Calixarenes Revisited

By C. David Gutsche

The Royal Society of Chemistry

Copyright © 1998 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-502-0

Contents

Chapter 1 From Resinous Tar to Molecular Baskets, 1,
Chapter 2 Making the Baskets: Synthesis of Calixarenes, 10,
Chapter 3 Proving the Baskets: The Characterization and Properties of Calixarenes, 32,
Chapter 4 Shaping the Baskets: Conformations of Calixarenes, 41,
Chapter 5 Embroidering the Baskets: Modifying the Upper and Lower Rims of Calixarenes, 79,
Chapter 6 Filling the Baskets: Complex Formation with Calixarenes, 146,
Chapter 7 Using the Baskets: Calixarenes in Action, 185,
Author Index, 209,
Subject Index, 223,

CHAPTER 1

From Resinous Tar to Molecular Baskets

‘The world of books is the most remarkable creation of man … Even the books that do not last long, penetrate their own times at least, sailing farther than Ulysses even dreamed of, like ships on the seas. It is the author’s part to call into being their cargoes and passengers — living thoughts and rich bales of study and jeweled ideas. And as for the publishers, it is they who build the fleet, plan the voyage, and sail on, facing wreck, till they find every possible harbor that will value their burden’

Clarence S. Day, The Story of the Yale University Press Told by a Friend

1.1 Introduction

The world of organic chemistry is populated by several million compounds distributed among hundreds of families. Some of these families have commanded the attention of chemists for many decades and have reached a venerable patrician status. Many others are more recently arrived and have yet to establish their place in the hierarchy of chemical importance. Among the latter is the family of compounds called the calixarenes which, although more than 50 years old, has gained widespread attention from the chemical community only during the last decade.

Calixarenes are [1n, metacyclophanes (1) that acquired their name because of the resemblance of the shape of one of the conformers of the smallest member of their family to a type of Greek vase called a calix crater (Figure 1.1). The name was initially chosen to apply specifically to the phenol-derived cyclic oligomers, but it has subsequently taken on a more generic aspect and is now applied to a wide variety of structurally related types of compounds. The calixarenes were first discussed in comprehensive fashion in 1989 in the first volume of Monographs in Supramolecular Chemistry, where the literature on the subject that had been published up to that time was covered in reasonably complete detail in 222 pages. Since 1989, however, there has been such a rapid expansion of the field that a somewhat less comprehensive coverage of topics is now necessary if this second volume is to be anywhere near as slim as the first. It is our endeavor in this second volume to include a significant portion of the pertinent literature citations in the field through 1996, but to do so in a somewhat selective fashion. The chapter headings used in the first volume are repeated in the present volume and include synthesis, characterization and physical properties, conformations, functionalization, complexation, and practical applications. For readers already familiar with calixarene chemistry this second volume should stand as an independent work. For readers new to the field, however, reference to the first volume should be made to provide the background on which the present volume builds.

1.2 Phenol-derived and Resorcinol-derived Calixarenes

The calixarene family can be subdivided into two major branches, the phenol-derived cyclooligomers (2) and the resorcinol-derived cyclooligomers (3), as shown in Figure 1.2. Both are discussed in the previous volume. The present monograph, however, will deal almost exclusively with the phenol-derived compounds, the resorcinol-derived compounds having been the subject of a 1994 publication in Monographs in Supramolecular Chemistry and a long review article.

1.3 Historical Perspective

The story of the ‘resinous tar to molecular baskets’ now called calixarenes is described in detail on pages 1–25 of the first volume, where particular emphasis is given to the work by Zinke and coworkers. Zinke’s investigations, starting in the early 1940s and extending into the 1950s, dealt with what were thought to be cyclotetramers obtained from the base-induced reactions of p-alkylphenols with formaldehyde. Experiments carried out by Cornforth and coworkers in the 1950s indicated that the Zinke products were actually mixtures, and the investigations by Gutsche and coworkers starting in the mid-1970s established the identity of three of the components of the mixtures as cyclic tetramer, cyclic hexamer, and cyclic octamer. It was in these early papers of Gutsche that the Zinke compounds acquired the name ‘calixarene’. During the 1980s this group devised simple and easily reproduced procedures for synthesizing p-tert-butyl -calix[4]arene (4; R = t-Bu), p-tert-butylcalix[6]arene (6; R = t-Bu), and p-tert-butylcalix[8]arene(8; R = t-Bu) (see Figure 1.3) in good to excellent yield on any scale, from a gram or less to many kilograms. The ready availability of these three calixarenes from cheap starting materials has been an important factor in the rapid escalation of research in this field during the last decade, the magnitude of which can be judged from the two books, and the many reviews (short, medium length, and long) that have been written on the calixarenes.

It is interesting to plot the growth of interest in the calixarenes, as depicted in Figure 1.4. Beginning with the 19th century experiments of Adolf von Baeyer, continuing through the early part of the 20th century with the introduction of Bakelite by Leo Baekeland, and extending to the early 1940s with the experiments of Zinke and Niederl, the growth curve is almost flat. A minor flurry of activity occurred in the 1950s in the laboratories of Cornforth and Hayes and Hunter, adding a slight positive lift. However, not until the 1970s with the entry of the Mainz group of Kämmerer (and then Böhmer), the Parma group of Andreetti, Pochini, and Ungaro, and the St Louis group of Gutsche (along with the Petrolite group of Buriks et al.) does the curve begin to move inexorably upward. Then, starting in the mid-1980s and continuing to the mid-1990s the curve becomes ever more steeply ascending, now reaching a plateau with the publication of five or more papers/week. The items of fascination that have led to this explosive growth are the subject of the remainder of this book.

1.4 Nomenclature and Representation

The original calixarene nomenclature implicitly included the OH groups as part of the structure being named. As the field has matured and proliferated, however, this presumption no longer seems warranted, and the term ‘calixarene’ is better applied only to the basic structures devoid of substituents, as illustrated in Figure 1.5 for the cyclic tetramer, dihomooxatetramer, cyclic hexamer, and cyclic octamer derived from a p-substituted phenol and formaldehyde. The phenol-derived and resorcinol-derived cyclooligomers can be differentiated by referring to the former as endo-OH calixarenes (i.e. the OH groups oriented toward the annulus) and the latter as exo-OH calixarenes (i.e. the OH groups oriented away from the annulus). As illustrated in the next chapter, calixarenes are now known that contain both endo- and exo-OH groups. Clearly, both the phenol-derived and the resorcinol-derived cyclooligomers are members of the calixarene family, as was recognized by the earlier assignment of the name ‘calixresorcarene’ to the latter. Unhappily, it is becoming increasingly the custom to shorten this to ‘resorcarene’, belying its cyclic array. By analogy, the phenol-derived cyclooligomers should be called ‘phenarenes’, clearly a less felicitious and descriptive name than ‘calixarenes’. It is hoped, therefore, that the ‘calixresorcarene’ name will be retained even though it flies in the face of the power of brevity.

Since vases ordinarily stand upright on their bases and since calixarenes derive their name from a Greek vase, calixarene structures should generally be depicted with the aryl carbon between the methylene groups (i.e. usually carrying an oxygen function) pointing downward and the aryl para carbon pointing upward. Accordingly, the face bearing the endo hydroxyl groups is designated as the ‘lower rim’, and the face bearing the para substituents is designated as the ‘upper rim’ (Figure 1.6). ‘Upside-down’ representations of the calixarenes frequently appear in the literature, and Böhmer has suggested the designations ‘narrow rim’ and ‘wide rim’ to avoid the orientation-dependency. All such designations, however, become vague when applied to larger calixarenes in which there may be no well-defined ‘upper, wide rim’ or ‘lower, narrow rim’. Still another designation that might be useful is based on the cyclic structure per se, without recourse to either its orientation or its shape. It names the lower, narrow rim as the ‘endo rim’ and the upper, wide rim as the ‘exo rim’. In this book, however, the ‘upper rim/lower rim’ nomenclature will be retained.

As already indicated, the term ‘calixarene’ is variously employed in different contexts. In colloquial usage (e.g. as often employed in the discussion section of a paper) the name implies the presence of hydroxyl groups as, for instance, in ‘p-tert-butylcalix[4]arene’ as applied to 4 (R = t-Bu). More precisely, in keeping with the suggestion above, the accurate specification of a compound (e.g. as used in the experimental section of a paper) implies only the basic skeleton to which the substituents, including the OH groups, are attached at positions designated by appropriate numbers. Thus, 4 (R = t-Bu) becomes 5,11,17,23-tetra-tert-butyl -calix[4]arene-25,26,27,28-tetrol. The abbreviated names will be frequently used when it is clear that all of the p-positions (exo positions) are occupied by the same group (e.g. four tert-butyl groups in p-tert-butylcalix[4]arene; eight tert-butyl groups in p-tert-butylcalix[8]arene, etc.). In cases where it might be ambiguous, however, the name will be made more explicit by indicating the number of p-substituents (e.g. tetra-p-tert -butylcalix[4]arene, mono-p-tert-butylcalix-[6]arene, etc.).

The calixarenes represented by the numbers 4–8 appear many times through -out this book, so to designate these structures they will be represented by a number (i.e.4–8) which specifies the number of aryl residues in the cyclic array) and a superscript which specifies the p-substituent (i.e. t-Bu, H, SO3,H, etc.) Thus, p-tert-butylcalix[4]arene is represented as 4t-Bu; p-H-calix[6]larene (more correctly named simply as calix[6]arene) is represented as 6H, etc. To avoid any confusion with the other numbers in the text the numbers 4–8 when used in this fashion appear in a characteristic font. In many instances when the generalized identity and position of attachment of substituents are made more specific, the following conventions are used: (a) the same group (i.e. R or Y) appearing on the carbon or oxygen of two or more aryl residues is specified as R1,2, R1,3,4, R1-4, Y2,4,6, etc.; (b) a group bridging two positions is specified as R1R2, R1R3, Y1Y4, etc.

Another nomenclature device that is used throughout the book as an easy way to indicate the arrangement of substituents on the upper or lower rims of a calixarene is to label the rings A, B, C, etc., and to specify the rings to which the substituents are attached. Thus, a di-p-tert-butylcalix[4]arene can be designated as an ‘A,B-‘ or an ‘A,C-di-p-tert-butylcalix[4]arene’; the symmetrical trimethyl ether of a calix[6]arene can be designated as an A,C,E-trimethyl ether, etc. The ways for naming and representing the conformational isomers of calixarenes are discussed in Section 4.1.

CHAPTER 2

Making the Baskets: Synthesis of Calixarenes

‘The whole difference between construction and creation is exactly this: that a thing constructed can only be loved after it is constructed; but a thing created is loved before it exists’

G. K. Chesterton, Preface to Dickens’s Pickwick Papers

This author’s attention to phenol–formaldehyde cyclooligomers began in the 1970s when it became clear that molecular baskets would be necessary for the construction of enzyme mimics. Already known at that time were the cyclodextrins and the crown ethers. However, the cyclodextrins were not available by de novo synthesis, being accessible only by isolation from natural sources, and the crown ethers in their unadorned form appeared to be more like discs than baskets. With neither of these systems meeting the author’s particular requirements at the time, a search for an alternative was initiated and, as chronicled in the first volume of this series, led to useful procedures for making the cyclooligomers that now are called calixarenes. Concomitant with the author’s exploration of one-step methods for synthesizing calixarenes, multi -step methods were being exploited first by Kämmerer and later by Böhmer. These two approaches provide the basis for the modern era of calixarene chemistry, complementing one another in their abilities to let the chemist fashion the basic baskets that ultimately produced the great variety of compounds discussed in this book.

2.1 One-step Synthesis of Calixarenes

2.1.1 Base-induced Reactions

Synthesis is the lifeforce, the sine qua non, for creating the members of chemical families. For some families of compounds the chemist must rely on Nature to achieve the task, but for many other families chemists can employ their own ingenuity in coaxing the elements into proper combinations. The ultimate utility of a family of chemical compounds is usually related to the ease with which this can be done, the calixarenes providing a good case in point. Like the cyclodextrins, which were discovered at the turn of the century but which did not become actively investigated until Dexter French showed how they could be separated and purified, the calixarenes languished for three decades following their discovery in the 1940s. The early procedures for their one-step preparation were not routinely reproducible and led to difficultly separable mixtures. This changed in the early 1980s with the introduction of reliable procedures for preparing p-tert-butylcalix[4]arene (4t-Bu), p-tert-butylcalix[6]arene (6t-Bu), and p-tert -butylcalix[8]arene (8t-Bu) (designated as the ‘major calixarenes’), although gaps remained in the family unit since neither the cyclic pentamer (5t-Bu) nor the cyclic heptamer (7t-Bu) (designated as the ‘minor calixarenes’) are obtained in comparable yields from one-step reaction mixtures. In response to the recent interest in the cyclic pentamer 5t-Bu, which retains the conformational features of the cyclic tetramer but possesses a somewhat larger cavity, moderately satisfactory syntheses have now been published which provide this compound in ca. 15–20% yield. A recent study directed to optimizing the yield of the cyclic heptamer 7t-Bu provides conditions for obtaining it in ca. 11–17% yield.

Although p-tert-butylphenol is the quintessential starting material for the one-step synthesis of calixarenes, a few other p-substituted phenols have been reported to yield calixarenes, albeit with generally less clean results. p-Benzylphenol, for example, gives a 33% yield of p-benzylcalix[6]arene along with p-benzylcalix[8]arene. The product mixture from p-phenylphenol and formaldehyde, previously reported to contain p-phenylcalix[6]arene (6Ph), p-phenylcalix[7]arene (7Ph), and p-phenylcalix[8]arene (8Ph), has been shown also to contain ca. 20% of p-phenylcalix[4]arene (4Ph). p-Cresol has been reported to give p-methylcalix[6]arene in 74% yield, p-adamantylphenol to give p-adamantylcalix[8]arene in 72% yield, and p-benzyloxyphenol to give p-benzyloxycalix[8] arene in 48% yield.

Interesting calixarenes and calixarene-related compounds have been obtained in one-step reactions from 1-naphthol, from the naphthalenediol disulfonate 11, and from and the bis-phenols 13, 15, and 17. Although 2-naphthol reacts with formaldehyde to yield a simple bis-naphthol, 1-naphthol produces a mixture containing 9.6% of the sym metrical exo-OH cyclic tetramer 10 accompanied by 5% and 16% of two other cyclic tetramers in which the naphthol residues are unsymmetrically placed in the cyclic array. When the disodium salt of 1,8 -dihydroxy-3,6-naphthalenedisulfonic acid (chromotropic acid) (11) is treated with an aqueous solution of formaldehyde and the mixture is allowed either to stand at room temperature for a week or is refluxed 6 h, a high yield of the endo-OH cyclic tetramer 12 is formed. The ease with which this condensation occurs is surprising in view of the deactivating effect of the sulfonic acid groups adjacent to the locus of condensation with the formaldehyde. Interesting cation effects have been noted in the one-step reactions of the bisphenols 13 and 15 with paraformaldehyde. With NaOH as the base, compound 13 affords a 90% yield of 14, while with LiOH, KOH, RbOH, or CsOH as the base, 13 gives yields only in the 10–36% range. With NaOH as the base, compound 15 affords a product containing 51% of 16b and only a trace of 16c, whereas with CsOH as the base, 16c is produced in 66% yield accompanied by only 4% of 16b. With KOH as the base, approximately equal amounts of the two cyclooligomers are formed, while none of the bases yielded any of the cyclic dimer 16a. A substituent effect is noted in the heat-induced condensation of 17 with formaldehyde to form 18 (containing exocyclic OH groups), the reaction proceeding in considerably higher yield when R = t-Bu than when R = Me. These compounds have also been prepared in a stepwise fashion starting with the bromomethylation of 20a to give 20b, condensation with a phenol to give 21 followed by treatment with HCHO in an autoclave at 180 °C to produce 49% of 18.

(Continues…)Excerpted from Calixarenes Revisited by C. David Gutsche. Copyright © 1998 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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