1.  Shell closure of two cavitands forms carcerand complexes with components of the medium as permanent guests Donald J. Cram, Stefan Karbach, Young Hwan Kim, Lubomir Baczynskyj, Gregory W. KallemeynJ. Am. Chem. Soc.; 1985; 107(8); 2575-2576. Abstract
2. Recent Highlights in Hemicarcerand Chemistry Ralf Warmuth and Juyoung Yoon, Accounts of Chemical Research Volume 4, Issue 2, Pages 95-105, 2001.
3.  The Inner Phase of Molecular Container Compounds as a Novel Reaction Environment Ralf Warmuth Journal of Inclusion Phenomena and Macrocyclic Chemistry 37: 1–38, 2000.
4.  Constrictive binding of large guests by a hemicarcerand containing four portals Mimi L. C. Quan, Donald J. Cram J. Am. Chem. Soc.; 1991; 113(7); 2754-2755. Abstract
5. One-Pot, 18-Component Synthesis of an Octahedral Nanocontainer Molecule Xuejun Liu, Yong Liu, Gina Li, Ralf Warmuth, Angewandte Chemie International Edition Volume 45, Issue 6 , Pages 901 – 904 2006 Abstract

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This review focuses on how self-assembly can form hosts capable of binding large guests. Its sister article, ”Guests within Large Synthetic Hydrophobic Pockets Synthesized Using Polymer and Conventional Techniques,” reviews like-minded work using either polymers or hosts synthesized by traditional synthetic approaches. As described in more detail in that paper, the focus here is on hosts capable of binding organic molecules of more than seven nonhydrogen atoms. Likewise, a similar definition of a ”pocket” is retained, with the focus on hosts possessing well-defined, highly concave or enclosed surfaces. An arbitrary value of greater than approximately 50% encapsulation has been set. ”Comprehensive Supramo-lecular Chemistry” covers much of our discussion topic up to 1995.[1] This review is therefore primarily interested with the literature since that time.

Motivators for supramolecular chemists include molecular storage/delivery, the detection of substances, and the conversion of one substance into another via catalytic processes. All these processes include at some point the binding of a guest to a host. The hard part in these endeavors is the synthesis of the host, with all the required functionality gathered in a converging array. One approach uses self-assembly, whereby molecular subunits are designed to merge in a specific pattern that possesses a hydrophobic pocket. In this regard, both self-assembly and self-assembly with covalent modification have been used. As with the polymer and traditional synthetic strategies, the self-assembly approach has pros and cons. Normally, relatively rigid subunits are used and so a common worry in cavity design—hydrophobic pocket collapse—is generally avoided. On the other hand, at our current level of understanding we are limited to relatively symmetrical subunits and assembled structures. Nevertheless, testimony to the power of this approach is found in the large cavities formed, some in the order of thousands of cubic Angstroms.

The bulk of recent self-assembly research has focused on understanding the rules that govern how one product can arise out of a reaction mixture that, if all things were equal, would lead to a highly complex mixture. Hence in a manner analogous to contemporary polymer research, the emphasis is on understanding how the structure of the product is reached, rather than on understanding the properties of any cavity in the product. As a result, many of the very large cavities created by self-assembly are ”simply” filled with a large number of (small) solvent molecules. Such examples are not dealt with explicitly here but can be found in citations throughout the text.

HOSTS BASED ON RESORCINARENES

In the last seven or so years it has become apparent that resorcinarenes, 1 (n=4), a family of molecules[2-5] held in much regard for their hosting properties and their use in the synthesis of a plethora of cavitands, also possess a spectacular flair for self-assembly. Two general assembly products have been identified (Fig. 1). Either two molecules can come together in apseudo C4h symmetric host, or six assemble into a pseudo-octahedral array. A second component, usually solvent, is necessary to ”glue” the subunits together. The first hint of this supramolecular chemistry was pinpointed by MacGillivray and Atwood, who identified the pseudo-octahedral complex both in the solid and the solution state.[6] The total assembly consists of six resorcinarenes, eight water molecules and has a solvent-filled cavity. Shortly thereafter, the dimer, again in part held together by 2-propoanol/water molecules, was identified independently by the Rose and Aoki groups.[7,8] The latter identified a tetraethylammonium ion within the cavity. A third such structure, this time hosting triethyl-ammonium, was identified shortly thereafter.1-9-1 Recently, Atwood et al. identified a more robust pseudo-spherical hexamer derived from pyrogallol[4]arenes 2,[10] while Shivanyuk and Rebek have determined that the corresponding dimeric assembly also forms and encapsulates large guests.[11] Thus, in deuterated methanol or aqueous acetonitrile, NMR evidence suggests that 2 (R=Pr) is monomeric. However, the addition of tropylium tetra-fluoroborate results in an intense red color indicating a charge transfer complex between 2 (R=Pr) and guest. Furthermore, at host/guest ratios larger than two, the 1H NMR at 233 K demonstrates that a 2:1 complex of 2 (R=Pr) and tropylium tetrafluoroborate exists. At this temperature, the kinetics of guest exchange is slow on the (600 MHz) NMR time-scale. Further experiments revealed that 1) at higher equivalents of guest a 1:1 complex was formed, and 2) a protic solvent was necessary for assembly of the dimer host. This latter point was noted when more lipophilic 2 (R=CnH23) was shown to only assemble in deuterated chloroform when a trace of methanol was present. Interestingly, resorcin-arenes 1 (R=Me, or Et) did not undergo this encapsulation of the tropylium ion.

Fig. 1 Dimeric and hexameric assemblies of resorcinarenes.

The octahedral assemblies of 1 (n=4)[12,13] have demonstrated some fascinating encapsulation properties. For example, in water saturated, deuterated chloroform, the hexamer of 1 encapsulates a range of ammonium ions in a manner that is intimately tied to the size and concentration of the guest.[14] Tetrahexylammonium bromide is an ideal guest and exchanges slowly, relative to the 600-MHz NMR time-scale, between cavity and free solution. Nuclear magnetic resonance evidence suggests that the larger guest tetraheptylammonium bromide is cramped within the confines of the assembly, while the still larger tetra-hexadecylammonium bromide was not complexed. With smaller guests, things became even more interesting. Thus, in the case of Bu4N+BF4~, the small counter ion is coencapsulated along with cation. In such cases, solvent is also present in the cavity but leaves when a more suitable space-filler is present. Hence, at the expense of bound water 4-phenyltoluene is also encapsulated along with Bu4N+BF4~. Still smaller ammonium ions instead template the assembly of the dimeric host. Bu4SbBr, along with a variety of co-encapsulated aromatic guests, is also seen within the hexameric assembly.[15] Co-guests included are benzene, p-xylene, 4-phenyltoluene, and naphthalene. In contrast, 4,4′-dimethylbiphenyl was not encapsulated with the antimony guest, suggesting that adding an extra methyl group to 4-phenyltoluene was enough to destabilize the complex. Size, however, is not the only important factor for encapsulation. Neither hexa-fluorobenzene, cyclohexane, nor pentane was coencapsu-lated. Rather, the antimony guest and presumably some solvent molecules occupied the cavity.

As the basis of cavitands, resorcinarenes have also been instrumental in the synthesis of carceplexes such as 3 (Scheme 1).[16-18] As defined by their inventor, Donald Cram, carceplexes are closed surface compounds that permanently entrap guest molecules or ions within their shell, such that guest escape can only occur by rupture of covalent bonds. Since their initial synthesis,[19] their self-assembly (with covalent modification) has been intensively investigated; as has the relationship between host shell (the carcerand) and guest. As it transpires, these two facets are intimately tied. Early work focusing on small guests established that templation[20] is essential for successful synthesis. The best yields arise when a template stabilizes the transition state of the rate-determining step (rds) for the synthesis. Furthermore, the transition state at the rds has a similar cavity to the product.[21-29] Hence good templates for assembly make good guests for the carcerands. In these initial studies, the best guest identified was pyrazine, while the worst guest, and hence the solvent of choice for many of these studies, was N-methylpyrrolidinone (NMP).

Scheme 1 Synthesis of carceplex 3.

Carceplexes can be increased in size to allow the encapsulation of large guests. One way is to use wide-bodied cavitands—cavitands derived from resorcin [5]arenes—in the carceplex reaction.[30] Another is to join several ”normal”-sized cavitands together.[31-33] To date, only relatively small molecules have been observed within hosts synthesized by these methods. A more common approach is to increase the size of the linker groups that join the two ”hemispheres” of the shell, i.e., replace bromochloromethane in the synthesis shown in Scheme 1 with a compound with two separate electro-philic centers.[34] The resulting products, such as 4 (R=-(CH2)4-),[35] are called hemicarceplexes; so named because the portals in the shell, or hemicarcerand, are large enough for guests to exit or enter the cavity without covalent bond rupturing.[36] The ability of over 68 molecules to template the formation of 4 (R=-(CH2)4-) has been recently studied.[37] Of these, 30 proved capable of templation, with the best template p-xylene proving to be 3600 times better than the worst N-formylpiperidine. However, in contrast to carceplex 3, the final host structure 4 did not appear to be a reasonable model of the transition state of the rds in its synthesis.

Although many hemicarceplexes can be assembled via templation, most have been synthesized by inserting the desired guest post-assembly. This has provided information about how solvent and the shape of the portals or guest influence thermodynamic stability, and complexa-tion and decomplexation rates. For example, after synthesizing hemicarceplex 4 (R=-(CH2)4-, guest= solvent), the guest solvent can be exchanged using the law of mass action. Either heating the hemicarceplex in the presence of 100 equivalents of new guest in a solvent too large to enter the cavity, or more simply heating the complex in neat guest, leads to exchange. Using this technique, it is possible to synthesize a range of hemicarceplexes.[38] In general, long, thin guests complexed the fastest, while for disubstituted aromatic guests a general order of com-plexation was demonstrated by the xylene isomers; p-xylene ^ m-xylene> o-xylene. Computational studies on a related hemicarceplex indicated that two type of gating processes, involving conformational changes in the intra-hemispherical linker groups, affect guest entry or egres-sion.[39,40]

How do guests inside the cavity interact with species in free solution? Host 4 (R=-(CH2)4-) was used to study the first Sn2 reactions of inner-phase guests with outer-phase reactants.[41] For example, when the complexes 4 (R= -(CH2)4-, guest=either 4-HOC6H4OH or 3-HOC6H4OH or 2-HOC6H4OH) were exposed to THF/NaH/CH3I, three different reaction outcomes were noted. The encapsulated para-isomer gave no reaction, the meta-isomer was doubly methylated, while the ortho-isomer gave a mixture of mono-and dimethylated guest. Different reactivity profiles were noted because each guest prefers a different orientation within the cavity. In the case of the 1,4-isomer for example, the two OH groups can reside deep within the ”poles” of the host and cannot be readily alkylated. A similar rationale explains the observed alkyllithium additions and borane reductions of 4 (R=-(CH2)4-, guest =benzaldehyde, benzocyclobutenone, and benzocyclobutenedione).[42] If a reactive species is generated within the cavity, it can sometimes react with the hemicarcerand shell. For example, reaction at 0°C between 4 (R=-(CH2)4-, guest =-benzocyclobutenedione) and an excess of MeLi gave diol 5 (Scheme 2). Experiments revealed that a possible mechanism for this conversion begins with the addition of one equivalent of MeLi to a C=0 group of the guest. The basic lithiate complex 6 can then induce a p-elimination in one of the linkers. This produces a butene ether derivative 7 that can then undergo a further elimination to yield the bis-phenoxide. Workup yields 5. The tetramethylene linkers are not the sole reactive sites in this hemicarcerand. Thus the methylene bridges in each hemisphere undergo reaction with the guest derived from methyl lithium addition to encapsulated N-methyl-2-pyrrolidinone.[42]

Scheme 2 Synthesis of diol 5 via an inner-molecular reaction.

By carrying out a two-step (hemi)carceplex reaction, lower symmetry hydrophobic pockets can be synthe-sized.[43,44] To point out just two examples, hosts such as 4 (R=-CH2-, or R=-(CH2)6-) were synthesized and their corresponding hemicarceplexes examined by X-ray crystallography, NMR, and computational studies.[45] As anticipated, introducing a dissimilar linker between the hemispheres altered the shape of the pocket, the orientation of the guest, and hence the thermodynamic and kinetic stability of the corresponding complexes. The kinetics of exchange were measured at different temperatures for 1,4-dimethoxybenzene vacating 4 (R= 1,3-(CH2)2C6H4), to show how AHz, ASz, and hence AGz varied as a function of solvent.[43] These studies revealed that solvation plays an important role in decomplexation. Hence decomplexa-tion rates in CDCl3 were 800 times faster than in deuterated 1,1,2,2-tetrachloroethane. An examination of different hemicarcerands showed that the structure of the unique linker also has a considerable effect on egression rates. For example, changing the dissimilar linker R in 4 from pentamethylene to hexamethylene increased the rate constant for egression by a factor of 177. Lower symmetry cavities can also be made by using two different cavitands to construct a hemicarceplex. For example, in hosts 8 and 9 methylene and dimethylene bridges link the phenol oxygens of the former, while dimethylene and trimethylene linkers are used in the latter.[46,47] Nuclear magnetic resonance evidence demonstrates that these subtle changes in the host are manifest in how the guest moves within the pocket. Hence when the guest in 8 is 1,2,3-trimethoxybenzene three signals are observed for the methoxy groups. The 1- and 3-methoxy groups reside within different hemispheres, and the movement of the guest that allows them to exchange is slow on the (500 MHz) NMR time-scale; in contrast, the slightly bigger cavity of 9 means that the corresponding process is fast on the NMR time-scale. Although no simple rules were discernable, the size of the bridges between the phenolic O-atoms undoubtedly influences guest movement and decomplexation rates.

Building on these developments, Cram moved the carceplex and hemicarceplex field into the realms of aqueous solution, while at the same time synthesizing chiral hosts. The first water soluble hemicarceplexes were isolated from hemicarcerand 10.[48] In aqueous solution, this host is capable of sequestering a number of guests including naphthalene and 1,3-dimethoxybenzene. Guests such as alkyl ammonium salts that are well solvated by water did not bind. Chiral hemicarceplexes can be synthesized by using the two-step process discussed above. Hosts 11 and 12 are two examples.[49] Introducing the chiral linker group of 11 in the presence of a racemic mixture of selected chiral guests resulted in ratios of the diastereomeric complexes of up to 1:1.5. Alternatively, higher diastereomeric ratios could be attained if the chiral hemicarceplex 11 containing chloroform was heated either in the presence of pure, racemic guest, or in diphenylether with an excess of racemic guest. By this approach the highest diastereomeric ratio observed was >20:1 in favor of the R-isomer of 4-MeC6H4S(O)Me binding to 11. In contrast, the diastereomeric ratio observed for complexing racemate C6H5S(O)Me was only 1.6:1 in favor of the R-isomer. Overall, the hemicarcerand 12 (guest=chloroform) was less discriminating than 11. This was attributed to the two ”nonchiral,” 26-membered ring portals in 12 being less encumbering than its two chiral portals.

As a rule, the shape and functionality of the guest can be transferred through a hemicarceplex shell to the external environment. A simple thin layer chromatography experiment is usually sufficient to demonstrate this point. Furthermore, hemicarcerand shells allow the transfer of triplet energy from aryl ketone guests to free naphthalene.1-50-1 These results notwithstanding, guests in carce-plexes or hemicarceplexes are in relatively sheltered waters, and this has allowed these unique hosts to be used as storage containers for highly reactive guests.[34,51,52] The first example, involving a small guest, was carried out over 12 years ago. Nevertheless, the trapping and room temperature analysis of cyclobutadiene 13 (Fig. 2), the Mona Lisa of organic chemistry as Cram described it, is always worth mentioning.[34] Equally as exciting was the trapping by Warmuth of o-benzyne 14 inside the cavity of 4 (R=-(CH2)4-).[51] This remarkable feat was accomplished by the photolysis of 4 (R=-(CH2)4-, guest=benzocyclo-butenedione) and allowed its :H and 13C NMR analysis. The former suggested that ”free” benzyne would possess :H NMR chemical shifts of d=7.0 and 7.6 ppm, while 13C-13C coupling in the latter suggests that 14 is best described as a cumulene. Interestingly, when warmed up to room temperature, the guest reacted with the hemi-carcerand in an inner-molecular Diels-Alder reaction.[53] Following on from this work, Warmuth and Marvel successfully trapped an enantiomeric mixture of 1,2,4,6-cycloheptatriene 15 inside hemicarceplex 4 (R=-(CH2)4), by first encapsulating phenyldiazirine and then irradiating the resulting hemicarceplex.[54] Protected by the host shell, 15 could not dimerize and was stable for weeks at ambient temperature. By carrying out the same chemistry within chiral host 12, a 3:2 ratio of the two resulting diastereomeric complexes was formed.[55] No coalescence of NMR signals could be observed when heating these complexes up to 100°C, which puts a lower limit to the enantiomerization barrier of > 19.6 kcal mol—1 This value was collaborated with a parallel experiment using the diastereomeric complex of 12 (guest= 16). Thus using line broadening analysis of the :H NMR signals from the methyl groups of the two complexes (d = — 1.47 and — 1.57 ppm), a similar isomerization barrier was determined.[56] Although tetraenes 15 and 16 are stabilized by the protective shell, the hemicarcerand cannot stop oxygen and other small reagents from entering the cavity. Hence when a solution of 4 (guest = 15) is exposed to oxygen, the spirodioxirane 17 forms, which upon heating evolves CO2 to leave an entrapped benzene guest. Furthermore, when heated entrapped 16 rearranges to the corresponding p-tolylcarbene, which goes on and reacts with the hemi-carcerand shell in a number of different ways.

Fig. 2 Reactive species trapped within hemicarceplexes.