Conformationally preorganised hosts for anions using norbornane and fused [ n ] polynorbornane frameworks

Norbornane and fused [n]polynorbornane frameworks are readily synthesised, can be tailored to a variety of predictable geometries and can be functionalised regiospecifically. As such, these highly preorganised scaffolds offer the supramolecular chemist an excellent starting point when designing hosts for specific guests. This feature article will highlight the evolution of our research from relatively simple norbornane based anion receptors to more sophisticated tetrathioureido functionalised fused [n]polynorbornane hosts.


Introduction
In the field of supramolecular chemistry the topic of anion recognition and sensing has become an intense pursuit for a growing number of research groups worldwide. 1Indeed, as a result of this effort, many excellent examples of hosts for anionic species have been successfully developed. 2n many instances new hosts are synthesised and are subsequently evaluated against a broad set of guests to see which of these 'fits' best.One of the principal objectives for undertaking the research featured herein was not to simply unveil a new host in this way but to develop a series of related hosts such that the supramolecular chemist, when faced with a specific guest, can employ a host of appropriate dimensions to complement that guest.
An approach that employs a framework comprised of n individual norbornane units (1, Fig. 1) fused together to form a [n]polynorbornane framework such as 2 is one that can provide hosts that contain a preorganised cleft of predictable dimensions.
This feature article will briefly outline the role of preorganisation in supramolecular chemistry then highlight the recent use of norbornane and in particular, topologically predefined, fused [n]polynorbornanes in the recognition of anionic species.

Preorganisation, induced fit, and complementarity
It was Emil Fischer who, in 1894, noted that ''only in the case of similar geometrical structure can the molecules approach each other as to initiate a chemical action. ..together like a lock and key''.This pioneering theory of enzyme:substrate binding was modified by Koshland who introduced a flexible hand in glove description for the topological adjustment-induced fit-that enzyme:substrate complexes undergo in order to achieve the optimum alignment of binding groups. 4n the realm of supramolecular chemistry it was Cram who used preorganised spherands and flexible podands to clearly demonstrate that ''preorganisation is a central determinant of binding power'' and also that the alignment of contact sites between the host and guest-complementarity-is crucial for specific recognition. 5Thus the goal of strong and selective anion recognition by charge neutral hosts can only occur if the host has an array of hydrogen bond donors suitably arranged in a predefined fashion for the guest.
In this context fused [n]polynorbornane frameworks again appear well suited as they can be readily synthesised to specific dimensions and can also be easily functionalised to include a variety of H-bond donors This article will focus on 'larger' scaffolds, nevertheless, researchers will be aware of anion hosts based on 'smaller' scaffolds such as pyrrole, 6 indole, 7 naphthalene, 8 naphthalimide, 9 and anthracene. 10In addition, suitably functionalised metal templated architectures have also emerged as suitable for anion recognition and the subject has been recently reviewed. 11

Norbornanes
The norbornane (bicyclo[2.2.1]heptane) framework 1 requires little introduction.It occurs naturally in terpenoid derivatives such as borneol, camphor and fenchone 12 and the cycoladdition methodology developed for its construction won its discoverers, Otto Diels and Kurt Alder, a Nobel prize in 1950. 13This simple scaffold has enjoyed use in a range of fields where conformational preorganisation is paramount including medicinal chemistry, 14 peptidomimetics 15 and as chiral auxiliaries for asymmetric synthesis. 16n the field of supramolecular chemistry tetra-amide norbornenes have been used as photo-switchable ion carriers (Fig. 2). 17Norbornadiene-quadricyclane isomerisation (3a-3b) alters the preorganisation of the four amide groups and has a direct impact on the binding (and in turn transport: organicaqueous) of a range of cationic guests. 17rbornanes and anion recognition 18,19 To demonstrate that norbornanes/enes could be employed as frameworks for anion recognition, hosts 4-6 were designed (Fig. 3).Each possessed a unique binding cleft flanked by two thiourea arms (throughout this article 2-ureidoethylamido substituents are referred to as arms for convenience). 18,19ynthesis of the hosts was achieved using Diels-Alder cycloaddition, amide bond formation and thiourea formation.For example, construction of endo/endo host 4 19 (Scheme 1) required cycloaddition of cyclopentadiene with acetylenedicarboxylic acid to afford norbornadiene diacid 7. Coupling with two equivalents of 2-(tert-butoxycarbonylamino)ethylamine using EDCI gave Boc protected diamide 8. Hydrogenation using Pd(OH) 2 afforded norbornane 9 with the desired endo/endo geometry.Deprotection (TFA/CH 2 Cl 2 ) and reaction with the appropriate isothiocyanate afforded hosts 6a and 6b.

Anion binding studies
Within this series (4-6) it was predicted that compounds 6a and 6b with endo/exo preorganisation would be more suited to tetrahedral anions such as dihydrogenphosphate and these anions would bind in the larger cleft of these hosts in a 1 : 1 host : guest (H : G) arrangement.
To evaluate host : guest interactions, both 1 H NMR and UV-Vis titration experiments were performed in DMSO.Selected results from these binding studies are summarised in Table 1. 19ectron withdrawing groups and H : G stoichiometry Most significant were the results obtained for acetate (Fig. 4).Five of the six hosts bound this anion in a 1 : 2 H : G stoichiometry (common for 2-armed thiourea receptors, 21 indicating that the urea groups are not acting cooperatively).However, host 6b bound acetate with a 1 : 1 H : G stoichiometry.The change from Ar-F to the more electron withdrawing Ar-NO 2 effected a change in H : G stoichiometry from 1 : 2 (for 6a ArF) to 1 : 1 (for 6b ArNO 2 ).Hosts 4b and 5b also contained the NO 2 substituent but 1 : 2 H : G stoichiometry with acetate was identified.This result implied that it was actually a combination of both the endo/exo preorganisation of host 6b and the electron withdrawing nature of the Ar-NO 2 that made host 6b unique when binding AcO À . 18,19 colour change was noted during the titrations of the hosts containing the nitro group (4b, 5b and 6b) and UV-Vis titrations confirmed the unusual 1 : 1 H : G stoichiometry of 6b with AcO À despite the initial host concentration being significantly lower (ca.5.0 Â 10 À5 M).Association constants calculated from this data were also consistent with those determined from 1 H NMR titrations; 4b log K 1 = 3.7, log K 2 = 3.6; 5b log K 1 = 3.7, log K 2 = 3.8; and 6b log K 1 = 3.9.18,19 To the best of our knowledge this was the first example in which a change in an electron withdrawing group (an Ar-F to a Ar-NO 2 ) could alter the final stoichiometry of the host : guest complex and suggests that H-bonding power can be used to control binding stoichiometry.

Targeting dihydrogenphosphate and lipid A 25
In all cases 1 : 2 H : G arrangements were noted for the binding of H 2 PO 4 À by receptors 4-6 (Fig. 5). 18,19Hosts 4 and 5 bound the guests symmetrically through three H-bonding interactions per arm (two from the thiourea NH's and one from the amide NH), however in the case of the endo/exo host 6 the binding of H 2 PO 4 À to the exo arm was by means of three H-bonds, whereas the endo arm bound H 2 PO 4 À solely through the thiourea N-H groups.
Given that each arm was acting independently in the binding of H 2 PO 4 À it was reasoned that this type of host might be capable of binding a diphosphate species such as lipid A. 22 (Fig. 6).Many potent antimicrobial agents interact strongly with the anionic lipid A portion of the bacterial outer membrane lipopolysaccharide (LPS).Examples include the naturally occurring polymyxin and defensin families of peptides. 23These compounds are facially amphiphilic; they have cationic groups (ammonium or guanidinium) correctly positioned to interact with the anionic phosphate groups of lipid A and hydrophobic residues to penetrate the hydrophobic layer.In order to mimic these features, 'lead' compound 6 was modified to include an octyl 'tail' and guanidine groups for anion recognition 24 (see 10, Fig. 6).Molecular modelling indicated that the exo/endo arms could easily span lipid A and bind to both phosphate groups. 25 A fluorescent displacement assay confirmed binding to the LPS target and compound 10 had an IC 50 of 9.5 mM (Colistin IC 50 = 6.0 mM).Simple disk diffusion studies identified that compound 10 was active (particularly against Pseudomonas aeruginosa ATCC 27853) and haemolytic tests confirmed that 10 did not lyse red blood cells at concentrations up to 125 mM. 25
Cyclic scaffolds that incorporate aryl fused norbornanes have also been pursued by Stoddart 48 who employed a molecular LEGO approach to constructing 'belts' such as Kohnkene (21,49 Fig. 11).More recent examples include the molecular 'tweezers' and 'clips' produced by Klarner. 50For example bisphosphate 22 51 (Fig. 11) binds cationic Lys residues and has been shown to 'unwind' amyloidogenic proteins.Fused polynorbornanes have also recently been used by Clever in the synthesis of metal organic cages 52 (such as 23, 53 Fig. 11).
Fig. 7 Examples of anion hosts based on cholic acid. 28,29g. 8 Examples of functionalised calixarene and calixpyrrole frameworks for anion recognition, sensing and transport. 35,36g. 9 Examples of preorganised tripods and macrocycle. 39,41,43g. 6 Structure of Lipid A (phosphate groups highlighted in red).Anion host 6 and custom modified host 10 are shown on the right. 25his journal is c The Royal Society of Chemistry 2013 Several cycloaddition strategies have been developed to access these fused polynorbornane structures [44][45][46][47][48][49][50][51][52][53][54][55] and inventive descriptions such as LEGO 48 are used to describe their construction.Other monikers including 'molecular glue' have been used to describe oxadiazole coupling 54 and also BLOCK as an acronym for 'bonzer little organic construction kit'. 55All such terminology hints at the modular nature of the various approaches to the ready assembly of these large molecular architectures.The terminology also clearly conveys the 'no atoms wasted' advantage inherent with a cycloaddition approach. 56e ACE reaction The key cycloaddition to assemble fused [n]polynorbornanes is the (2+3) [p4 s + p2 s ] 1,3 dipolar cycloaddition of a resonance stabilised, electron deficient, carbonyl ylide (such as 24, Scheme 2), generated by electrocyclic ring opening of a cyclobutane epoxide (23), to a norbornene partner (25). 57This reaction of an Alkene with a Cyclobutane Epoxide is termed the ACE reaction.More recently a microwave-assisted version of this cycloaddition has been used to effect the transformation in high yields and reduced reaction times (10-15 minutes). 58simple two step methodology has been devised for the construction of the requisite epoxides (Scheme 3).First is the ruthenium catalysed Mitsudo reaction 59 of a norbornene with an acetylene dicarboxylate diester (equivalent to a [2+2] cycloadditon) which affords cyclobutene diesters (such as 28).This reaction can be performed in a microwave reactor and near quantitative yields are achieved in under 5 minutes. 60The second step is a modified Weitz-Scheffer epoxidation 61 of this electron deficient alkene using tert-butylhydroperoxide (TBHP) with a catalytic amount of potassium tert-butoxide in THF. 62poxide 29 and bisepoxide 30 are both routinely used in framework construction and are easily prepared using the protocol of Mitsudo reaction followed by epoxidation.
Fused [n]polynorbornanes and anion recognition [65][66][67][68][69] With the goal of creating a family of new hosts that could be used to target a range of larger and biologically relevant anions, such as dicarboxylates and pyrophosphate, a series of thiourea based anion receptors 36-41 (both symmetric and non-symmetric, Fig. 13) were designed.Using molecular modelling (AM1) it was calculated that the [3]polynorbornane 36 spans ca.6.6 Å from imide N to imide N and the [5]polynorbornane 37 spans 10.4 Å. 65 Thus the cleft dimensions of these polynorbornanes are significantly different and ideally suited to recognition of larger/longer anions.Again the 2-ureidoethylamido substituents are referred to as arms and as such the hosts will be referred to as 2, 3 or 4-armed [n]polynorbornanes, for example host 40a (Fig. 13) is a 4-armed [3]polynorbornane.
For hosts 38-41 the previously synthesised norbornenes 4 and 5 and their precursors could be used as substrates for the construction of the 3-and 4-armed frameworks.Thus for the synthesis of 4-armed [5]polynorbornane host 41 norbornene 8 was employed, and in this case ACE reaction of bis-epoxide 30 with two equivalents of 8 provided the 4-armed [5]polynorbornane scaffold 46.Subsequent hydrogenation, deprotection and coupling with the requisite isothiocyanates afforded hosts 41a and 41b.
Of the results obtained for the 'smaller' anions, the most useful were those obtained from the titrations against H 2 PO 4 À .
For the [3]polynorbornane based host 36 1 : 1 H : G stoichiometry was observed in both cases, whereas [5]polynorbornane based hosts 37 formed 1 : 2 H : G complexes (Fig. 14).The H : G stoichiometry can be attributed to the shorter cleft width of host 36; the H 2 PO 4 À anion is simply too small to span the cleft of host 37 so cannot be bound cooperatively by the two anionophoric arms, instead each arm binds independently.This notion of the arms acting independently is further supported by the binding constants K 1 and K 2 being similar in magnitude (Table 2).
A trend was expected in which short chain dicarboxylates would complement the [3]polynorbornane host 36 and longer chain alkyl dicarboxylates would prefer the larger cleft of the [5]polynorbornane hosts 37.However, no such trend was found and in all cases strong 1 : 1 H : G complexes were observed (Table 2).In Fig. 15 two binding arrangements are shown; in the case of the [3]polynorbornane 36 binding suberate it is the flexibility of (i) the arms of the host and (ii) the alkyl chain of the guest that allows a conformation in which a strong host : guest complex forms.In the second example, despite the longer [5]polynorbornane scaffold of host 37 the flexibility of the arms still allows the host to capture the shorter succinate guest.The deliberate allowance for induced fit designed into these receptors was sufficient to over-ride the preorganisation imparted by the rigid scaffold.
The rigid terephthalate guest (7.0 Å long) can only bind strongly to a host with an appropriate cleft width and while a 1 : 1 H : G arrangement for both hosts 36 and 37 was identified there were significant differences between the titration isotherms and the binding constants.Host 37b bound terephthalate 100 times more strongly than host 36b. 67The cleft width of the host was now the controlling factor in the binding of the guest (illustrated in Fig. 16) where the larger cleft of host 37 better complements the width of the rigid dianionic guest.These results neatly reinforce the ideas of Cram who in his principle of preorganisation stated that ''the more highly hosts and guests are organised for binding and low solvation prior to their complexation the more stable will be their complexes''. 71he interaction of host 37 with terephthalate could also be monitored by following the 'internal' framework C-H resonances as these protons are deshielded by the ring-current effect 72 of the phenyl ring (Fig. 17). 73Although the observed change was small (Dd B 0.2 ppm) the binding isotherm clearly indicated the formation of a 1 : 1 complex (Fig. 17).
3 and 4 armed hosts: multiple H-bond donors 68,69 The 3-and 4-armed [n]polynorbornane hosts 38 and 39 provide up to 12 H-bond donors per host (both thiourea and amide).As such they are ideally suited to larger guests with multiple H-bond acceptor sites and dihydrogenpyrophosphate (H 2 ppi 2À ) and adenosinediphosphate (ADP 2À ) were also included in the already large list of titrants for these hosts. 69Selected results are provided in Tables 3 (for 3-arm) and 4 (for 4-arm).
Hosts 38 and 39 bound terephthalate in a 1 : 1 H : G arrangement and the guest was bound cooperatively through all six thiourea H-bond donors (no contribution from the amide groups).Due to the unsymmetrical nature of the 3-armed hosts, five H-bond donor signals could be followed throughout the 1 H NMR titration (Fig. 18) and as such an increase in the amount of information regarding the binding could be gathered.A global method of calculating binding constants (taking into account all H-bond donors) could also be used to accurately determine log K. 70 It was also noted that the change in chemical shift of the thiourea protons of the one-armed end were approximately      This journal is c The Royal Society of Chemistry 2013 double that (at the equivalence point) of the shifts observed for the four thiourea H-bond donors of the 2-armed end.This result reinforces the idea that one carboxylate of the dianion is being bound by both thiourea groups from the 2-armed end of the host while the other carboxylate is being bound by the single thiourea group (Fig. 18).

Regioselective recognition 69
The most remarkable behaviour for this series of hosts was observed when either alkyl dicarboxylates or pyrophosphate were added to the 3-armed hosts (38 and 39).A stepwise regioselective binding process occurred in the case of the alkyl dicarboxylates and in the case of pyrophosphate, a H : G complex formed in which the 1-armed end was completely ignored and the anion bound exclusively to the 2-armed end.
For the 3-armed hosts with alkyl dicarboxylates the clearest example of the stepwise binding was observed for host 38a with pimelate (Fig. 19).The binding isotherms indicated that an initial 1 : 1 binding event occurred at the 2-armed end.When one equivalent of dicarboxylate had been added there was little change in the urea protons of the 1-arm end (Fig. 19).When more than one equivalent of dicarboxylate was added no further change was observed at the 2-arm end, however, there was a distinct 'jump' in the N-H signals of the 1-arm end.The isotherm for the 1-armed end after one equivalent is reminiscent of a standard 1 : 1 binding isotherm and indicates modest binding of a second equivalent of pimelate at that end.Hence the overall process can be considered a stepwise regioselective process where the first dicarboxylate preferentially binds tightly at the 2-armed end. 69Modelling (H-F 3-21G*) also supported the binding of the dicarboxylate at the 2-arm end (Fig. 20). 69o further demonstrate the regioselective binding of hosts 38 and 39, mixed anion titrations were conducted.By adding one equivalent of dicarboxylate (pimelate or malonate) followed by an excess of acetate is was possible to assemble in, a stepwise fashion, pimelate at the 2-armed end then acetate at the 1-arm end.
Our recent investigations into the binding of dihydrogenpyrophosphate (H 2 ppi 2À ) to the [n]polynorbornane hosts have used the tributylammonium salt [(Bu 3 NH) 2 H 2 ppi] and 3-arm hosts 38 and 39 both bound this form of H 2 ppi 2À in a 1 : 1 H : G stoichiometry.The binding isotherms (Fig. 21) clearly indicate that the anion interacts with both the urea NÀH protons as well as the amide NÀH protons of the two-armed end whereas the single armed side appears to be completely ignored even when an excess of pyrophosphate was added.Regardless of the size of the binding cleft (either [3] or [5]polynorbornane) no response from the 1-arm end was noted.The cleft width also had little or no effect on the strength of the binding (Table 3).The contribution from the amide groups was considerable with the magnitude of the observed changes in chemical shift approaching that of the thiourea NÀH (Fig. 21).
Due to the regioselective recognition ability of 38 and 39 with pyrophosphate and the stepwise assembly process previously   accomplished using pimelate/acetate it was envisioned that with pyrophosphate bound at the 2-armed end, the single armed end should be free to bind a smaller anion such as phosphate or acetate.However, upon titration, the single armed end was still ignored, even when an excess of phosphate was added.Even when the anion addition order was reversed (one equivalent of phosphate was added followed by an excess of H 2 ppi 2À ) the isotherm quickly morphed into what would be expected of a pure H 2 ppi 2À titration.
Both the size of the cleft and the urea electron withdrawing groups (Ar-F or Ar-NO 2 ) had an influence on the ability of these hosts to regioselectively bind anions.The larger hosts (39)  showed less selectivity than their smaller counterparts.The b-series (Ar-NO 2 ) also showed less tendency towards regioselectivity than the a-series (Ar-F).While the exact cause of the regioselective binding remains unknown, one possibility, the formation of larger symmetric H : G complexes (e.g. 2 : 2), has been ruled out using NMR diffusion experiments.

One guest or two?
The last examples to be featured are those of the 4-arm hosts 40 and 41.In the titrations of dicarboxylates against these hosts a distinct 'inflection' in the binding isotherm appeared at approximately 1.0 eq. of anion (Fig. 22).It was reasoned that up until ca.1.0 eq. of dicarboxylate had been added a 1 : 1 H : G arrangement was preferred then once an excess of anion was added a 'switch' to a 1 : 2 H : G stoichiometry occurred (Fig. 22).
When titrations were performed using terephthalate and the 4-armed hosts a 1 : 1 H : G arrangement was noted for the [3]polynorbornane 40 but a 1 : 2 H : G complex for the longer [5]polynorbornane 41 (Fig. 23).Host 41 can encapsulate two rigid terephthalate dianions as the ethylene arms can flex away from the framework to minimise electrostatic repulsion between the two terephthalate units.
For H 2 ppi 2À the titrations and Job plots showed that the 4-armed hosts 40 and 41 bind in a symmetric 1 : 2 H : G stoichiometry.The titrations identified that all 12 H-bond donors of the host were involved and the strength of the 1 : 2 complexes formed was independent of the cavity width of the host as evidenced by log K values The combination of results suggests that each side of the host was acting independently and the dianions are not spanning the cleft (Fig. 24).

Conclusions and outlook
The outlook for further applications of norbornanes and [n]polynorbornanes in supramolecular chemistry is excellent as the full range of possible framework and cleft geometries is yet to be explored.The group at Deakin is currently developing multicomponent strategies for the rapid construction of [n]polynorbornane frameworks and aims to further expand the current range of hosts to include fluorescent signalling moieties and also to use these functionalised frameworks in applications such as organocatalysis. 74A full series of analogues of the LPS binder 10 are also in preparation.The results of these endeavours will be reported in due course.

Fig. 2
Fig.2Photoisomerisation of 3a to 3b enables cation recognition and transport from chloroform to water.17

Fig. 4 Fig. 5
Fig. 4 Proposed 1 : 2 H : G binding conformation of host 7a with two equivalents of AcO À and 7b in a 1 : 1 arrangement with AcO À .Fig. 5 Proposed 1 : 2 H : G binding conformation of hosts 5 and 6 (also representative of the binding mode of 4) with H 2 PO 4

Fig. 12
Fig.12Examples of [n]polynorbornane frameworks with curved and linear geometries as predicted by molecular modelling (r is the calculated radius of curvature).63

a
B5.0 B5.0 B5.3 Terephthalate 2À (n = phenyl) max Dd (ppm) 3.38 3.51 3.64 3Max Dd obtained from ArN-H after addition of 5.0 eq. of anion; log K were determined by 1 H NMR titration using WinEQNMR software 20 (fittingprogram 70 for terephthalate) with error r 15%.Values for log K Z 5 are indicated as approximate as they are at the limits of accuracy for NMR.Titrations were carried out with [H] i of B1.2 Â 10 À2 M. D indicates deprotonation thus H : G stoichiometry and log K could not be determined.

Fig. 16
Fig. 16 Molecular model calculated at H-F 3-21G* level of theory depicting the 1 : 1 complexes formed between the rigid aryl dicarboxylate, terephthalate 2À and (a) host 36b and, (b) host 37b.Internal CH protons highlighted in red.

Fig. 17
Fig. 17Titration isotherm for 37 against terephthalate using the internal C-H protons.
Fig. 17Titration isotherm for 37 against terephthalate using the internal C-H protons.

a
Max Dd obtained from ArN-H after addition of 5.0 eq. of anion; log K were determined by 1 H NMR titration using WinEQNMR software20 (fittingprogram70 for terephthalate) with (error r 15%).Titrations were carried out with [H] i of B2.5 Â 10 À3 M. D indicates deprotonation therefore H : G stoichiometry and log K could not be determined.A indicates a high degree of aggregation was noted and assessment of the titration data was impossible.R indicates that binding was regioselective or occurred at one end of the framework only.

Fig. 18
Fig.18Titration isotherm of host 39b upon the addition of terephthalate and proposed 1 : 1 complex formed between the 3 armed[5]polynorbornanes and terephthalate.

Fig. 19
Fig. 19 Titration isotherm of host 38a with pimelate (above) and an illustration of the stepwise binding process.

Fig. 21
Fig. 21 Titration isotherm of 3-arm host 38a upon the addition of H 2 ppi 2À and illustration of the regioselective recognition of H 2 ppi 2À by the 3-arm host 38.

Fig. 22
Fig. 22 Isotherm and proposed binding of adipate by host 40b clearly showing the 'switch' from a 1 : 1 to a 1 : 2 H : G arrangement with an excess of guest.

Fig. 24
Fig. 24 Proposed binding arrangement of host 41 (also representative of 40) with two equivalents of H 2 ppi 2À .

Table 1
20ximum observed chemical shifts, host : guest (H : G) stoichiometries and calculated association constants (log K) for hosts 5-7 a a log K were determined by 1 H NMR titration using WinEQNMR software,20(error o 14.0%).Titrations were carried out with initial host concentrations, [H] i , of B1.2 Â 10 À2 M. Max Dd obtained from ArN-H after addition of 5.0 eq. of anion.

Table 2
Maximum observed chemical shifts, H : G stoichiometries and calculated association constants (log K) for 2-arm hosts 36 and 37 a

Table 3
Maximum observed chemical shifts, H : G stoichiometry and calculated association constants (log K) for 3-arm hosts 38 and 39 a

Table 4
70ximum observed chemical shifts, H : G stoichiometries and calculated association constants (log K) for 4-arm hosts 40-41 a Max Dd obtained from ArN-H after addition of 5.0 eq. of anion; log K were determined by 1 H NMR titration using WinEQNMR software20(fittingprogram70for terephthalate) with (error r 15%).Titrations were carried out with [H] i of B2.5 Â 10 À3 M. a