Tautomerism E-Book
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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Covering the gap between basic textbooks and over-specialized scientific publications, this is the first reference available to describe this interdisciplinary topic for PhD students and scientists starting in the field. The result is an introductory description providing suitable practical examples of the basic methods used to study tautomeric processes, as well as the theories describing the tautomerism and proton transfer phenomena. It also includes different spectroscopic methods for examining tautomerism, such as UV-VIs, time-resolved fluorescence spectroscopy, and NMR spectroscopy, plus the theoretical and practical background information. With its excellent overview of the methods, theories and examples, this is the perfect guide for any scientist dealing with tautomeric compounds in a wider context.
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Seitenzahl: 697
Veröffentlichungsjahr: 2013
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Table of Contents
Related Titles
Title Page
Copyright
Dedication
Preface
References
List of Contributors
Chapter 1: Tautomerism: Introduction, History, and Recent Developments in Experimental and Theoretical Methods
1.1 The Definition and Scope of Tautomerism: Principles and Practicalities
1.2 Causes of Reversal in Tautomeric Form: Aromatic Resonance
1.3 Causes of Reversal in Tautomeric Form: Lone-Pair and Dipolar Repulsion
1.4 Causes of Reversal in Tautomeric Form: Selective Stabilization Through “Far” Intramolecular Hydrogen Bonding
1.5 Changes in Tautomeric Form Brought About by Electronegative Substituents
1.6 The Influence of Solvent on Tautomeric Form
1.7 Tautomeric Equilibrium: Historical Overview of an Analytical Problem
1.8 Short Historical Overview of Tautomerization Dynamics
1.9 Conclusions and Outlook
References
Chapter 2: Absorption UV–vis Spectroscopy and Chemometrics: From Qualitative Conclusions to Quantitative Analysis
2.1 Introduction
2.2 Quantitative Analysis of Tautomeric Equilibria
2.3 Analysis of Real Tautomeric Systems
2.4 Concluding Remarks
References
Chapter 3: Studies of Photoinduced NH Tautomerism by Stationary and Time-Resolved Fluorescence Techniques
3.1 Introduction
3.2 Photoinduced Proton/Hydrogen Atom Transfer
3.3 Fluorescence Techniques for Studying Tautomerism
3.4 Tautomerism in Bifunctional NH/N Azaaromatics
3.5 Ab initio and DFT Computational Methods
3.6 NH Tautomerism as a Tool in Biophysics
3.7 Concluding Remarks
Acknowledgment
References
Chapter 4: Femtosecond Pump–Probe Spectroscopy of Photoinduced Tautomerism
4.1 Introduction
4.2 Ultrafast Pump–Probe Spectroscopy
4.3 Dynamics from Pump–Probe Spectroscopy
4.4 Reaction Mechanism
4.5 Reaction-Path-Specific Wavepacket Dynamics in Double ESIPT
4.6 Internal Conversion
4.7 Summary and Conclusions
Acknowledgments
References
Chapter 5: NMR Spectroscopic Study of Tautomerism in Solution and in the Solid State
5.1 Introduction
5.2 Methodologies of NMR Spectroscopy to Study Tautomerism
5.3 Types of Tautomerism Studied by NMR Spectroscopy
5.4 Conclusions and Outlook
Acknowledgments
References
Chapter 6: Isotope Effects on Chemical Shifts as a Tool in the Study of Tautomeric Equilibria
6.1 Introduction
6.2 Experimental Requirements
6.3 Isotope Effects on Chemical Shifts
6.4 Secondary Equilibrium Isotope Effects on CS
6.5 Primary Isotope Effects
6.6 Solid State
6.7 Theoretical Calculations
6.8 Examples
6.9 Overview
References
Chapter 7: Tautomer-Selective Spectroscopy of Nucleobases, Isolated in the Gas Phase
7.1 Introduction
7.2 Techniques
7.3 Guanine
7.4 Adenine
7.5 Cytosine
7.6 Uracil and Thymine
7.7 Base Pairs
7.8 Outlook
Acknowledgments
References
Chapter 8: Direct Evidence of Solid-State Tautomerism by Diffraction Methods: Isomers, Equilibria, and Kinetics
8.1 Application of X-Ray Diffraction to Study Tautomerism
8.2 Examples of X-Ray Diffraction Analysis of Proton Transfer
8.3 Other Diffraction Methods Used to Study Proton Transfer Reactions
References
Chapter 9: Dynamics of Ground- and Excited-State Intramolecular Proton Transfer Reactions
9.1 Introduction
9.2 Transition State Theory
9.3 Two Examples of Tautomerization
9.4 The Role of the Solvent
9.5 Solvent Friction and Solvent Dynamics
9.6 The Solvent Coordinate: Basics
9.7 Polarization Fluctuations
9.8 The Solvent Coordinate: An Application
9.9 Electronic Rearrangement
9.10 The Rug that Ties the (Classical) Room Together
9.11 Quantum and Classical
9.12 Quantum Decay
9.13 Coupling Quantum and Classical Motion: A Simple Example
9.14 Nonlinear Optics
9.15 Femtochemistry
9.16 Concluding Remarks
References
Chapter 10: Force Field Treatment of Proton and Hydrogen Transfer in Molecular Systems
10.1 Introduction
10.2 Computational Approaches to Proton Transfer
10.3 Proton Transfer Reactions with MMPT
10.4 Applications of MMPT
10.5 Discussion and Outlook
Acknowledgments
References
Chapter 11: The Scope and Limitations of LSER in the Study of Tautomer Ratio
11.1 Introduction
11.2 The Taft–Kamlet LSER Methodology
11.3 LSER Case Histories in the Field of Tautomerism
11.4 Overview
Appendix 11.A: Earlier Approaches
References
Chapter 12: The “Basicity Method” for Estimating Tautomer Ratio: A Radical Re-appraisal
12.1 Introduction
12.2 Experimental Protocol
12.3 The Derivation of Correction Factors
12.4 Regularities Revealed by Correction Factors
12.5 Complicating Factors in the Use of the “Basicity Method”
12.6 Tautomeric Problems to Which the “Basicity Method” Is Inapplicable
12.7 Overview
References
Chapter 13: Quantum Chemical Calculation of Tautomeric Equilibria
13.1 Introduction
13.2 Computational Procedures
13.3 Solvent Effects
13.4 Applications of Quantum Chemical Methods to Tautomeric Equilibria
13.5 Concluding Remarks
References
Index
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Wiley-VCH Verlag GmbH, Weinheim
The Editor
Prof. Liudmil Antonov
Bulgarian Academy of Sciences
Inst. of Organic Chemistry
Acad. G. Bonchev str., bl. 9
1113 Sofia
Bulgaria
Cover
The cover picture presents schematically the 3-way tautomerism of the neuroprotective agent 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one: enolisation, ketonisation and switching from imine to enamine. In solution this compound exists always as a three component tautomeric mixture. More details are given in Section 11.3.3.
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This book is dedicated to the memory of Peter J. Taylor (1929—2012), without whose help, enthusiasm, and encouragement this book would not have been possible.
Preface
Tautomerism is a process of migration of an atom (elementotropism) or a functional group within the same organic molecule, leading to a change in its structural skeleton, electronic density distribution, and chemical properties. Consequently, tautomerism is a special case of structural isomerism, dynamic in nature, and potentially reversible [1]. The most common case includes migration of a hydrogen atom (proton), called prototropic tautomerism; also, examples for elementotropism including exchange of metal ions or metal-containing functional groups (metallotropism) or Cl (chlorotropism) can be found in the literature [2]. The possibility for transfer of various functional groups (methyl, acyl, aryl, substituted amino) has been described [2] as well.
This book is devoted to prototropic tautomerism. In spite of the discussions on when and by whom it was discovered, and in spite of the advances in scientific equipment and theoretical methodology, we have to admit that tautomerism and the proton transfer remain even now very challenging subjects of study. If we recall the words of one of the pioneers of tautomerism studies, L. Claisen, in 1896, “Es gibt Verbindungen, welche sowohl in der Form –C(OH)=C< wie in der Form –CO–CH< zu bestehen vermögen von der Natur der angelagerten Reste, von der Temperatur, bei den gelösten Substanzen auch von der Art des Lösungsmittels hängt es ab, welche von den beiden Formen die beständigere ist” [3], the obvious conclusion is quite simple – the most important observations were available that time, but the explanations are still pending. The unanswered questions and the increasing number of tautomeric or potentially tautomeric organic compounds lead, as seen from Figure 1, to a growing number of published scientific communications in this field. This research activity very clearly shows that tautomerism is of practical and fundamental interest in various branches of science. But, at the same time, the word “tautomerism” is only briefly mentioned in textbooks of organic chemistry.
Figure 1 Number of scientific papers related to tautomerism (as recognized by at least one of the words “tautomer,” “tautomeric,” or “tautomerism”) as a function of time.
Therefore, the aim of this book is to build a bridge between the basic knowledge about tautomerism, tautomeric compounds, and methods for their investigation, which other textbooks give, and the highly specialized scientific papers that describe the state of the art. This book creates an image of tautomerism using the viewpoints of professionals with recognized expertise in various theoretical and experimental methods [4]. Each chapter gives first an overview of the corresponding method and describes its applicability in the case of tautomeric systems. Then real examples follow, showing how this methodology could be practically used. The obvious conclusion to be made is that there is no universal method, and the best results can be obtained by combining various experimental and theoretical approaches. We do not pretend that this book covers all existing experimental methods and theoretical developments dealing with tautomerism, but we hope to develop this book in future with the help of the readers.
Finally, we would like to mention several books tracing the understanding of tautomerism and tautomeric compounds during the last century. In 1934, the first book on tautomerism, written by J. W. Baker, was published [5], describing the results and their interpretation at that time. A few year later, in 1938, the book of B. Eistert Tautomerie und Mesomerie: Gleichgewicht und “Resonanz” [6] clarified the features of tautomeric equilibrium systems. In 1976, a monograph entitled The Tautomerism of Heterocycles was issued as Supplement 1 to Advances in Heterocyclic Chemistry giving a detailed picture of tautomerism in heterocyclic compounds [7]. In 1988, the book Molecular Design of Tautomeric Compounds [8] provided a well-organized discussion of a large number of tautomeric transformations. In 2007, the current state of the art in proton transfer was summarized in Hydrogen Transfer Reactions [9], a multivolume work providing comprehensive, up-to-date reference on the theory, occurrence, and application of hydrogen transfer processes.
Tokyo-Berlin-Sofia
Liudmil Antonov
2011/2012
References
1. Müller, P. (1994) Glossary of terms used in physical organic chemistry. Pure Appl. Chem., 66, 1077–1184.
2. Alkorta, I., Goya, P., Elguero, J., and Singh, S.P. (2007) Natl. Acad. Sci. Lett., 30, 139–159.
3. Claisen, L. (1896) Annalen, 291, 25–137.
4. The recent review of J. Wirz about use of flash photolysis could be considered as a natural part of this book: Wirz, J. (2010) in Advances in Physical Organic Chemistry, vol. 44 (ed. J.P. Richard), Academic Press, New York, pp. 325–356.
5. Baker, J.W. (1934) Tautomerism, G. Routledge & Sons Ltd, London.
6. Eistert, B. (1938) Tautomerie und Mesomerie: Gleichgewicht und “Resonanz”, Enke, Stuttgart.
7. Elguero, J., Marzin, C., Katritzky, A.R., and Linda, P. (1976) The tautomerism of heterocycles, in Advances in Heterocyclic Chemistry (eds A.R. Katritzky and A.J. Boulton), Supplement 1, Academic Press, New York.
8. Minkin, V.I., Olekhnovich, L.P., and Zhdanov, Y.A. (1988) Molecular Design of Tautomeric Compounds, D. Reidel, Dordrecht.
9. Hynes, J.T., Klinman, J., Limbach, H. H., Schowen, R. L., eds. (2006) Hydrogen Transfer Reactions, vols. 1–4, Wiley-VCH Verlag GmbH, Weinheim.
List of Contributors
Chapter 1
Tautomerism: Introduction, History, and Recent Developments in Experimental and Theoretical Methods
Peter J. Taylor, Gert van der Zwan, and Liudmil Antonov
1.1 The Definition and Scope of Tautomerism: Principles and Practicalities
Prototropic tautomerism, defined by one of its early investigators as “the addition of a proton at one molecular site and its removal from another” [1], and hence clearly distinguished from ionization, is one of the most important phenomena in organic chemistry despite the relatively small proportion of molecules in which it can occur. There are several reasons for this. Enantiomers, or cis and trans isomers, possess a formulaic identity just as tautomers do but are difficult to interconvert and hence easy to isolate. Tautomers are different. Tautomers are the chameleons of chemistry, capable of changing by a simple change of phase from an apparently established structure to another (not perhaps until then suspected), and then back again when the original conditions are restored, and of doing this in an instant: intriguing, disconcerting, perhaps at times exasperating. And a change in structure means changes in properties also. A base may be replaced by an acid and vice versa, or more to the point perhaps, a proton acceptor group by a proton donor, as, for instance, carbonyl by hydroxyl. Hence, if the major tautomer has biological activity, the replacement of this structure by another may result in a total mismatch in terms of receptor binding or the partition coefficient. It therefore becomes vital, on the most elementary level, to know which tautomer is the major one, since not only the structure but also the chemical properties are bound up with this. This problem is compounded by another: there is no automatic guarantee that, if the great majority of known compounds in a given category exist chiefly as one tautomer, the next one to be investigated will follow their lead. Examples of this sort will be described below. Hence an understanding of the factors that give rise to this problem becomes more important as time goes by.
Except for proton transfers on and off carbon,1 whose rate depends on pH and can sometimes take weeks. Proton transfer in the course of tautomerization is typically a very fast process. The equilibrium between tautomers is dynamic.
1.1
where the equilibrium constant is given by
1.2
Since the sum of the forward and reverse rates () determines the measured rate, as indicated in Eq. (1.1), whichever is the faster will dominate the process. With the exception noted above, when and are similar in magnitude and rises toward the relative diffusion limit as the imbalance between them increases; that is, as or in Eq. (1. 2) is approached. At such speeds, there is simply no hope of “ freezing” the process, and worse, no way of isolating a minor tautomer, as on attempting isolation it would instantly be transformed into the major one. The classic way around this is to use the properties, for example, of “model compounds,” chosen that are as close electronically as possible to those of the minor tautomer. This is described in Chapter 12, along with certain pitfalls in their use which are often neglected. Another technique that can sometimes bypass the problem is to use linear solvation energy relationship (LSER) methods, which are described in some detail in Chapter 11. The reader is referred to both these chapters for further details.
On the other hand, the small differences in free energy between the components make them very useful. In biological systems, delicate and subtle control is needed for the organization of chains of reactions. Life is the controlled motion of electrons and protons. The thermodynamics and kinetics of electrons are to a large extent governed by redox centers, and the equally important motion of protons can be viewed as an extended series of tautomerization reactions. DNA is built from bases all of which have a number of different tautomers. There are even a few enzymes, called tautomerazes, that enable rapid tautomerization between keto and enol forms of molecules [3]. Tautomers are interesting for many reasons, technological as well as fundamental. Their optical properties make them suitable as signaling molecules in sensors, as they can rapidly switch between states. Many biologically important molecules have several tautomers. Adenine, for instance, an important moiety in DNA and adenosine triphosphate (ATP), comes in three varieties, the main one–according to some people–chosen by nature to avoid fluorescence. One of the more interesting and complicating properties is that tautomeric equilibria in the ground state are often vastly different from those in the excited states. In addition, tautomeric equilibria are easily shifted by the environment.
Tautomers are also the prime molecules for studying proton transfer. Initially this was thought to be an advantage: Lapworth and Hann [1], in one of the earlier kinetic studies of tautomerization, state:
Of the various types of isomeric change, that which involves a change of position of one hydrogen atom only, as in a simple desmotropic change, would, for various reasons, appear to be the most simple, and probably the most easy to investigate.
Of course, this was before the invention of quantum mechanics, and they could not have foreseen the enormous literature that proton transfer reactions would generate in the next century and the conceptual problems this seemingly simple reaction would engender. The fact that the proton is at the borderline between classical and quantum mechanics is another complicating factor, of which some of the issues will be explored in Chapter 9.
In the next few sections, we describe the influence of a number of parameters: aromatic resonance, lone-pair and dipolar repulsion, internal hydrogen bonding, electronegative substituents, and the surrounding solvent on the relative stability of tautomeric forms. The remainder of this chapter is devoted to a brief history of tautomeric equilibria and tautomer dynamics.
1.2 Causes of Reversal in Tautomeric Form: Aromatic Resonance
Change of aromaticity in a ring system influences the position of the equilibrium between tautomers. This may be the reason for the excited-state proton transfer reactions in ortho-hydroxybenzaldehyde derivatives, where the excited state loses aromaticity, but it is also evident in the ground state of a number of compounds.2
This can happen in a number of contexts but we present just one case. Figure 1.1 displays the effect on 1a, in which the enol 1b is a minor tautomer [5, 6] of inserting carbon–carbon double bonds to give 2 [7], thus allowing the ring to become aromatic in 2b, while the accompanying reversal in the energetics of the tautomers, at , is equivalent to kcal mol−1, that is, a value not far short of current estimates for the resonance energy of benzene.
Figure 1.1 Tautomerism in some alicyclic and aromatic ketones and amides.
Here, an important contrast is with 3 and 4, where an estimate for piperidine-2-one 3 is contrasted with the (corrected) value for 2-pyridone 4.3 In that case, the estimated rise in is only , leaving the latter's amide character reduced but intact. The explanation must lie in the conjugation present in 2-pyridone 4a itself, which, while less than the aromaticity of its iminol 4b, is sufficient for the purpose, in contrast to 2a which possesses no through conjugation at all. Katritzky and coworkers [8, 9] have drawn attention to the aromaticity still present in 2-pyridone and related compounds and have made attempts to quantify it.
1.3 Causes of Reversal in Tautomeric Form: Lone-Pair and Dipolar Repulsion
Figure 1.2 is a diagrammatic representation of the repulsion between two -acceptors (5), two -donors (7), and the compromise position (6) with one of each, which is always taken up except when, as can happen with linked equilibria, the overall result is a less favorable energetic position than before. Note (i) that lone-pair repulsion in 5 disappears on twisting one nitrogen atom through , as in azobenzene, but (ii) that bond angle does not appear to matter in 7 as far as present evidence goes [4]. Also note that NH is not the only -donor that can be involved; if one NH is replaced by an O, the effect is considerably greater, and S is also capable of causing dipolar repulsion when contiguous with NH, though its position in the “pecking order” is probably closer to NH than to O [4]. Finally, note that the effect of replacing one NH by NR is dependent on the electronic effect of R on N; while NH and NMe are roughly on the same level, NPh lies about half way between either and O in its overall effect [4].
Figure 1.2 Diagrammatic representation of lone-pair 5 and dipolar 7 repulsion.
Figure 1.3 (a) The most extreme examples known, 8 and 9, of for dipolar repulsion in related amides. (b) An unquantified case of dipolar repulsion, 10, set against a quantified case, 11, of lone-pair repulsion.
1.4 Causes of Reversal in Tautomeric Form: Selective Stabilization Through “Far” Intramolecular Hydrogen Bonding
Although a shift in the real tautomeric equilibrium can be achieved as a rule by changes in the environment and, as rule again, it is difficult to be done in controlled manner, there are some cases where controlled switching is possible through structural modifications that do not directly influence the tautomeric skeleton. This happens in 12 (Figure 1.4), where, compared to the parent compound 13, the intramolecular hydrogen bonding between the tautomeric OH group and the basic nitrogen from the side arm leads to the disappearance of the keto tautomer [12, 13]. The situation changes upon protonation (or complex formation) – the basic nitrogen is protonated and a new hydrogen bonding, this time between protonated sidearm and tautomeric carbonyl group, shifts the equilibrium toward the keto form 12H+. In this way, by changing pH (or salt concentration) of the solution, controlled shift in the position of the enol–keto equilibrium can be achieved. Unfortunately, the efficiency of the switching system crucially depends on tautomerism in the parent skeleton: it works in the case of the azonaphthols 13 and 14 [14] and the heterocyle 15 [15], but does not in azophenol 16 or azoanthranol 17, where the tautomeric equilibrium is strongly shifted a priori. The replacement of the side arm, as it is in 18 [16] and 19 [17], does not stabilize the enol tautomer because of keto dimer formation (18) or double hydrogen bonding stabilization of the keto tautomer (19).
Figure 1.4 Intramolecular hydrogen bonding with a side chain group.
1.5 Changes in Tautomeric Form Brought About by Electronegative Substituents
This problem, which is specially prominent in oxoheterocycles, is caused largely by the effect of electronegative substituents in engineering a switch from the oxo to the less polar hydroxyl tautomer. There is little good documentation on this subject in the literature so we have generated our own [4]. The type of equation we have tried, and which works well enough to be provisionally worth pursuing, typically takes the following form:
1.3
where is that of the parent oxoheterocycle, refers to that resulting from substitution, and lists the relevant -values for the substituent, of which there may be more than one. We have so far distinguished four situations, each with its own governing equation. Positions adjacent to NH are much more sensitive to substitution than any others, and two equations are required each with two terms, one for lactams (e.g., 2-pyridone) and the other for vinylogous amides (e.g., 4-pyridone):
1.4
1.5
where and are the so-called electrical effect substituent constants used in correlation analysis for the equilibrium constant [18]. Here, for 4-pyridones is derived from Taft's equation [19] for the values of 2-substituted pyridines, dominated by the term , while resulted from a trial-and-error approach which suggested that a similar but less extreme value should fit the corresponding equation for 6-substitution into its 2-hydroxy derivative. The term with its opposite sign monitors the partially cancelling effect of the 2-pyridone tautomer. The apparently universal use of here and elsewhere, and never , is at first sight surprising but may be due to the considerable reduction of resonance transmission in heterocycles relative to purely benzenoid structures. Only for one other position in 2-pyridone do we possess adequate data for both the NH and (as OMe) the OH tautomers, but these give values of and respectively, leading to for , which, rounded off to , also fits the scattered data for 3- and 5-substituted 2-pyridones and, very accurately, the 5-position of 4-pyrimidone [4]. On this suggestive, though fundamentally inadequate, evidence, we provisionally adopt Eq. (1.6) for all but one of the substituent positions in any monocyclic oxoheterocycle not covered by Eqs. (1.4) and (1.5):
1.6
1.7
The exception is 3(5)-substituted 4-pyridones, to which Eq. (1.7) applies. Katritzky and coworkers [20] have drawn attention to the extreme shallowness of this response, which could be due to the symmetrical positioning of between the O and N cations. If so, there may be other such positions in oxoheterocycles waiting to be discovered. The force of Eq. (1.7) is that even the nitro group should reduce the dominance of the oxo form by only .
Figure 1.5 contains calculations, above the compound number, of for in all those monocyclic oxoheterocycles of known parent which are seriously at risk of going over to the hydroxyl tautomer in aqueous solution – in any other solvent this will be more likely. The nitro group was chosen as the most electronegative of common aromatic substituents, but it should be noted that multiple substitutions can make the risk even greater. Particular attention should be drawn to perhalogenation, a very common feature among such molecules and likely to prove a particularly lethal one. Benzofusion, which leads to a considerable rise in 1.0 or 1.8 according to its position with respect to ring NH,5 will clearly reduce the risk, so no examples are considered. Also note that aminoheterocycles are not at risk at all, since these are less polar than their imino tautomers, and electronegative substituents can only increase their dominance.
Figure 1.5 For , monocyclic oxoheterocycles likely take up the hydroxyl form.
1.6 The Influence of Solvent on Tautomeric Form
Figure 1.6 Some effects of the structure and solvent on tautomer preference.
The other persistent source of trouble is hydrogen bonding in the solid state, which may not correspond to what happens in solution. Elvidge and Redman [24] studied the tautomerism of 28 and concluded that it exists as 28a, the same dominant tautomer as for the related “maleic hydrazide,” both in aqueous solution and the solid state. In fact, while this is true for the solid state, with a strong peak and a solitary strong , it is not true for aqueous solution, in which the UV spectrum of 28 much more closely resembles that of 30 than of 29 [24]. So why the difference? A likely reason is that, instead of the amide dimers that 28b might be expected to form in the solid state, 28a will form iminol dimers, which are generally much stronger.6 While this might not be sufficient to generate a tautomeric switch if the energy difference between 28a and 28b were great enough, in the present case the gap is probably small enough to allow it. We have encountered other cases [4] in which this situation probably occurs.
1.7 Tautomeric Equilibrium: Historical Overview of an Analytical Problem
It is difficult to trace when and how exactly tautomerism was discovered. In the first tautomeric book, written by Baker [25], the priority is given to Berzelius, who in 1832 used the term “metamerism” to explain reciprocal conversion of cyanic and cyanuric acid. In Ingold's [[26], Chapter 11] review on tautomerism, ethyl acetoacetate, discovered in 1863 by Geuther [27], is mentioned as the first tautomeric compound described (Figure 1.7).
Figure 1.7 Historically relevant compounds. The tautomeric structures are presented as they were in the original papers.
The real fact is that many compounds were discovered in the second half of the nineteenth century, whose properties and behavior were impossible to explain with the available concepts at that time in structural chemistry. Here we can mention some of them: preparation of -bromodiazoaminobenzene 31 in two ways (Griess, 1874, [28]); the interaction between sulfuric acid and thrimethylcarbinol giving two isomeric di-isobutylenes 32 and 33, that is, isomerizing through addition and elimination of water (Butlerov, 1877, [29]); attempts to isolate alcohols in which the hydroxyl group is attached directly to a double-bonded carbon atom as in 34, giving, however, always isomeric carbonyl compounds (Erlenmeyer, 1880, [30]); and ethyl malonate (Conrad and Buschoff, 1880, [31]).
In 1882, Baeyer and Oekonomides [32] found out that isatin 35 gives two isomeric (- and -) methyl derivatives. They explained this fact with pseudomerie [33] – the possibility of one compound to have more than one structure obtained in the process of interaction, which, being unstable, converts very fast to the stable configuration.
In 1884, Zincke and Bindewald [34] obtained the same orange dye by coupling benzenediazonium chloride with 1-naphthol and by condensing phenylhydrazine with 1,4-naphthoquinone. They supposed that a mobile equilibrium existed between two forms, namely azo (13b) and quinonehydrazone (13a), a phenomenon classified by them as ortisomerie.
Obviously, it was time for summarizing the results and formulating some rules in this business. This was done by Laar in 1885 [35, 36] with the paper “Ueber die Möglichkeit mehrerer Strukturformeln für dieselbe chemische Verbindung,” where the existing examples of compounds that combine properties of two isomers are discussed in terms of the uncertainty of the position of one hydrogen atom and a double bond. He defines these systems as triadic (HX–Y=Z and X=Y–ZH) and postulates that they cannot be separated experimentally, being two border cases of one intramolecular oscillation. The process was named tautomerie. As result, the question about the real existence of the isomers gave rise to two contradictory theories: pseudomerie/ortisomerie or tautomerie.
The dispute was in fact resolved in 1896 by Claisen [37], who isolated acetyldibenzoylmethane as two separate solid forms, each with different melting points and chemical properties (interaction with metallic salts). Claisen correctly diagnosed them as the enol and keto forms having the structures 36b and 36a, respectively. More important still was the observation that, if either the keto or the enol form was heated in a solvent such as alcohol, or fused in the absence of solvents, a mixture was obtained from which both the keto and enol forms could be isolated. As result of this discovery, the pseudomerie/ortisomerie theory about the real existence of the isomers was proven to be correct. Ironically, the term tautomerism came into use to describe the process. In some natural way, according to the early reviews [38–46], tautomerism was considered and it is still considered in most of the cases as an equilibrium7 between forms coexisting in solution,8 and was defined as “one of the most difficult subjects of experimental science.”
It is worth remarking here that the pioneers of tautomerism were not armed with some extraordinary equipment. They had to trust mainly their eyes and their abilities to reach conclusions based on a limited amount of experimental information, which, actually, was enough for them to correctly define the factors influencing tautomerism in solution: the chemical structure (main tautomeric skeleton and substituents) and the environment (solvents, temperature, acidity, salt additions).
The problem is that each of these factors brings two questions: how and to what extent the tautomeric equilibrium is affected. The first question is qualitative; it brings as answer a descriptive explanation of the effects or a relative description, comparing to other compounds. Such a study can be done (and it was in the beginning) even without equipment by looking for visual changes (color change, precipitation, etc.). In terms of molecular spectroscopy methods, which are traditionally used for stationary state study of tautomeric systems (UV–vis absorption, fluorescence, IR, NMR), it means change in the registered instrumental signal.
The second question is quantitative. Its answer requires the values of the equilibrium constants (and related parameters) to be estimated in the terms of analytical chemistry. Following this, the concept for quantitative instrumental analysis postulates that the individual responses of the components of a mixture must be previously measured, that is, be known. However, taking into account that even if the individual tautomers are isolated in the solid state, in solution they always convert to a mixture, and such a requirement cannot be easily fulfilled. This contradiction has left a mark on the studies of tautomeric systems even today. Many compounds have been studied, but the conclusions are approximate and do not allow exact treatment of environmental effects and structure–tautomeric property relations. Of course, there have been attempts to mimic instrumental responses of individual tautomers by using model fixed compounds, where the movable proton is replaced by a methyl group, or by using compounds whose structure approximates the structure of the tautomers under investigation. As described in Chapters 2, 5, and 12, these approaches work reasonably well in some limited cases, but they always remain semiquantitative, because there is no physical ground for full correspondence between instrumental signals (as both the shape and intensity) of the model and of real tautomers.
In the first, “descriptive,” period of tautomeric studies, UV–vis, IR, and NMR spectroscopy, which are considered in Chapters 2–6, became the basic experimental tools. To trace the development, it is worth mentioning the first review devoted to absorption spectroscopy (from the UV to the IR region) in organic chemistry and particularly in elucidating structures of tautomeric compounds, written by Dobbie et al. in 1921 [51]. According to this review, the first study using absorption spectroscopy was performed by Hartley and Dobbie [52] in 1899, who proved the constitution of isatin and other tautomeric compounds by comparison of their absorption curves with those of their nitrogen and oxygen methyl derivatives. In 1908, von Liebig [53] studied the fluorescence of organic dyes, some of which are tautomeric. In 1931, Raman effect was discussed in relation to the tautomerism of acetoacetic ester by Dadieu and Kohlrausch [54]. According to Kol'tsov and Kheifets [55], the first study in which NMR was employed to investigate tautomerism was published in 1953 [56]. Although mass spectrometry is not related to solution, we have to recognize the first attempts (in 1967) devoted to its application in the structural study of tautomeric compounds [57].
As seen from the publication trend shown in the Preface, the number of scientific articles dealing with tautomeric compounds boomed after World War II. The main reason, along with the rapid developments in organic chemistry, was the commercialization of scientific equipment, which allowed reproducible spectral investigations to be performed on accessible, user-friendly equipment. In addition, the development of electronics allowed digitalization, storage, and processing of experimental data. It was a time of transition and hope in the 1960s and 1970s, when the traditional spectral charts, containing beautiful pictures of shifting a tautomeric equilibrium by changing factors influencing it, became spectral files, ready for processing. The “quantitative” phase of tautomeric research commenced with the development of chemometric methods to obtain analytical signals of the individual tautomers in a mixture even though these are never present in their pure form [58, 59]. Availability of this information makes it possible to obtain thermodynamic and kinetic parameters needed for an exact description of the environmental effects and defining the structure-tautomeric property relations needed for modeling tautomeric processes. The quantitative analysis of tautomeric systems is discussed in Chapters 2 and 5, because UV–vis and NMR spectroscopies are the major experimental tools in this respect.
However, in the end, we have to pay attention to the first chemometric work in 1973 by Metzler and collaborators [60, 61], who studied strictly quantitatively the two-component tautomeric equilibrium between the neutral form 37b and the dipolar ion 37a of 3-hydroxypyridine in water and water/methanol binary mixtures at various temperatures by using band-shape analysis. The same approach was applied in the case of the three-component tautomeric system 5-deoxypyridoxamine 38, showing that the tautomeric equilibrium is not an analytical problem anymore.
1.8 Short Historical Overview of Tautomerization Dynamics
Elucidation of reaction mechanisms requires the study of reaction kinetics. Investigation of equilibria as a function of temperature can give insight into the differences in free energy, enthalpy, and entropy between tautomers but, in order to clarify the way tautomers are converted into one another, detailed information about the dynamics of transformation is needed. Tautomers present a particular difficulty, both for equilibrium as well as dynamic studies, in that it is impossible to separate them and create a good starting point for the study of kinetics. The study of the dynamics of prototropic tautomerization reactions therefore fall in two classes. Before the 1970s, only a few papers were published, and these dealt mainly with acid- or base-catalyzed tautomerization reactions where the conditions could be chosen to bring the rates into the measurable range. Very few papers dealt directly with intramolecular ground-state proton transfer reactions. That changed in the second half of the twentieth-century. In the late 1950s, Weller's [62–64] experiments on salicylic acid led him to propose an intramolecular excited state proton transfer reaction (ESIPT), and the advent of fast pulsed (pico and femtosecond) lasers later that century made it possible to study this directly. This resulted in numerous papers on ESIPT on a large variety of compounds, as well as numerous theoretical studies.
The study of prototropic tautomerization is intimately related to the study of proton transfer reactions. The study of the dynamics of proton transfer is as old as the study of reaction kinetics itself. Indeed, the first reactions studied, that is, the inversion of sugar by Wilhelmy in 1850 [65], involves a proton transfer as the elementary step in the reaction. In the first studies on the dynamics of tautomerization, primarily keto–enol tautomerization in acetone-like compounds were studied, which is a slow process involving a number of reaction steps of which the acid catalyzed keto–enol conversion was taken as the rate determining one [66]. In the past century, since 1910, nearly 2000 papers have been published on the kinetics of tautomerization, and in the first 60 years most of those were devoted to the ground-state reactions of the keto–enol type involving a C atom. Until the mid-1950s, only a handful of papers can be found; this was obviously due to experimental limitations. Two things are needed: a method to start the reaction, and a method to follow it. In Dawson's experiments [66], the rate could be influenced by the amount of acid present, and the reaction could be followed because the enol produced reacts rapidly with iodine, and the disappearance of iodine due to formation of iodoacetone can easily be followed using optical spectroscopy. Reaction times were on the order of hours to days. And the situation almost remained like that until the 1960s. Several faster techniques became available around that time.
One of the topics much under discussion in the early years of kinetics research was the nature of the two tautomeric forms, or where the proton actually resided. Laar [35] had proposed a so-called oscillatory model, where a hydrogen atom vibrates continuously between the two possible positions. Other early observations include dielectric effects: the polarity of the solvent could help release a proton from one position, thus making a transfer possible [1]. Although a tautomerization reaction is not an ionization (Section 2.1), an ionization step does play a crucial role, and may in many cases be the rate-determining step.
Apart from NMR, in which the equilibrium fluctuations of a reaction can be monitored in order to make an estimate of the reaction rates, until the mid-1970s basically three methods were available to measure direct proton transfer. The first is the temperature jump technique, where a rapid (of the order of microseconds) jump in temperature shifts the equilibrium, and the decay of the system to this new equilibrium can be followed with optical techniques. This technique was again mainly used in tautomerizations involving an ionization step [67], but in the mid-1970s the technique was also used for intramolecular studies [68, 69] in order to get insight into the question of whether ground-state proton transfer was as rapid as the proton transfers suggested in the excited state, which at that time were thought to be faster than 1 ns. These experiments did not give conclusive evidence of a direct intramolecular proton transfer step, although for the fitting of the data it was necessary to take the possibility into account, as was done by Ahrens [70] in an earlier paper who suggested the, rather unlikely, possibility shown in Figure 1.8, which is reminiscent of Laar's ideas [35].
Figure 1.8 Ahrens's proposition for intramolecular proton transfer in 5-deoxypyridoxal. It is still considered a two-step process, where a collision first is needed to produce the intermediate.
A second method for studying tautomerization rates makes use of the fact that in vapor or in different solvents the equilibrium constant between the tautomers can be vastly different. Watarai et al. [71–74] studied the tautomerization rate of acetelacetone (Figure 1.9) in a variety of solvents and solvent mixtures. Their method makes use of the fact that, in the vapor, the enol content is 93.3%, whereas in water the enol fraction is only 0.15. The reaction can be followed by UV spectroscopy, since the enol has an absorptivity at 273 nm, whereas the keto form barely absorbs at all (). The reaction is initiated by injecting the vapor into the solvent.
Figure 1.9 (a) Enol and (b) diketo form of acetylacetone. In the vapour, the enol form is dominant, and in water the diketo form.
The third type of experiment is photolysis, where the product is one of a tautomer pair [2, 7, 75]. Again, almost all reactions studied are keto–enol tautomerizations where the proton transfer is not direct but in a number of steps via the solvent. Since the first step is often an ionization (proton transfer to solvent molecule), which is thought to be diffusion-controlled [67], it does give some insight into proton transfer reactions, but exact elucidation is hard, since often there are numerous possibilities for reaction mechanisms and roles of solvent molecules and internal vibrations [76, 77]. In view of the lack of understanding of proton transfer reactions, it would be much better to have a simpler and more direct way to initiate intramolecular proton transfer. This possibility is offered by looking at intramolecular proton transfer reactions in the excited state, which can be initiated much faster and followed on a much shorter timescale than ground-state reactions.
The vast majority of papers devoted to tautomerization dynamics deal with ESIPT reactions. Since Weller's suggestion that the large Stokes shift he measured for salicylic acid fluorescence was caused by rapid proton transfer in the excited state [62], and the development of techniques to study this on a femtosecond timescale, the field has blossomed. Most of the 2000 papers on tautomerization dynamics is on ESIPT, from both an experimental and a theoretical point of view. The number of compounds exhibiting ESIPT is far too large to discuss here. It ranges from molecules as simple as malonaldehyde to systems as complicated as 3-hydroxyflavone or 2-(2′-hydroxyphenyl)benzothiazole. In particular, substituted salicylic acids and ortho-hydroxybenzaldehydes have attracted much attention from both experimentalists and theoreticians. Weller's idea is depicted in Figure 1.10.
Figure 1.10 Weller's explanation for the red-shifted fluorescence found in salicylic acid. The dashed arrow indicates the excited-state proton transfer. There are a few cases of dual emission from both the normal (E) and tautomeric (T) forms. Salicylic acid is not one of them in most solvents.
In the case of salicylic acid, only one tautomer (E) is present in the ground state. Upon excitation of this tautomer, a rapid proton transfer takes place in the excited state. Traditionally, this was attributed to the idea that in the excited state the phenolic OH becomes acidic, and the carboxyl group instead acquires more basic properties, providing the driving force due to the change in free energy in the excited state. This rapid conversion competes with normal fluorescence to the point where that is no longer observed, and only decay from the state results, which, as the diagram shows, has a considerable red-shifted – often of the order of 10 000 cm−1 – fluorescence. Since in fluorescence experiments no accumulation in the T state is observed, the back reaction to E is also considered fast, although no direct experiments have confirmed this so far.
This observation has led to many other cases in which a large red shift is found, and where ESIPT is invoked to explain this. Since absorption and emission wavelengths can be modified by substituents at various places in the ring system, and there is a considerable dependence on the solvent or other environment (protein, membranes), many reporter systems have been designed on the basis of this idea. Salicylic acid and the related ortho-hydroxybenzaldehyde derivatives have attracted most attention in the literature for fundamental research, but there are a few other groups of ESIPT molecules that have attracted attention as well.
Although it is not a commonly used molecule for experiments, a few words can be said about one of the simplest of tautomeric molecules, namely malonaldehyde, shown in Figure 1.11.
Figure 1.11 Proton transfer in malonaldehye. In the gas phase, the proton is thought to tunnel through the transition state (middle) barrier.
This molecule is often thought of as model system for tautomeric proton transfer [78], although experimentally it does not give many possibilities for study. Only gas-phase measurements of the tunneling frequencies between the two equilibrium states have been reported [79, 80]. Although in the picture the molecule looks symmetric, in fact it is not. We discuss this molecule here to point out another problem with calculations in tautomers. Accurate ground-state calculations of tautomeric ratios have been shown to be exceedingly hard because of the small free energy differences between the tautomeric forms [81, 82]; the situation with calculations of barriers between the tautomeric forms is not much better. Even apart from the question of whether it is just the barrier heights that are needed to estimate the tunneling frequencies – this idea probably derives from Arrhenius and the transition-state theory, but in tunneling other parameters are also relevant – no consensus can be found between various methods to calculate these. Kar et al. [83] reported a comparison of a number of calculations where the barrier heights in the ground state vary from kcal mol−1 (not a barrier at all) to kcal mol−1. In the excited states, this is even worse. In the first excited singlet state, the value ranges from to kcal mol−1, and in other excited states it can vary by as much as 60 kcal mol−1. It is not immediately obvious whether such calculations in these and in the much more complicated molecules that are of real interest contribute to our understanding of proton transfer dynamics in the ground and excited states.
The situation is somewhat better for experimental results, since trial and error as well as careful modeling using measurable properties of solvents and parameterization of substituents can lead to the design of molecules with desired properties. Flavones (Figure 1.12), for instance, form a large group of biologically relevant molecules whose properties can be modulated by various substituents to make them sensitive to properties of the environment [84–86]. They absorb visible wavelengths up to about 450 nm, and emit above 500 nm.
Figure 1.12 3-Hydroxyflavone (flavonol) exhibits ESIPT as a result of motion of the OH proton to the nearby oxygen in the excited state. (a) The generic level scheme used to describe this type of reaction. In the flavones, often both compounds are present in the excited state, and dual emission can occur, leading to the possibility of using the color change as indicator. The forward and reverse rates ( and ) in the excited state are usually much faster than the emission rates. The tautomer emission () wavelength has a large Stokes shift because of the lower excited state and higher ground state of the tautomer. This adds to the Stokes shift as a result of vibrational and solvent relaxation. The backtransfer (dashed arrow) to the normal (N) ground state is usually also thought to be fast. (b) In the tautomer, the positive charge is likely to be delocalized so that the ring system remains aromatic.
Molecules like this can be used as a platform structure to design probes for microenvironments [87, 88]. In some of these cases, both tautomers are present in the ground state, and dual emission takes place so that monitoring the color of the emission gives direct insight into the local environment, for instance in electric field strength inside membranes or proteins. Proton transfer in these compounds, although not as favorable geometrically as in salicylic acid or similar molecules, is still very fast so as to apparently allow equilibration of the excited state before the emission takes place. Although in the 1990s some hope was expressed that these compounds could also be used to “... demonstrate the accuracy and applicability of our direct ab initio dynamics approach for studying quantal effects in proton transfer reactions and also to establish a reference point for our future studies of proton transfer reactions in biological systems” [89]; further theoretical work on this type of compounds appears to be very limited (Figure 1.12).
Research of a more fundamental nature – not directly geared toward finding useful applications – has been reported on two other groups of molecules. 7-Azaindole is another biologically relevant molecule since it is closely related to indole, the core of the amino acid tryptophan. Tryptophan is an important reporter molecule in protein spectroscopy, and replacement of the indole group by an azaindole makes it even more suitable for its simpler decay characteristics and red-shifted spectrum [90]. It was also extensively investigated by Kasha and coworkers [91], and has been the subject of much theoretical work [92]. The tendency of 7-azaindole to form dimers in particular solvents has also led to the study of double proton transfer reactions in the excited state [93, 94]. Some of these issues are complicated by the possible presence of anion fluorescence [95] (Figure 1.13).
Figure 1.13 (a) Enol and (b) keto forms of ortho-hydroxybenzaldehyde (R=H) and salicylic acid (R=OH). Another compound often investigated is methoxysalicylic acid (). Many substitutions on the ring are also investigated. For most of these molecules, the enol form is the only one present in the ground state, and dual emission is rare. Salicylic acid is present as the anion is water. It also exhibits ESIPT [96, 97].
The most extensively investigated class of molecules is the ortho–hydroxybenzaldehyde derivatives (Figure 1.13). Almost every conceivable technique has been used to probe its properties in the gas phase as well as in a large variety of solvents and solvent mixtures. Starting with the work of Weller, both steady-state and time-resolved fluorescence remain the most commonly used techniques [96]. Femtosecond spectroscopy gives details of proton transfer on a very short timescale [98, 99]. The available literature on these compounds is too vast to be treated here. It ranges from very low temperature high-resolution spectroscopy to gas-phase photoelectron spectroscopy, from steady state to femtosecond fluorescence upconversion, and a variety of other nonlinear optical techniques. Numerous different solvents and substituents on the ring or carboxyl group have also been the topics of investigation. In addition, it has been the subject of multiple theoretical investigations, both for ground- and excited-state properties, up to and including exploration of the “path” the proton takes.
The conclusion we can draw from all this research is that there is still no coherent picture of intramolecular ground and excited-state proton transfer reactions in tautomers. The topic is complicated from an experimental as well as a theoretical point of view, and many questions remain. Intramolecular ground-state proton transfer is hard to study directly, and although femtosecond pulsed lasers allow initiating and following proton transfers in the excited state on a very short time scale, these methods bring their own complications to the interpretation of the results.9
1.9 Conclusions and Outlook
In the foregoing sections, we have outlined some of the difficulties in the study of tautomerism, which, as indicated, have been present from the very first until the most recent investigations. The small free energy difference between tautomers and the low barrier between them make it impossible to study them in isolation and make them very sensitive to the properties of the local environment and to parameters like pH, temperature, and salt concentration – indeed almost anything that influences the energy and entropy of the molecule in solution. Accurate calculation of the properties in the ground and excited states is equally problematic as long as the current accuracy of numerical methods is not at least improved by one or two orders of magnitude. Quantum aspects of the proton transfer reaction present a particular theoretical challenge. Most of the work has a high phenomenological content, and the parameters used in solvent descriptions (dielectric constant, proton donating, or accepting properties) are themselves hard to calculate from first principles. The study of tautomers will remain a challenging field for some time to come.
In this book, we have tried to put together a number of approaches to these topics, which, on one hand, highlight these problems, and, on the other, try to offer solutions to at least a few of them. In a number of chapters, tools are presented for the experimental and theoretical study of tautomerism: absorption in combination with chemometrics to unravel the composition of a tautomeric mixture (Chapter 2); steady-state and time-resolved optical techniques to investigate transfer dynamics (Chapters 3 and 4); the use of NMR to elucidate equilibrium properties (Chapters 5 and 6); the properties of tautomers in nonsolvent environments: biological molecules, gas phase, and solids (Chapters 7 and 8); some theoretical investigations into proton transfer and electronic properties of tautomers (Chapters 9, 10, and 13); and a number of techniques to classify solvent and substituent effects on the position of tautomeric equilibria, and methods to investigate properties of the individual components (Chapters 11 and 12).
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