (Organic Chemistry) in 1990, DSc. (Organic Chemistry) in 2013 (both at N.D. Zelinsky Institute of Organic Chemistry). Postdoctoral fellowships: Lund University, Lund, Sweden (with Prof. Göran Magnusson) in 1994–1995 (2 years) and RIKEN, Wako, Saitama, Japan (with Prof. Tomoya Ogawa) in 1995–1996 (1 year). Leonid Kononov is a member of the Editorial board of the Russian Chemical Bulletin.

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Introduction

The theory of chemical reactivity is commonly considered to be well developed as the mechanisms of most organic† chemical reactions have been elucidated over the years.¹ However, as most practitioners of chemistry would probably agree,² understanding the mechanism of a reaction between the isolated molecules of reagents does not necessarily mean success in the practical preparation of the desired product in high yields and stereoselectivity (in case of stereoselective reactions). Although almost everyone seems to be content with the current situation in organic chemistry, there is a vaguely expressed feeling that something important has been missed. This feeling becomes more pronounced as one becomes more acquainted with chemical literature devoted to areas remote from “pure” organic chemistry.

One might recall an opinion of Seebach published a quarter century ago,³ who discussed the current status and perspectives of organic synthesis at that time and was really sceptical about future development of organic chemistry within its own field of science and stressed that “new synthetic methods are most likely to be encountered in the fields of biological and organometallic chemistry” and the “discovery of truly new reactions is likely to be limited to the realm of transition-metal organic chemistry”.

Although many of his predictions remain valid, one has to point out that recent development of micro-flow chemistry (another name – microfluidic chemistry; for more details see the section on micro-flow chemistry below)^4–26 revealed a possibility of a distinctly different reactivity pattern^8,27–29 of a given compound under microfluidic conditions from that exhibited by the same compound under conventional batch stirring. In fact, the use of microfluidic technology unveiled new, previously unknown, chemical properties of known compounds involved in seemingly the same known reactions but performed under microfluidic conditions. Importance of these unusual findings (which the author proposes to call “microfluidic effect”) was immediately realized and “the need to reinvestigate the traditional or imaginary reactions which have so far been performed and evaluated only in batch apparatus” formulated.⁸ Quite recently, another group of researchers, without any reference to the predecessors, in a similar way suggested to use “continuous flow chemistry” as a tool for discovery of “new chemical reactivity patterns”.²⁹ In fact, an ambitious program of development of the “new organic chemistry” of the “old compounds”, which could have chemical properties not yet described in the common textbooks,¹ has been advanced.^8,28

It appears that chemistry is now facing a revolutionary change as until recently it was almost unthinkable for a compound to have different chemical properties depending on “minor” differences in experimental setup such as the mode of mixing reagent solutions (batch-wise in a flask or continuously in a microfluidic mixer). As it will be evident from further discussion, the existence of multiple reactivity patterns of a compound is not limited to microfluidic effect only. Similar observations have also been made for reactions under traditional batch conditions. At present there is no generally accepted theoretical concept that allows discussion of these issues.

In author's opinion, a clue to the problem of multiple reactivity patterns (including the microfluidic effect) may be found by careful consideration of the well-known fact that most chemical reactions are performed in solutions. Indeed, real-world chemical reactions occur in non-ideal solutions and definitely not between the isolated molecules of reagents “in vacuo”. Solvent effects on the chemical reactivity and reaction outcome have been the subject of numerous studies^30–32 for more than century since the first report by Berthelot^33,34 concerning the influence of the nature of solvent on the rate of esterification of ethanol with acetic acid has been published. It may look like a solid knowledge has already been accumulated, analysed and understood. In this review the author argues that this view is not entirely correct. Although many chemical reactions are performed in the presence of solvent (i.e., in solution), little is known how the reaction outcome is influenced by solution structure, which reflects the nature of solute-containing species and their distribution in solution. Moreover, consideration of the reactivity of the species, other than just solute molecules, in solution may require a revision of reaction mechanisms that currently involve¹ mostly molecules of reagents.

This review will focus on recent findings on the structure of solutions and will discuss how this new knowledge may widen understanding of the nature of chemical reactivity (and selectivity) and eventually revolutionize current approaches to chemical reactions in solutions. The chemistry is now on the way to paradigm shift. The author sincerely hopes that a reader will support this claim after considering all the arguments presented in this review.

Current views on solution structure: commonly used solutions are not homogeneous

Textbook knowledge is incomplete: discovery of mesoscale inhomogeneities in solutions

Undersaturated solutions of highly soluble substances, especially those with low molecular mass are usually assumed to be essentially homogenous at length scales larger than dimensions of individual molecules. Only some degree of short range local structuring due to specific interactions on the sub-nanometre scale (e.g., molecular clusters, solvation shells), usually not exceeding several solute molecules, is commonly allowed. However, recent experimental evidence, which is continuously growing, has revealed that it is not the case. To put it simply, there are regions in solution where solute molecules are concentrated as compared to the rest of solution forming solute-rich domains. These large-scale structures with sizes on the order of 10² nm and larger (occasionally up to tens of micrometers)^35,36 are, surprisingly, present in most solutions encountered in everyday life and ordinary laboratory practice.^37–41 These mesoscale inhomogeneities (also called microheterogeneities, mesospecies, solution domains, supramolecular assemblies, giant clusters) are long-lived real and discrete objects.^37,40

For the history of development of this important, yet still controversial, area of research and the leading references a reader is directed to the introductory sections of the key recent publications^{35,36,40–48} as well to a special journal issue of Faraday Discussions devoted to “Mesostructure and Dynamics in Liquids and Solutions”.⁴⁹ Similar phenomena were observed in solutions of polymers,^50–61 which are outside the scope of this review; other references relevant to mesospecies in solutions of polymers may be found elsewhere.^41,48 Here only the most important aspects relevant to the subject of this review will be highlighted.

Systems exhibiting the presence of mesospecies

Since the first publication in 2000,⁶² in which the experimental evidence was interpreted in favour of the presence of large clusters in solutions of low-molecular-mass substances, many solute–solvent combinations have already been studied (more than one hundred pairs for binary solutions^37–40), covering most common inorganic and organic electrolytes, nonionic solid compounds, and a large variety of simple liquids. An attempt of classification of solutions with respect to the capability of formation of the large-scale structures has been advanced.³⁹ In the systems studied by Sedlák, the “presence and intensity of the large-scale structures was correlated with properties of constituent molecules and ions such as their charge, dipole moment, protic vs. aprotic character, etc. Electrolytes of both inorganic and organic origin exhibited large-scale structures in aqueous solutions (in all cases) and in organic solvents (selectively). Solutions of nonelectrolytes including mixtures of liquids exhibit large-scale structures in aqueous solutions (in all cases) and in organic solvents (selectively). Nonaqueous mixtures did not exhibit large-scale organization in the case of nonpolar and weakly polar components. Large-scale structures were observed in systems where at least one component had the ability to form hydrogen bonds, especially the ability of spatial networking by hydrogen bonding”.³⁹

In most studies mainly (although not exclusively^37–39) water was used as the solvent. In addition to a vast number of examples studied by Sedlák,^37–41 the presence of large objects was also confirmed (by other researchers) in aqueous solutions of such well-soluble compounds as amino-acids,^44,63 citric acid^37,40 and its sodium salt,⁶² urea,^37,40,64 3-methylpyridine,^35,65 glucose,³⁷ α-cyclodextrin,^64,66,67 2-butoxyethanol,^68,69 tetrahydrofuran,^42,64,70 1,4-dioxane,⁷⁰ and several other organic solvents⁷¹ (methanol, ethanol,^37,64 propan-1-ol, propan-2-ol, acetone, acetic acid³⁷) and simple salts (sodium chloride,^37,62,72 potassium and ammonium chlorides,⁷² magnesium sulfate,⁴⁰ ammonium sulfate⁶²). Mesoscale inhomogeneities in aqueous solutions of tert-butanol, which is infinitely miscible with water, attracted the greatest interest and were studied in most detail.^{35,36,40,41,43,46–48,69,73–76}

Methods used for detection and study of mesospecies

Light scattering. The presence of mesoscale inhomogeneities in solutions was detected primarily by static and dynamic light scattering (SLS and DLS, respectively), which were used almost in every publication on this subject. An anomalously high intensity of scattered light in SLS experiments as compared to that of the pure solvent features these solutions. It was a combination of SLS and DLS that allowed Sedlák^37–41 to study these objects in detail and propose the first model of their structure (see the respective section below). A common feature of DLS data for systems containing mesoscopic mesoscale inhomogeneities is the presence of the second slow relaxation mode of the time-dependent correlation function (relaxation time in the millisecond range corresponding to a diffusion coefficient ∼10⁻¹³ to 10⁻⁹ cm² s⁻¹ and apparent hydrodynamic radius ∼10¹ to 10³ nm)^35,36,48 in addition to the expected fast mode (relaxation time in the microsecond range corresponding to a diffusion coefficient ∼10⁻⁷ to 10⁻⁵ cm² s⁻¹ and apparent hydrodynamic radius ∼10⁻¹ to 10⁰ nm),^35,36,48 which is usually attributed to the “mutual molecular diffusion”^35,36,48 or to the “well-understood” “ordinary diffusion”^37–39 of solute (Fig. 1–3).

Fig. 1 Typical example of bimodal dynamic light scattering (DLS) from solutions of low molar mass compounds and mixtures of liquids. Data were obtained on a 4.1 mass% aqueous solution of D-glucose. The faster mode corresponds to “ordinary diffusion of solute”. The slower mode appears due to the presence of inhomogeneous solute distribution (solute association) at large length scales. Scattering angle θ = 90°. Reprinted with permission from ref. 37 (M. Sedlák, J. Phys. Chem. B, 2006, 110, 4329). Copyright (2006) American Chemical Society.

Fig. 2 Typical example of bimodal autocorrelation functions from dynamic light scattering experiments on aqueous tert-butanol solutions. Red curve: concentration 150 g kg⁻¹ (molar fraction 0.041). Green curve: concentration 330 g kg⁻¹ (molar fraction 0.107). While both fast and slow diffusive modes are clearly seen at 330 g kg⁻¹, the slow diffusive mode is dominating at 150 g kg⁻¹, since its amplitude is incomparably higher than the fast mode amplitude. Scattering angle θ = 90°. Reprinted with permission from ref. 41 (M. Sedlák and D. Rak, J. Phys. Chem. B, 2014, 118, 2726). Copyright (2014) American Chemical Society.

Fig. 3 Time-dependent correlation function (open circles) for the 0.083 mole fraction tert-butanol aqueous solution at a scattering angle θ = 30° obtained at T = 22.8 °C. The solid curve represents a fit of the data to two exponential decays with two decay times corresponding to the molecular diffusion (diffusion coefficient D = 1.5 10⁻⁶ cm² s⁻¹) and the mesoscale diffusion (diffusion coefficient D = 4.2 × 10⁻⁹ cm² s⁻¹), respectively. An additional longtime tail of the dynamic correlation function is assumed to be a background contribution. Reprinted with permission from ref. 35 (D. Subramanian, D. A. Ivanov, I. K. Yudin, M. A. Anisimov and J. V. Sengers, J. Chem. Eng. Data, 2011, 56, 1238). Copyright (2011) American Chemical Society.

The origin of the fast mode in DLS may require reconsideration since it was found⁷⁷ to be correlated with changes in solution as a whole (see below the section devoted to the use of polarimetry).

Other scattering methods. Small-angle neutron scattering (SANS)^42,47,78 and small-angle X-ray scattering (SAXS)^48,79 were occasionally used in attempts to characterize the mesospecies although with mixed results. Scattering contrast between the solute-rich domains and the rest of solution was emphasized to be critical for “observation” of the mesoscale inhomogeneities by scattering methods.^{40,42,47,48,70} Inability to detect these objects by a particular method (SANS^42,47 or SAXS⁴⁸) under specific conditions does not necessarily mean the absence of large structures in solution as was clearly demonstrated for THF–water mixtures (in the presence or absence of trace amount of antioxidant BHT) by a combination of methods (DLS/SLS/SANS).⁴² In the latter example the presence of BHT was claimed⁴² to create an additional contrast and facilitate observation of mesospecies. Note, however, that according to the Anisimov's model (see the respective section below), the hydrophobic BHT would promote THF aggregation rather than simply change contrast.

Microscopy. “Direct experimental observation” of mesospecies was achieved by confocal microscopy,³⁵ Brownian Microscopy/Nanoparticle Tracking Analysis (NTA)^40,41,63,80 in solution (Fig. 4) and by Cryogenic Transmission Electron Microscopy (Cryo-TEM)⁴⁴ and atomic force microscopy (AFM)⁶³ for solution samples deposited on a support. See also the section on aggregation in dilute solutions below.

Fig. 4 Microscopic image from the NTA (nanoparticle tracking analysis) experiment on an aqueous solution of tert-butanol (TBA) (c = 150 g kg⁻¹). TBA was first purified, subsequently doped with a known amount of octadecane (0.0053% octadecane in TBA), and finally mixed with water. A still image from a video sequence is shown where the captured area is 80 × 100 μm² while the focal depth is approximately 20 μm. The experiment was performed at room temperature. Reprinted with permission from ref. 41 (M. Sedlák and D. Rak, J. Phys. Chem. B, 2014, 118, 2726). Copyright (2014) American Chemical Society.

Mass-spectrometry. Electro-spray mass-spectrometry (ESI-MS)^63,81 was used as an auxiliary tool for gaining insight in solute aggregation in solution in which mesospecies were observed. Although some relevant correlations between ESI-MS and scattering data were obtained, there is still a continuing debate^82–92 on whether cluster peaks observed in ESI-mass spectra are generated within a mass-spectrometer or indeed reflect the situation in the solution being analysed and their intensities are proportional to the concentrations of the parent species in solution.

Osmometry. Vapor pressure osmometry was used by Sedlák in order to prove that the systems under SLS/DLS study are true solutions rather than conventional colloid systems.³⁷ One can expect that dissolution of a solid is a complex process and “small pieces” of “undissolved” solute may still be present in the seemingly homogeneous solution. Osmotic coefficients for aqueous solutions of D-glucose and urea in the concentration range, where light scattering experiments showed the presence of mesoscale inhomogeneities, were found to be equal to unity (1.0) at all concentrations studied suggesting complete dissolution of the solute and the absence of classic aggregation in the solutions studied.

Polarimetry. Recently, polarimetry was found to be useful in studying mesoscale inhomogeneities in aqueous solutions of D-levoglucosan.^77,93 Optical rotation of both freshly prepared⁷⁷ and aged⁹³ aqueous solutions of D-levoglucosan was studied experimentally in the 0.03–4.0 mol L⁻¹ concentration range and a nonlinear concentration dependence of specific optical rotation (SR, [α]_D) was revealed. Discontinuities observed in the concentration plot of SR (Fig. 5) are well correlated with those found by SLS and DLS (Fig. 5 and 6) and, in authors' opinion, identify concentration ranges in which different solution domains (“supramers” in authors' terminology) may exist (see below the respective section on supramers).

Fig. 5 Concentration dependence of specific optical rotation ([α]²⁸_D) of freshly prepared solutions of D-levoglucosan in water at 28 °C and SLS data for aqueous solutions of D-levoglucosan with different concentrations – Debye plot where the slope (equal to the second virial coefficient A₂) indicates the “solvent quality”. Each point represents an average of 10 measurements (relative error <1% unless specified otherwise, see the error bars; the error bar is on the order of the symbol size if not visible). Horizontal red and blue bars near the concentration axis indicate different areas of concentrations between critical points (marked by vertical arrows) where different supramers may exist. Adapted with permission from ref. 77. Copyright© 2014 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.

Fig. 6 Intensity-weighted size distribution of light-scattering particles in aqueous solutions of D-levoglucosan with different concentrations and time-dependent correlation function for solution with concentration 0.03 mol L⁻¹. Red and blue bars near the concentration axis indicate different areas of concentrations between critical points (identical to those found by polarimetry and SLS) where different supramers are supposed to exist. Adapted with permission from ref. 77. Copyright© 2014 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.

Especially important is the finding⁷⁷ that the concentration dependence of hydrodynamic radii for the fast mode in DLS in aqueous solutions of D-levoglucosan has critical points corresponding well to those found by polarimetry, SLS and the whole set of DLS data. This means that the objects manifested in DLS as the fast mode behave upon changes in concentration in the same fashion as does the solution as a whole.

These concerted responses of three fundamentally different physical methods, polarimetry, SLS and DLS, which seem not to be related to each other since they probe drastically different properties, to changes in solute concentration are not only unusual but also suggest that all the methods used provide information on the changes in the solution as a whole rather than on the solute alone. This fact may seem puzzling at the first glance but the observed correlation clearly indicates that the existence of the critical points reflects a fundamental property of non-ideal (i.e., real) solutions, a possibility of drastic and abrupt changes of the structure of supramers, which can be probed by a variety of physical methods.

Other methods. It is generally accepted that molecular clustering (aggregation) in solutions (and liquids in general) would result in changes (as compared to ideal solutions) in various thermodynamic functions of solutions (Gibbs energy, enthalpy, entropy) which can be probed by measuring an array of response functions: activity coefficients, heat capacity, compressibility (hence sound velocity), dielectric (permittivity) and optical (refractive index and its fluctuation derivatives) properties, etc.^94–96 It has to be noted that small amphiphilic solute molecules like simple alcohols (hydrotropes, see below) usually exhibit only a dynamic, loose, non-covalent clustering in the water-rich region. This clustering can be viewed as “micelle-like structural fluctuations”. Although these fluctuations are short-ranged (∼1 nm) and short-lived (10–50 ps), they may lead to thermodynamic anomalies.⁴⁷ For the discussion on how study of thermodynamic anomalies may provide insight into solute–solvent interactions and on the structural changes that occur at the molecular scale see ref. 47 and references cited therein. On the contrary, it was pointed out that large long-lived mesoscale inhomogeneities discussed in this review might be of limited thermodynamic significance (“thermodynamically inconsequential”).⁹⁷ Indeed, as experiments have demonstrated, the heat capacity anomaly in aqueous tert-butanol solutions is rather insensitive to the presence or absence of mesoscale inhomogeneities (the heat capacity anomaly persists even after the mesoscale inhomogeneities have been eliminated by filtration).⁴⁷ Clearly, more experiments are required to clarify this issue.

Origin, nature and stability of mesospecies

The very existence of mesoscale inhomogeneities seems now to be established. However, this fact has immediately raised a bunch of so far unanswered questions and unresolved issues related to the origin and nature of the mesospecies as well to the mechanism of their stabilization preventing macroscopic phase separation, which “have been discussed in the literature over the past decade and still remain highly debatable and controversial subjects”.⁴⁸

No nanobubbles. It has been demonstrated^40,43,48,71 by a series of ingenious experiments that the large structures present in solutions are not kinetically arrested gaseous nanobubbles stabilized by solute adsorbed at the gas/water interface as suggested^64,66,67 earlier. For this reason, “previous reports of nanobubbles based on scattering experiments should be reconsidered” taking into account “that the scattering objects are not actually gaseous”.⁷¹

Real and discrete objects. The mesoscale inhomogeneities were shown to be long-lived real (not fluctuations) and discrete objects (not bicontinuous phases with large correlation lengths).^37,40 In some cases the mesospecies are quite stable and can be sedimented by centrifugation^37,40 or removed by filtration through appropriate filters (e.g., Anopore filter with 20 nm pores).^{36,41,43–48,62,70}

Equilibrium structures?. In other cases the mesospecies can re-emerge in the filtered solutions after a short time (several minutes)^41,44,63 or even pass through a filter, the result being dependent⁴⁴ on the material of the filter used. This re-emergence of mesoscale inhomogeneities in the filtrates (Fig. 7) suggests, in opinion of some authors, an equilibrium distribution of the solute molecules between solute-rich mesospecies and the surrounding bulk solution.^44,63 Other authors,⁴¹ for a particular case of tert-butanol–water mixtures, emphasize the role of molecularly dissolved hydrophobic impurities possibly present in the filtrate and suggest that “upon removal of the mesoscale structures” by filtration, “the quasi-equilibrium is distorted and molecularly dissolved hydrophobes segregate into new mesoscale structures” (see below the discussion on the role of admixtures).

Fig. 7 NTA images after filtration of p-amino salicylic acid (3 mmol L⁻¹; pH 9, by NaOH; room temperature) through a 20 nm filter (Anotop 25 inorganic membrane filter, Whatman, UK) after 30 s (A), after 90 s (B), and after 210 s (C). Reproduced from ref. 63.

Although it is not always clear yet whether these large structures are at equilibrium with the rest of the solution in different systems studied, it was demonstrated, at least in two cases^48,65 that mesospecies may be at a nonequilibrium state (and disappear after several hours or days after sample preparation), although sometimes extremely long-lived (for at least one year or longer)^36,47 apparently existing in a kinetically arrested state due to a high barrier.

Kinetics of formation and long-time stability of mesospecies. It should be born in mind that in most publications on mesoscale inhomogeneities detailed kinetics of formation was not studied. The rare exception is the comprehensive study by Sedlák³⁸ in which “kinetics of the formation of large-scale supramolecular structure and its long-time stability were investigated in detail in solutions of electrolytes, nonelectrolytes, and mixtures of liquids. This structure comprises submicron-sized domains (large clusters) with higher solute concentration than in the rest of solution. In the case of mixtures of liquids, a complete real-time monitoring of the structure formation was possible in all cases. In the case of solutions of solid samples, the observation was possible in cases when the structure formation was significantly slower than the dissolution process. The time scale on which the supramolecular structure develops varies from minutes to weeks, depending on the concrete system. The long-time stability of the developed structure was investigated in time intervals ranging up to 15 months. In some systems the resulting domain structure appears stable, in others a very slow ceasing of domains is observed over very long time intervals. In all cases, however, slow kinetic effects are present in the systems investigated” (Fig. 8).³⁸

Fig. 8 Kinetics of formation of large-scale supramolecular structures in representative solutions monitored by SLS and DLS. Adapted with permission from ref. 38 (M. Sedlák, J. Phys. Chem. B, 2006, 110, 4339). Copyright (2006) American Chemical Society.

This means that most studies published previously (before the advent of the era of mesoscale inhomogeneities) on association, aggregation, etc. in liquid state might be dealing with systems at an unknown moment of their evolution. The structure, hence properties, of such systems might reflect the system state at this particular moment rather than its “intrinsic” properties. Moreover, it might be possible that any discussion⁴³ of the “genuine equilibrium mesoscale structures” and “genuine solution structure” without referring to the history of the particular sample under investigation might be misleading and potentially useless. For this reason, caution should be exercised when analysing the data described and conclusions made in these publications.

Multiple mesoscale phenomena?. The variety of opinions and explanations is not surprising since the mesoscale structures “may or may not have similar origin”⁴¹ in different systems and in fact “one might be dealing with multiple mesoscale phenomena”.⁴⁸

Implications for chemical reactivity. For further discussion of chemical reactivity, it is very important that various large objects incorporating solute molecules indeed can emerge in solutions of reagents. And even though these entities could change their structure or disappear after several hours or days, their participation in the chemical reactions involving solute cannot be excluded especially considering that many reactions would have been finished by that time.

Aggregation upon dilution

Common concentration range. It is quite natural to vary concentration when studying solute aggregation. Indeed most studies of mesospecies in solutions reported the relevant concentration dependencies. A publication entitled “Unexpected solute aggregation in water on dilution” was published in 2001.⁹⁸ The authors observed (Fig. 9) that the hydrodynamic radius (200–5000 nm) of light-scattering objects was larger in dilute aqueous solutions than in more concentrated solutions of sodium chloride (0.785–5.5 mol L⁻¹), a DNA oligonucleotide (M_n 9.745, M_w 13.205 kg mol⁻¹; polydispersity 1.335) (4.5–25 g L⁻¹), β-cyclodextrin (3.5 × 10⁻⁴ to 1.4 × 10⁻²·mol L⁻¹), sodium guanosine monophosphate (<0.02 mol L⁻¹) and fullerene–cyclodextrin conjugates (1 × 10⁻⁵ to 2 × 10⁻⁴ mol L⁻¹). The authors⁹⁸ interpreted this decrease in hydrodynamic radius in more concentrated solutions as an indication that solute molecules aggregate upon dilution forming aggregates of micrometer size. Scanning electron microscopy of the samples of solutions deposited on a support revealed large structures of comparable sizes which proved, in authors' opinion, solute aggregation in solution.

Fig. 9 Aggregation upon dilution. Increasing average particle size (Z_av) with decreasing concentration for different compound classes. Reproduced from ref. 98.

However, considering Sedlák's results (see below the discussion of the model proposed, see Fig. 10),^37–39 there are no grounds to support the view that these light-scattering objects in dilute solutions are undoubtedly solute aggregates. More realistic is an assumption⁷⁷ that these large “clusters”, which manifest themselves as the slow modes in DLS, may comprise both solute and solvent molecules, the proportion of the latter in the clusters increasing upon dilution.

Fig. 10 Sedlák's model. Schematic illustration of two examples of possible domain structures in solutions and mixtures of liquids. Limiting cases of loose (A) and tight (B) structures are shown. Solute molecules are shown as closed circles. Solvent molecules are assumed to occupy the rest. Domains are discrete regions with a higher concentration of solute inside domains than outside domains. An exact calculation of this concentration difference is not possible; however, it can be shown that domains are not completely tight associates without solvent molecules inside as shown in part (B). Reprinted with permission from ref. 37 (M. Sedlák, J. Phys. Chem. B, 2006, 110, 4329). Copyright (2006) American Chemical Society.

Ultra-dilute solutions. The view that solvent aggregation makes a substantial contribution to light scattering is supported by detection of slow modes in DLS data (corresponding to hydrodynamic diameter ∼10² nm) of ultra-dilute solutions (10⁻¹⁸ to 10⁻⁹ mol L⁻¹), which hardly contain any substantial amount of solute molecules. The reality of the “nanoassociates” (in authors' terminology), formed in ultra-dilute solutions (only in the presence of ambient electromagnetic field), was confirmed by correlations with several other physical methods including their visualisation by AFM (these studies have recently been reviewed⁹⁹). A recent review¹⁰⁰ discussed other experiments in which large “water clusters” (containing 10⁶ to 10⁹ of water molecules) in somewhat more concentrated (10⁻⁸ to 10⁻⁷ mol L⁻¹) solutions prepared from aqueous solutions of polar solutes by repeated dilution, were directly imaged under the transmission electron microscope and AFM. The existence of such aggregation upon dilution has recently been substantiated by quantum electrodynamics (QED).^100–106

Do mesospecies in dilute solutions contain solute?. A similar concentration dependence of hydrodynamic radius of solution domains (i.e., increase upon dilution) was revealed in a study of aqueous solutions of D-levoglucosan (0.03–4.0 mol L⁻¹) by DLS (see Fig. 6).⁷⁷ However, the discovered fact that rearrangements of domains, induced by concentration changes, correlate with polarimetry data (see Fig. 5) implies, importantly, that a chiral solute is indeed a part of solution domains that are detectable by SLS/DLS. An alternative explanation of this correlation would require resorting to the recently discovered¹⁰⁷ phenomenon of “solvent imprinting” by a chiral solute, which was shown⁷⁷ not to be related to the particular case of D-levoglucosan solutions. It is important to stress that no other physical method (except for mass-spectrometry; see above the comments on limitations of mass-spectrometry for the study of solutions) was able to unequivocally prove the presence of solute in mesospecies detected by light scattering methods.

Mechanical (in)stability of mesospecies

The fact that after nanopore filtration of solutions mesoscale inhomogeneities are initially absent^{36,41,43–48,62,70} in the filtrate (see above) was interpreted⁹⁷ as an indication that mechanical forces during filtration or stirring⁴⁴ may destroy these clusters rather than just simply remove them from the solution. This view on solution domains (mesospecies) as rather fragile objects⁵⁸ is best discussed and analysed in terms of Sedlák's model³⁷ of structure of solution domains (see the following section) and will be extremely useful in further discussion of microfluidic effect (see the respective section below).

Models of structure of mesospecies

Sedlák's model. An unparalleled extensive experimental study^37–39 of ca. 100 solute–solvent combinations accompanied by insightful analysis of angular dependence of intensity of scattered light (SLS) and intensity of the slow mode in DLS complemented by osmotic pressure data obtained by vapor pressure osmometry allowed Sedlák to propose³⁷ the first model of the structure of mesoscale inhomogeneities (Fig. 10). According to Sedlák, “these regions can be characterized as close-to-spherical discrete domains of higher solute density in a less dense rest of solution. These domains do contain solvent inside and can be therefore characterized as loose associates (giant clusters, aggregates). Their size distributions are significantly broad, ranging up to several hundreds of nanometers. Characteristic sizes of these inhomogeneities thus exceed angstrom dimensions of individual molecules by several orders of magnitude. The number of solute molecules per domain varies approximately in the range 10³ to 10⁸”. Solution “domains form due to directional attractive interactions between solute molecules via hydrogen bond bridges formed by one or several solvent molecules, which are themselves hydrogen bonded”.

For further discussion of chemical reactivity, it is very important that solution domains are loose aggregates and that solvent molecules can penetrate the giant clusters although the latter behave as kinetically independent objects as shown on left panel marked with letter A (Fig. 10). Sedlák's model allows one to rationally discuss consequences of mechanical impact on the structure of supramers during filtration and under microfluidic conditions (see the respective sections).

Anisimov's model. The studies of the group of Anisimov^{35,36,43,45–48} were focused on fewer systems, mainly aqueous solutions of solutes such as tert-butanol or 3-methylpyridine that belong to the class of hydrotropes.^108,109 The molecules of hydrotopes are amphiphilic but too small to form micelles in aqueous solutions and usually exhibit only dynamic clustering in the water-rich region due to short-ranged (∼1 nm) and short-lived (10–50 ps) “micelle-like structural fluctuations”.⁴⁷ Stable mesoscale inhomogeneities (∼10² nm in size) were shown to “occur in aqueous solutions of nonionic hydrotropes only when the solution contains a third, more hydrophobic, component. Addition of a hydrophobe seems to stabilize the water–hydrotrope structural fluctuations, and leads to the formation of larger (mesoscopic) droplets. The structure of these mesoscopic droplets is such that they have a hydrophobe-rich core, surrounded by a hydrogen-bonded shell of water and hydrotrope molecules (Fig. 11). These droplets can be extremely long-lived, being stable for over a year”.⁴⁷ The phenomenon of formation of mesoscopic droplets in aqueous solutions of nonionic hydrotropes containing hydrophobes was termed mesoscale solubilisation.

Fig. 11 Anisimov's model. Schematic representation of mesoscale solubilization in aqueous solutions of hydrotropes containing a hydrophobe. The mesoscopic droplets have a hydrophobic core surrounded by a hydrogenbonded microemulsion-like hydrotrope–water shell. Reproduced from ref. 47.

The authors stress that the discovery of mesoscale solubilisation of hydrophobic compounds in water, which is intermediate between “true” molecular solubility and macroscopic phase separation, makes the traditional definition of solubility ambiguous”. “Moreover, the bulk equilibration may require an unrealistically long time, making the definition of thermodynamic equilibrium also ambiguous”.⁴⁷

Impurities present in reagents or solvents may trigger formation of supramers with various chemical properties

The critical role of hydrophobic (or solvatophobic in case of non-aqueous solutions) impurities present in reagents (solute^{35,36,41–43,45,47,48} or solvent⁷¹) used for the preparation of solutions or solubilized from plastic labware (e.g., polypropylene syringes)⁷¹ in formation and stabilization of mesoscale inhomogeneities was emphasized in many publications. For example, addition of minute amounts of hydrophobic additives (e.g., 0.0053% octadecane) to specially purified tert-butanol and subsequent mixing of the latter with water was demonstrated to promote (in dose-dependent manner) formation of the large structures solution detectable by DLS and NTA (Fig. 4).⁴¹

This pretty low level of impurities is naturally expected in most “research-grade compounds of p.a. purity and even after special in-lab purification procedures”.⁴¹ This means that almost any chemical of a real purity is capable of forming large structures in solutions (under favourable conditions) as it always does contain at least trace amounts of solvatophobic impurities (hydrophobic in case of solutions in water). This claim remains valid irrespective of the outcome of current debate whether absolutely “pure” compounds are “genuinely” capable of forming mesoscale heterogeneities in solutions.

This conclusion may have important consequences for chemistry as a whole as it implies that a particular compound may exist in solution (in some solvent) as an array of supramolecular species (solute clusters that may comprise solvent molecules too as discussed above) differing in their size and structure depending on conditions (e.g., solvent, concentration, temperature, presence of other compounds, etc.). These quasi-isomeric supramolecular species (a term “supramers”, i.e., supramolecular isomers, has been coined^77,110,111 to describe these possibly diverse structures) are expected to have different chemical properties as, for example, solute molecules located within the cluster core (assuming validity of Sedlák's model) and on its periphery (surface) obviously have different accessibility for other reagents, which is directly linked to the looseness of the cluster determined by its fractal dimension.¹¹² This issue of possibility of multiple patterns of chemical reactivity of the same chemical compound will be discussed in more detail in the remaining part of this review.

Chemical reactions may involve species more complex than just molecules of reagents

The idea that aggregates of reagent molecules are involved in actual chemical reaction is not new

These unusual features of solutions, which have been revealed only recently and are described in the previous sections of this review, imply that for understanding chemical reactivity in solutions one should consider the possibility of presence of various supramolecular species, including mesoscale inhomogeneities (solution domains, solute clusters, solute aggregates, supramers), along with non-aggregated (“free”) solute molecules in real solutions. These solute aggregates may differ dramatically in their chemical properties from those of “isolated” molecules, the latter being commonly considered¹ as the genuine chemical properties of the corresponding compound.

In fact, the idea that aggregates of reagent molecules are involved in actual chemical reaction is not new. Indeed, molecules in such aggregates may be linked with each other by a variety of known intermolecular forces.¹¹³ Mentioning of formation of dimers of molecules of reagents, which exhibit altered chemical behaviour, is regularly published in the chemical literature. The main issue preventing general recognition of the possibility of involvement of larger aggregates in chemical reactions seems to be the expected short life-time of these species with a typical estimate of 10–50 ps as was mentioned above.⁴⁷

However, there is a possibility of more complex and unusual type of aggregation of reagents that is directly related to the long-lived mesospecies in solutions as discussed in the previous sections. These novel views on aggregation of reagents in solution are apparently unknown to most of researchers performing chemical reactions. For this reason it is quite natural that quite different models were invoked when interpreting the results obtained, which are discussed below.

Various unusual experimental findings forced researches to assume that the situation in reaction solutions is much more complex than it is usually believed. In this section several known approaches to chemical reactions will be briefly discussed which explicitly suppose that species much more complex than isolated molecules (or just dimers or trimers) are involved in the reaction. As one can envision, analysis of numerical data, especially those that do not fit an expected traditional model, may give insight into peculiar details of a chemical reaction and solution structure which may otherwise escape attention. For this reason it is unsurprising that new approaches have mainly been suggested by the researchers involved in studies of chemical kinetics and stereoselectivity issues.

Known examples of influence of supramolecular aggregation in solution on chemical reactivity and selectivity

Alcohol association may change kinetics. In order to interpret unusual concentration dependencies of reaction rates of the reaction (at 80–150 °C) of ethylene oxide with various alcohols (ranging from methanol to dodecanol)^114–118 dissolved in dodecane, p-xylene or 1,4-dioxane (initial alcohol concentration C₀ = 1–10 mol L⁻¹) Stul et al. assumed that large linear alcohol oligomers formed in these solutions are the real kinetically independent species in which only terminal hydroxyl groups, not involved in intermolecular hydrogen bonding, participate in the reaction thus making its rate linearly proportional to the concentration of the n-mer. By fitting experimentally observed reaction rates to the model they managed to calculate the average degree of association (n = 8–17) of the oligomers formed under different conditions. It is important that these estimates of average degree of association correlated with data obtained independently by completely different experimental and theoretical methods.^94–96

Changes in supramolecular structure in aqueous solutions of nitric acid and acetone determine oxidation kinetics. Kinetic characteristics for the initial stages of acetone oxidation by aqueous HNO₃ were reinvestigated using specially purified nitric acid and found to be substantially different from those obtained with commercially available nitric acid. Using a combination of high-precision ¹⁷O and ¹H NMR spectroscopy and dynamic calorimetry Lagodzinskaya et al. revealed unexpected non-monotonous concentration dependences of the initial rate of acetone oxidation and various NMR characteristics (chemical shifts and linewidths of signals of the species present) of the reaction solutions. The data obtained were best explained by assuming changes in aggregation of acetone, nitric acid and water into nano-sized supramolecular complexes of various structures (Fig. 12) that strikingly resemble the Sedlák's model (Fig. 10).^119,120

Fig. 12 Aggregation of nitric acid and water into nano-sized supramolecular complexes. Schematic image of the gaseous clusters of HNO₃·7H₂O (a) and their possible association in the liquid by filling vacancies to form hydrogen bonds shown by green; side view (b), ball, view from above, the scale is decreased (c). Reprinted from ref. 120 with kind permission from Springer Science and Business Media. Copyright© 2013 Springer Science+Business Media, Inc.

Pre-association of reactants modulate reactivity. Analysis of unusual concentration dependences of initial reaction rate and reaction outcome of alkylation of various tertiary amines with ethylene chlorohydrin in aqueous solutions, accompanied by viscosimetry data for model systems, allowed Kazantsev et al. to link these effects to “pre-reaction association involving reagents and products”.¹²¹ The authors revealed the existence of “favourable” and “unfavourable” concentration regions where different associates are formed and the reaction is promoted or retarded, respectively. The idea that reagents may form aggregates before the actual chemical reaction is very fruitful as it will be seen in subsequent sections of this review (see the forthcoming section on chemical properties of supramers). This concept was invoked, in combination with viscosimetry and NMR spectroscopy data, for rational explanation of spontaneous (co)polymerization of (meth)acrylamide and its derivatives in concentrated aqueous solutions, which is thought to proceed within supramolecular associates formed by acrylic monomers.^122–126

Association of reagents to “flickering” H-bonded pseudo-polymers determine reaction order. A series of nucleophilic addition reactions with known mechanism (e.g., reactions of alcohols with isocyanates) are featured by a reaction order (with respect to nucleophile) that may vary considerably for the same reaction depending on reaction conditions. In attempts aiming at understanding this unusual kinetics Tiger et al.^127–137 have been developing an original concept which is now supported by extensive experimental and computational studies. They hypothesised that experimentally determined concentration dependencies of reaction rate constants (apparent reaction order) in associated solutions are not directly related to the reaction mechanism but rather reflect the solution structure. Their studies demonstrated that a “critical” concentration C_cr exists, above which the reaction solutions are microheterogeneous (for aliphatic alcohols C_cr ∼ 0.1–1 mol L⁻¹) since the alcohol molecules form hydrogen-bonded polymeric clusters with fractal structure. According to the authors, there are analogies in the structure, conformation and behavior of linear-chain associates of alcohols formed via hydrogen bonding and classic flexible-chain polymers in solutions. “In the same reaction, the reaction order with respect to the alcohol may differ depending on the ability” of the solvent (good, poor and θ solvents),¹³¹ additive,¹³⁴ or temperature¹³⁴ to stabilize the polymer-like structure or change in its conformation (similar to coil–globule transition for polymers) in reaction solution. Using scaling concepts for polymer solutions,^112,138 the authors demonstrated that the reaction rate constant is determined by the solution structure and depends on the concentration of clusters according to the power law: k ∼ (C/C_cr)^γ. The exponent gamma (γ) of this power law corresponds to the observed kinetic order of the reaction with respect to the concentration of alcohol belonging to the clusters. Its value is determined by the accessible surface of the clusters and depends on their fractal dimension,^135–137 which correlates with the looseness of the cluster.

Since the average hydrogen bond lifetime is known¹³⁹ to be ∼1 to 20 ps, the authors were very concerned with the lifetime of these hydrogen-bonded pseudo-polymers and assumed that these polymers have dynamic nature and the hydrogen bonds in the polymers are flickering (making and breaking again like in fluctuating network of flickering hydrogen bonds in water) but the whole cluster remains linked together and behave as one polymeric “molecule” on a time-scale large enough for it to react as an individual object. This problem now seems to be obviated after the existence of long-lived mesoscale inhomogeneities in solutions was established as discussed in the previous sections of this review. In fact, the Tiger's theory is well correlated with the Sedlák's model for the solution domains and it not unlikely that it is the solution domains that are reacting in systems studied by Tiger et al.

Distinct solute–solvent clusters are the real reactive species in solution. Stereoselectivity is a major topic in organic synthesis. Temperature dependency of stereoselectivity is commonly analysed in terms of modified Eyring eqn (1), which relates temperature dependence of the ratio of overall reaction rate constants (k and k′) leading to different facial stereoisomers, which for kinetically controlled reactions is equal to the ratio of stereoisomers, to the differences of activation enthalpies ΔΔH^# and entropies ΔΔS^# between the two distinct reaction pathways.

ln(k/k′) = (ΔΔS^#/R) − (ΔΔH^#/R)(1/T) (1)

Basing on extensive experimental studies,^140–153 which have been reviewed,¹⁴⁰ Cainelli et al. analysed the influence of variety of solvents (aliphatic and aromatic hydrocarbons, halohydrocarbons, ethers) and their mixtures on temperature dependences of the ratio of stereoisomers formed in many types of stereoselective reactions (nucleophilic additions, cycloadditions, photochemical and enzymatic reactions). Eyring plots of enantiomeric (or diastereomeric) ratios were found to be non-linear in many cases, two or more linear segments being separated by “inversion temperature (T_inv)” (Fig. 13). This critical temperature separates temperature intervals where activation parameters of the reaction are fundamentally different. The authors emphasize that the existence of T_inv “does not imply any change in the rate-determining step or in the reaction mechanism”. According to their hypothesis, “T_inv represents the interconversion temperature between two” different types of solute–solvent clusters. “These two dynamic solvation clusters behave like two different molecules, with different thermodynamic parameters and therefore different stereoselectivities”.¹⁴⁰ This view is supported by numerous temperature dependencies of various spectroscopic properties (present in NMR, circular dichroism and ultraviolet spectra) which exhibit discontinuities in the respective plots vs. temperature exactly at T_inv (Fig. 14 and 15) These observations suggest that “inversion temperature” is a feature of a solution rather than that of the reaction (Fig. 15).

Fig. 13 A critical temperature, “inversion temperature (T_inv)”, separates temperature intervals where activation parameters of the reaction are fundamentally different. Adapted from ref. 140.

Fig. 14 Detection of critical temperatures (T_NMR) by NMR. Non-linear plots of ¹³C NMR chemical shift of C=O vs. temperature for O-(TBS)-lactal in two different deuterated solvents. Reproduced from ref. 140.

Fig. 15 Critical temperature is a feature of a solution (T_NMR, T_CD, T_UV) rather than that of the reaction (T_inv). Temperature-dependent data for O-(TBS)-lactal in n-dodecane: (a) ¹³C NMR chemical shift of C=O, (b) CD ellipticity, (c) anti/syn ratio upon n-BuLi addition and (d) UV absorbance. Reproduced from ref. 140.

The most impressive is the demonstration of the fact that critical temperature of the reaction (“inversion temperature”, T_inv) does not depend on the type of a chiral catalyst, the nature of which is not critical.^140,149 All effects are valid both for organocatalysis and enzymatic catalysis. The critical temperature of the reaction (T_inv) is influenced mostly by the solvent and temperature. This means that it is not critical what reaction is performed with a particular solute and what catalyst is used. The only important issue is what reactive solute-containing species, differing in their “structure and reactivity”, are present in the solution, which is determined by solute–solvent combination and temperature. Careful analysis of their own and literature data led the authors to the conclusion that “distinct solute–solvent clusters” “are the real reactive species in solution” (Fig. 16).¹⁴⁰ In fact, the authors are claiming that unusually stable solvates exist in solutions and that the properties of these species determine the reaction outcome.

Fig. 16 Critical temperature (T_inv) in an Eyring plot as the interconversion temperature between two solute–solvent clusters. Reproduced from ref. 140.

In terms of the supramer approach (see below the respective section) these “solute–solvent clusters” represent a subclass of supramers. Since Cainelli et al.¹⁴⁰ were mainly interested in studying solvent effects on stereoselectivity the possibility of solute–solute interactions in solutions was not discussed in their publications. One can easily see that their results do not exclude the possibility of formation of supramers containing several solute molecules and are fully compatible with supramer approach.

Supramer approach. An important area of modern synthetic organic chemistry deals with the preparation of oligosaccharide chains of natural glycoconjugates (and their analogues) involved in a wide range of biological phenomena ranging from cell–cell adhesion and mobility to oncogenesis and recognition by viruses and bacteria. Monosaccharide residues in oligosaccharides are linked via acetal (glycosidic) bonds which during assembly of an oligosaccharide must be created by a series of glycosylation reactions.^154–157 Although substantial progress has been achieved in this booming area,^158,159 including a much deeper understanding of mechanism of the chemical glycosylation,^160–164 poor predictability and reproducibility of results are still typical of the glycosylation reaction. In many cases, seemingly minor changes in the structures of the reactants or reaction conditions dramatically influence the yield and stereoselectivity of glycosylation. Especially notorious in this respect is the stereoselectivity of glycosylation with sialic acid derivatives (sialylation), which can sometimes vary considerably even upon repetitive glycosylations performed by the same person, not to mention the results for seemingly identical sialylations reported by different research groups. There has been a long-standing need for an approach to rationalize the outcome of a particular glycosylation experiment, which can be confusing.

An attempt of developing of such an approach, which was reviewed,¹¹¹ has recently been made by Kononov et al.^{111,165–169} They introduced a novel concept, a “supramer approach”,¹¹¹ which emphasizes the importance of supramolecular aggregation in the reaction mixture leading to formation of supramers (short of supramolecular isomers)¹¹⁰ of reagents, which are differently arranged supramolecular assemblies incorporating the solute (and solvent) molecules (see also the discussion below). According to this hypothesis, depending on the molecular structure and reaction conditions, molecules of reagents can form fundamentally different supramers, which can be distinguished by physical methods and differ in their chemical properties. The accessibility of the reaction centre in the supramers present would determine the apparent (macroscopic) reactivity and the outcome of a reaction – product yield and reaction (stereo/regio/chemo)-selectivity.

Using light scattering (SLS, DLS) and polarimetry Kononov et al. have recently presented evidence that Sedlák's solution domains and supramers are related objects (see also the section on polarimetry above) thus making formation of supramers related to the changes in solution structure.⁷⁷ These supramers comprising both solute and solvent molecules behave as individual objects, detected by DLS. This means that several distinct supramers, present in solution, may correspond to the same solute. The validity of this view on the solute in solutions may have enormous importance for better understanding of the results of chemical reactions performed in solutions. For example, seemingly minor changes in reaction conditions, which significantly modify the structure of supramers of the reacting solute, may lead to dramatic changes in the reaction outcome.^{111,140,165–169}

Using the supramer approach, new variables, which can modulate stereochemical outcome of glycosylation reaction, have been discovered. The previously unrecognized factors include (1) concentrations of reagents,^167,169 (2) presence of other compounds in the reaction mixture (including “non-reacting” additives or reaction products),^{165,167–169} and (3) time¹⁶⁸ of reaction. All these parameters may influence the structure of supramers formed by the molecules of reagents in the reaction solution as was demonstrated by IR-spectroscopy,^165,167,169 polarimetry^{77,93,167,169,170} and laser light scattering^77,169 on a series of representative examples. The changes in the structure of supramers, hence their reactivity, were shown to correlate with outcome of glycosylation influencing both the yield of glycosylation product and its anomeric ratio.

Using polarimetry (see above the use of polarimetry for characterisation of mesospecies) it was demonstrated that the dependence of structure of supramers on concentration exhibits discontinuities (critical points) and that different supramers influence reaction rate and selectivity differently implying that the manner of concentration dependence of stereoselectivity and the product yield for a given glycosylation reaction may vary as a function of the concentration range studied (Fig. 17).¹⁶⁹ Especially important is the demonstration (by polarimetry and DLS) of the fact that for a particular system the molecules of reacting glycosyl donor and glycosyl acceptor, when their concentration exceeds a certain threshold, do form hetero-supramers before the beginning of the reaction.¹⁶⁹ These mixed supramers exhibit chemical properties noticeably different from those of homo-supramers formed at lower concentrations (Fig. 18).

Fig. 17 Concentration dependence of yield and stereoselectivity of a glycosylation reaction (right panel) correlates with discontinuities of the concentration plot of specific optical rotation ([α]_D) of glycosyl donor (1) (left panel). Outcome of glycosylation changes dramatically in high concentration range where hetero-supramers {1 + 2} are formed. Vertical thick arrows indicate critical concentrations (50, 69 and 103 mmol L⁻¹). Shaded area marks the concentration range where hetero-supramers {1 + 2} exist. Adapted with permission from ref. 169. Copyright© 2012 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.

Fig. 18 Discovery of hetero-supramers. Optical rotation (α²⁸_D) of solutions of glycosyl donor (1), glycosyl acceptor (2) in MeCN and their 1 : 1 mixtures at different concentrations. Hydrodynamic radii (R) of light-scattering particles in MeCN in solutions of glycosyl donor (1), glycosyl acceptor (2) and their 1 : 1 mixtures at different concentrations. Shaded area marks the concentration range where hetero-supramers {1 + 2} exist. Full DLS data for the solutions with concentration 69 mmol L⁻¹) are also presented in the right lower corner. Adapted with permission from ref. 169. Copyright© 2012 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.

This finding that molecules of reagents can interact and form some type of “complex” before the actual chemical reaction step correlates with ideas of Kazantsev et al.¹²¹ about pre-association of reagents (see the respective section above) and is becoming increasingly popular in the carbohydrate field. However, although several publications emphasize hydrogen bond^171–174 or halogen bond¹⁷⁵ mediated interactions between the reagents prior to reaction, their authors are clearly stating that it is an interaction between two molecules that is important for the reaction outcome. The possibility that changes in solution structure related to formation of large supramolecular species may be involved was never mentioned. Since the outcome of these reactions was clearly dependent on concentration (in cases where the concentration was varied), there are grounds to believe that the systems studied in the mentioned publications may well involve large objects similar to supramers with altered chemical properties. Additional studies of these solutions by physical methods may clarify this issue.

The supramer approach was shown to be useful for explanation, prediction and discovery of a series of unexpected phenomena (like change of stereoselectivity during the course of glycosylation reaction¹⁶⁸ or synergistic activation^165,167 of a glycosyl donor with low “intrinsic” reactivity by another highly reactive glycosyl donor) and allowed the development of highly efficient and stereoselective glycosylation reactions that lead to formation of Neu-(α-2-3)-Gal and Neu-(α-2-6)-Gal linkages found in many natural sialo-oligosaccharides of biological and medical significance.

The results presented in this section clearly demonstrate that the same chemical compound may react according to different patterns depending on the structure of the reaction solution and particularly on the type and structure of the supramers of reagents present suggesting that chemical properties are the feature of a supramer rather than that of a molecule.^111,169 At present, Kononov et al. deliberately do not make distinction between the supramers comprising only solute molecules and those containing solvent molecules too (like Cainelli's solvation clusters¹⁴⁰ and Sedlák's solution domains^37–39) since these two situations are not easily discriminated. Kononov et al. propose the use of the term “supramer” to describe all types of these differently arranged supramolecular entities incorporating solute molecules which may react differently. Such an approach allows consistent treatment of a variety of literature data from the unified point of view.

Microfluidic mystery unveiled?

After considering current knowledge of solution structure at the mesoscale and several approaches to understanding chemical reactivity and selectivity, which rely on complexity of reaction solutions, it is possible to discuss the issues related to microfluidic effect,^8,27–29 which is a phenomenon of altered chemical properties of compound involved in reactions under microfluidic conditions as compared to batch reactions of the same compound in a flask (see the next section as well as the Introduction section).

Basics of micro-flow chemistry

Organic reactions are traditionally performed in flasks (or other reactors) which are charged with reagents batch-wise (in portions). In continuous flow chemistry, a chemical reaction is carried out with a continuous supply of reagents. The actual reaction occurs when continuously flowing streams of reagents (or their solutions) are mixed together (using a simple T-shaped union or a special mixer) in a flow-through reactor (which might incorporate a mixer). Usually small devices with diameter of flow passages <1 mm are called micromixers and microreactors, hence micro-flow chemistry. The reaction proceeds within a microreactor and in capillary tubing that exits the reactor. At the certain moment a third (quenching) flow is usually introduced to stop the reaction. The flow rate and the volume of the microreactor (or micromixer) with exiting capillary tubing determines the time of contact of reagents (called the residence time) which is equal to time of reaction. Flow chemistry is a well-established technique for use at a large scale (e.g., in industry) when manufacturing large quantities of products. However, the term has been coined only recently for flow applications on a laboratory scale where the terms micro-flow chemistry, microfluidic chemistry or, more general (not limited to chemistry only), microfluidics are widely used.^4–26

Known explanations of microfluidic effect

The fundamental reasons of the modified reactivity pattern under microfluidic conditions are currently unknown and usually not mentioned. Explanations suggesting this new reactivity to originate either from “efficient mixing, precise temperature control and the easy handling of the reactive intermediates by controlling their residence time”^8,27,28 or from “suppressing back mixing and precise control of temperature in a flow reactor set up”²⁹ do not seem to be entirely satisfactory since they do not leave any room for discussion of substantial changes in stereoselectivity observed^27,28 in other studies where the origin of microfluidic effect was also ascribed to “mixing artifacts in the flask apparatus”²⁸ absent under microfluidic conditions.

Although the latter idea²⁸ was not elaborated further it emphasizes an obvious yet fundamental difference in the mode by which the solutions of reagents are physically mixed in microfluidic and traditional batch reactions. The question can be now reformulated. What are these “artifacts” or what actually happens to solution structure when the reagents are mixed?

Rearrangement of supramers upon mixing – a possible reason of microfluidic effect

Using the Sedlák's model³⁷ for the solution domains (supramers, see the respective section above, Fig. 10) one can analyse this issue in detail. Let us imagine that there are two binary solutions of the reagents R1 and R2 in the same solvent (Fig. 19). One solution contains compound R1 (red) and another contains compound R2 (blue) as the solutes. In each solution the expected domains {R1} and {R2} composed of the molecules of the respective compounds are present. This situation is shown on the left panel of Fig. 19. What happens when these two solutions are mixed? The situation in the first moments after mixing is shown on the right panel of Fig. 19. Both types of domains are present in the solution. However, it is obvious that for the molecules R1 to react with molecules R2 they first should contact each other. It is also clear that reagent molecules inside domains {R1} and {R2} cannot do it. For this reason, “internal” molecules of reagents R1 and R2 cannot react with each other. The product P is formed only from the molecules which are located on the surface of domains or between them. This conclusion immediately suggests that in order to achieve high yields of the product P one should destroy domains (supramers) of reagents either completely (to molecules) or partially (to smaller supramers with larger surface hence reactivity) (Fig. 19).

Fig. 19 Reagent molecules inside domains {R1} and {R2} cannot react with each other. Efficient destruction of domains is required for all molecules of reagents R1 and R2 to react – a clue for increasing reactivity of reagents and achieving high yield of product P. Adapted with permission from ref. 37 (M. Sedlák, J. Phys. Chem. B, 2006, 110, 4329). Copyright (2006) American Chemical Society.

This is an opportune moment to recall that solution domains (and other mesospecies in solution) are in fact fragile objects^44,58 which can disintegrate partially or completely upon mechanical impact (see the respective section above). Different ways of mixing create different level of shear stress and may destroy domains differently and to a different extent. It is this feature of solution that causes the results of reaction in the flask or using different mixers^28,176 to differ so much depending on the mode of mixing.

The size of supramers (domains) is known to increase in more dilute solutions (see the respective section above) due to incorporation of additional solvent molecules into the domain (see also the section above devoted to Cainelli's solvation clusters¹⁴⁰). This means that reactions in dilute solutions should proceed slower than in more concentrated solutions since in dilute solutions the solute molecules are buried within huge solution domains composed mainly of solvent molecules, which makes them less accessible for the reaction partner. This qualitative conclusion seems to correlate with the established “law of mass action” initially suggested by Guldberg and Waage in 1864–1879 and based on entirely different principles. However, according to the supramer approach this tendency of slower reactions in dilute solutions may be overridden (for the same concentration) by changing the mode of reagents mixing. More effective “mixing” (e.g., with special microflow mixers like those used by Fukase et al.^8,28) would create smaller supramers with increased reactivity hence faster overall reaction. Preliminary results obtained in the author's laboratory¹⁷⁷ support this prediction.

The situation becomes even more complex if one considers that the solution domains (supramers) may react on their surfaces (see above the section on Tiger's theory^129–137 of reactivity of H-bonded pseudo-polymeric fractal clusters). The solute molecules located on the surface of a supramer inevitably have asymmetric environment thus creating conditions for preferential attack from one of the faces hence for stereoselectivity. The peculiar features of the supramer surface (supramer “structure”), characterised by its fractal dimension, would determine the degree of the achievable stereoselectivity. One can even speculate that stereoselectivity of reaction is determined to a great extent by “asymmetry” of surface of supramers of reagents. See also the section above devoted to stereoselectivity in reactions involving Cainelli's solvation clusters.¹⁴⁰

Disaggregation of supramers would create smaller species with potentially changed fractal dimension featured by altered asymmetric environment around the solute molecules located on its surface. This would modify stereoselectivity of the reaction involving these species. So one should expect modulation of stereoselectivity upon changes in the mode of reagents mixing. Experiments on glycosylation with sialic acid derivatives support this prediction (Fig. 20). While a reaction in a flask results in formation of disaccharide in low yield (∼50%) and selectivity (α : β ∼ 3 : 1), the same reaction between the same reagents under microfluidic conditions is almost quantitative (80–95%) and nearly stereospecific (α : β > 99 : 1).²⁸ It is interesting that it is not critical to finish the reaction in flow. Important is only the mixing step, after which the mixture is allowed to react in a flask, as shown in Fig. 20, giving comparable yield (89%) and stereoselectivity (α : β = 94 : 6) as under “true” microfluidic conditions.

Fig. 20 Molecular structure of glycosyl donor was found to be less essential for the outcome of glycosylation than the mode of reagents mixing. Adapted from ref. 28.

In other words, one can hypothesize that the miraculous “microfluidic effect” may be related to differences in disaggregation or even just rearrangement of supramers upon mixing under different conditions. Preliminary results obtained in the author's laboratory¹⁷⁷ support this conclusion.

Conclusions

Recent studies revealed, quite unexpectedly, that commonly used solutions are not homogeneous as it is usually assumed. Long-lived mesoscale inhomogeneities, which are large supramolecular aggregates comprising numerous solute and solvent molecules, were found in a wide range of solutions.

The results obtained suggest that a solute, depending on concentration, solvent, temperature and the presence of other compounds including impurities, may exist in solutions as a variety of supramolecular species (supramers) differing in size and structure, hence physical and chemical properties. Changes in solute concentration influence structure of the corresponding supramers in a step-wise manner. The concentration ranges, where supramers of similar structures hence chemical properties exist, are separated by critical concentrations from other concentration ranges, where differently arranged supramers featured by altered chemical properties (reactivity, selectivity) are formed. Similarly, critical temperatures accompany rearrangements of supramers induced by changes in temperature.

Research on chemical reactions under microfluidic conditions and some other reactions performed in batch-wise mode revealed that the same compound involved in the same chemical reaction performed under slightly different conditions may exhibit a significantly altered chemical reactivity pattern (i.e., different chemical properties).

These two unprecedented phenomena – inhomogeneity of solutions and multiple reactivity patterns of a single chemical compound – together may induce a paradigm shift in understanding chemical reactivity in solutions, which in that case would no longer be related to molecular species but rather involve consideration of more complex solute-containing entities (supramers) and their interconversions in reaction solutions. In author's opinion, it is the further progress in understanding the structure of supramers formed by the solute molecules in solution that will be determining advances in chemical reactions performed in solutions.

Acknowledgements

This work was supported financially by the Russian Foundation for Basic Research (Projects 05-03-32579, 08-03-00839, 11-03-00918, 13-03-00666).

Notes and references

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Footnote

† Although for the sake of simplicity the discussion is intentionally limited to organic chemistry only, the conclusions made in this review may well be applicable in other areas of chemistry.

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