SUPRA MOLECULAR CHE MISTRY - SCOPE A N D PERSPECTI VES M OLEC ULES - S UPER M OLEC ULES - MOLECULAR DEVICES

Nobel lecture, Dece mber 8, 1987 b y J E A N - M A R I E L E H N

Institut Le Bel, Université Louis Pasteur, 4, rue Blaise Pascal, 67000 Stras- bourg and Collège de France, 11 Place Marcelin Berthelot, 75005 Paris.

Abstract Supra molecular che mistry is the che mistry of the inter molecular bond, cover- i n g t h e str u ct ur es a n d f u n cti o ns of t h e e ntiti es f or m e d b y ass o ci ati o n of t w o or more che mical species. Molecular recognition in the super molecules for med by receptor-substrate binding rests on the principles of molecular co mple mentar- ity, as found in spherical and tetrahedral recognition, linear recognition b y coreceptors, metalloreceptors, a mphiphilic receptors, anion coordination. Su- pra molecular catalysis by receptors bearing reactive groups effects bond clea- vage reactions as well as synthetic, bond for mation via cocatalysis. Lipophilic receptor molecules act as selective carriers for various substrates and allo w to set up coupled transport processes linked to electron and proton gradients or to light. Whereas endo-receptors bind substrates in molecular cavities by conver- gent interactions, exo-receptors rely on interactions bet ween the surfaces of the receptor and the substrate; thus ne w types of receptors such as the metallonu- cleates may be designed. In co mbination with poly molecular asse mblies, recep- tors, carriers and catalysts may lead to molecular and supra molecular devices, defined as structurally organized and functionally integrated che mical syste ms built on supra molecular architectures. Their recognition, transfer and transfor- mation features are analyzed specifically fro m the point of vie w of molecular devices that would operate via photons, electrons or ions, thus defining fields of molecular photonics, electronics and ionics. Introduction of photosensitive groups yields photoactive receptors for the design of light conversion and charge separation centres. Redox active polyolelinic chains represent molecular wires for electron transfer through me mbranes. Tubular mesophases for med by stacking of suitable macrocyclic receptors may lead to ion channels. Molecular selfasse mbling occurs with acyclic ligands that for m co mplexes of double helical structure. Such develop ments in molecular and supra molecular design and engineering open perspectives to wards the realization of molecular pho- t o ni c, el e ctr o ni c a n d i o ni c d e vi c es, t h at w o ul d p erf or m hi g hl y s el e cti v e r e c o g ni- J.- M. L e h n 4 4 5 tion, reaction and transfer operations for signal and infor mation processing at the molecular level.

1. Fro m Molecular to Supra molecular Che mistry Molecular che mistry, the che mistry of the covalent bond, is concerned with uncovering and mastering the rules that govern the structures, properties and transfor mations of molecular species. Supra molecular che mistry may be defined as “che mistry beyond the mole- cule”, bearing on the organized entities of higher co mplexity that result fro m the association of t wo or more che mical species held together by inter molecular forces. Its develop ment requires the use of all resources of molecular che mistry co mbined with the designed manipulation of non-covalent interactions so as to for m supra molecular entities, super molecules possessing features as well de- lined as those of molecules the mselves. One may say that super molecules are to molecules and the inter molecular bond what molecules are to ato ms and the covalent bond. Basic concepts, ter minology and definitions of supra molecular che mistry were i ntr o d uce d earlier [ 1- 3] and will only be su m marized here. Section 2.3. belo w provides a brief account on the origins and initial develop ments of our work which led to the for mulation of supra molecular che mistry. Molecular associations have been recognized and studied for a long ti me [4] and the ter m “über moleküle”, i.e. super molecules, was introduced already in the mid-1930’s to describe entities of higher organization resulting fro m the association of coordinatively saturated species [5]. The partners of a supra molecular species have been na med molec ular receptor a n d s ubstrate [ 1, 2, 6 5], t h e s u bstr at e b ei n g usually the s maller co mponent whose binding is being sought. This ter minol- ogy conveys the relation to biological receptors and substrates for which P a u l E hrlic h stated that molecules do not act if they are not bound (“ Corpora non a g u nt nisi fi x at a ”). T h e wi d el y e m pl o y e d t er m of liga nd see med less appropriate in vie w of its many unspecific uses for either partner in a co mplex. Molecular interactions for m the basis of the highly specific recognition, reaction, trans- p ort, r e g ul ati o n et c. pr o c ess es t h at o c c ur i n bi ol o g y s u c h as s u bstr at e bi n di n g t o a receptor protein, enzy matic reactions, asse mbling of protein-protein co m- ple xes, i m munological antigen-antibody association, inter molecular reading, translation and transcription of the genetic code, signal induction by neuro- tra ns mitters, cell ular rec o g niti o n, etc. T he desi g n of artificial, a bi otic, rece pt or molecules capable of displaying processes of highest efficiency and selectivity requires the correct manipulation of the energetic and stereoche mical features of the non-covalent, inter molecular forces (electrostatic interactions, hydrogen bonding, Van der Waals forces etc.) within a defined molecular architecture. In doing so, the che mist may find inspiration in the ingenuity of biological events and encourage ment in their de monstration that such high efficiencies, s el e cti viti es a n d r at es c a n i n d e e d b e att ai n e d. H o w e v er c h e mistr y is n ot li mit e d t o s yst e ms si mil ar t o t h os e f o u n d i n bi ol o g y, b ut is fr e e t o i n v e nt n o v el s p e ci es and processes. Bi n di n g of a s u bstrate t o its r e c e pt or yields the super molecule and Sche me 1 . Fro m molecular to supra molecular che mistry: molecules super molecules, molecular and supra molecular devices.

involves a molecular recognition process. If, in addition to binding sites, the receptor also bears reactive functions it may effect a che mical transfor mation on the bound substrate, thus behaving as a supra molecular reagent or catalyst. A lipophilic, me mbrane soluble receptor may act as a carrier effecting the translocation of the bound substrate. Thus, molec ular recog nitio n, tra nsfor matio n a n d tra nslocatio n represent the basic functions of supra molecular species. More co mplex functions may result fro m the interplay of several binding subunits in a polytopic coreceptor. In association with organized poly molecular asse mblies and phases (layers, me mbranes, vesicles, liquid crystals, etc.), functional su- per molecules may lead to the develop ment of m olec ul ar de vices. T h e pr es e nt t e xt describes these various aspects of supra molecular che mistry (diagra m matically sho wn in Sche me 1) and sketches so me lines of future develop ment (for earlier g e n e ra l p re s e n ta tio n s s e e [1 -3 , 6 -9 ]). T h e results discussed here, taken mainly fro m our o wn work, have been co mpleted by references to other studies, in order to dra w a broader picture of this rapidly evolving field of research. E mphasis will bear on conceptual fra me work, classes of co mpounds and types of processes. Considering the vast literature that has developed, the topics of vari o us meeti n gs a n d s y m p osia, etc., there is no possibility here to do justice to the nu merous results obtained, all the more to provide an exhaustive account of this field of science. Supra molecular che mistry, the designed che mistry of the inter molecular bond, is rapidly expanding at the frontiers of molecular science with physical and biological pheno mena.

2. Molecular Recognition

2.1. Recog nitio n - I nfor matio n - Co mple me ntarity Molecular recognition has been defined as a process involving both bi ndi ng a n d selectio n of substrate(s) by a given receptor molecule, as well as possibly a s pecific f u nctio n [ 1]. M er e bi n di n g is n ot r e c o g niti o n, alt h o u g h it is oft e n t a k e n J.- M. L e h n 4 4 7 as s u c h. O n e m a y s a y t h at r e c o g niti o n is bi n di n g wit h a p ur p os e, li k e r e c e pt ors are li ga n ds wit h a p ur p ose. It i m plies a str uct urall y well defi ne d patter n of inter molecular interactions. Bi n di n g of σ t o for ms a super molecule characterized by its ther modyna m- ic a n d ki netic sta bilit y a n d selecti vit y, i.e. b y t he a m o u nt of e ner g y a n d of infor mation brought into operation. Molecular recognition thus is a question of i nfor matio n storage a n d rea d o ut at t h e s u pr a m ol e c ul ar l e v el. I nf or m ati o n m a y b e stored in the architecture of the ligand, in its binding sites (nature, nu mber, arrange ment) and in the ligand layer surrounding bound σ; it is r e a d o ut at t h e rate of for mation and dissociation of the super molecule. Molecular recognition thus corresponds to opti mal infor mation content of f or a gi v e n σ [ 1, 3]. T his a mounts to a generalized do uble co mple me ntarity pri nciple extending over energeti- cal (electronic) as well as geo metrical features, the celebrated “lock and key”, st eri c fit c o n c e pt e n u n ci at e d b y E mil Fisc her in 1894 [10]. Enhanced recognition beyond that provided by a single equilibriu m step may be achieved by multi- step recognition and coupling to an irreversible process [11]. The ideas of molecular recognition and of receptor che mistry have been penetrating che mistry more and more over the last fifteen years, na mely in vie w of its bi o or g a ni c i m pli c ati o ns, b ut m or e g e n er all y f or its si g nifi c a n c e i n i nt er m o- lecular che mistry and in che mical selectivity [1-3, 6-9, 12-21].

2.2. Molec ular Receptors - Desig n Pri nciples Receptor che mistry, the che mistry of artificial receptor molecules may be consid- ered a generalized coordination che mistry, not li mited to transition metal ions b ut e xt e n di n g t o of all t y p es of s u bstr at es: c ati o ni c, a ni o ni c or n e utr al s p e ci es of organic, inorganic or biological nature. In order to achieve high recognition it is desirable that receptor and sub- strate be i n c o ntact o ver a lar ge area. T his occ urs w he n is a ble t o wra p around its guest so as to establish nu merous non covalent binding interactions a n d t o se nse its m olec ular size, s ha pe a n d arc hitect ure. It is t he case f or receptor molecules that contain intra molecular cavities into which the sub- str at e m a y lit, t h us yi el di n g a n i n cl usi o n c o m pl e x, a c r y pt at e. In such concave receptors the cavity is lined with binding sites directed to wards the bound species; they are endopolarophilic [1] a n d co nverge nt, a n d m a y b e t er m e d e ndo- rece ptors ( s e e als o b el o w). Macropolycyclic str uct ures m e et t h e r e q uir e m e nts f or d esi g ni n g artifi ci al r e c e p- tors: - they are large ( macro) and may therefore contain cavities and clefts of appropriate size and shape; - they possess nu merous branches, bridges and connections (polycyclic) that allo w to construct a given architecture endo wed with desired dyna mic features; - they allo w the arrange ment of structural groups, binding sites and reactive functions. The balance bet ween rigidity and flexibility is of particular i mportance for the dyna mic properties of a n d of σ. Although high recognition may be achieved with rigidly organized receptors, processes of exchange, regulation, cooperativity and allostery require a built-in flexibility so that may adapt and respond to changes. Flexibility is of great i mportance in biological receptor- 4 4 8 Che mistry 1987 substrate interactions where adaptation is often required for regulation to occur. Such designed dyna mics are more difficult to control than mere rigidity and recent develop ments in molecular design methods allo wing to explore both structural and dyna mical features may greatly help [22]. Receptor design thus covers both static and dyna mic features of macropolycyclic structures. T he sta bilit y a n d selecti vit y of σ binding result fro m the set of interaction sites i n a n d m a y b e str u ct ur all y tr a nsl at e d i nt o accu mulation ( or c ollecti o n) + orga nizatio n (or orientation) i.e. bringing together binding sites and arranging the m in a suitable pattern. Model co mputations on ( N H 3 ) n cl usters of differe nt geo metries have sho wn that collection involves appreciably larger energies than changes in orientation [23] . One may note that these intersite repulsions ar e b uilt i nt o a p ol y d e nt at e li g a n d i n t h e c o urs e of s y nt h esis [ 1]. We have studied receptors belonging to various classes of macropolycyclic structures ( macrocycles, macrobicycles, cylindrical and spherical macrotricy- cles, etc.) expanding progressively our initial work on macrobicyclic cationic cryptates into the investigation of the structures and functions of super mole- cules presenting molecular recognition, catalysis and transport processes.

2. 3. I niti al St u dies. S p heric al Rec o g niti o n i n Cr y pt ate C o m ple xes. T h e si m pl est r e c o g niti o n pr o c ess is t h at of s p h eri c al s u bstr at es; t h es e ar e eit h er positively charged metal cations (alkali, alkaline-earth, lanthanide ions) or the negative halide anions. During the last 20 years, the co mplexation che mistry of alkali cations deve- lopped rapidly with the discovery of several classes of more or less po werful and selective ligands: natural [24] or synthetic [25, 26] macrocycles (such as valino mycin, 18-cro wn-6, spherands) as well as macropolycyclic cryptands and crypto-spherands [1, 6, 9, 26-29]. It is the design and study of alkali metal cryptates that started our work which developed into supra molecular che mis- tr y. It m a y b e s uit a bl e at t his st a g e t o r e c o u nt bri efl y t h e ori gi ns of o ur w or k, tr yi n g t o tr a c e t h e i niti al m oti v ati o ns a n d t h e e m er g e n c e of t h e first li n es of r es e ar c h. I n t he c o urse of t he year 1 9 6 6, m y i nterest f or t he pr ocesses occ urri n g i n t he n er v o us s yst e m, l e d m e t o w o n d er h o w a c h e mist mi g ht c o ntri b ut e t o t h e st u d y of t h es e hi g h est bi ol o gi c al f u n cti o ns. T h e el e ctri c al e v e nts i n n er v e c ells r est o n changes in the distributions of sodiu m and potassiu m ions across the me m- br a n e. T his s e e m e d a p ossi bl e e ntr y i nt o t h e fi el d, si n c e it h a d j ust b e e n s h o w n that the cyclodepsipeptide valino mycin [24c], whose structure and synthesis had been reported [24d], was able to mediate potassiu m ion transport in mitochondria [24e]. These results [24d,e] made me think that suitably de- signed synthetic cyclopeptides or analogues could provide means of monitoring cation distribution and transport across me mbranes. Such properties were also dis pla ye d b y ot her ne utral a nti bi otics [ 2 4f] of t he e n niati n a n d acti n [ 2 4 g] groups, and were found to be due to selective co mplex for mation with alkali metal cations [24h-1], thus making these substances io nophores [24 m]. Ho wever, since cation co mplexation might also represent a means of increasing the reactivity of the counteranion (anion activation) [6, 35], it beca me desirable to J.- M. L e h n 4 4 9

envisage molecules which would be che mically less reactive than cyclic pep- tides [a]. Thus, when the cation binding properties of macrocyclic polyethers (cro wn ethers) were reported by Charles Pedersen [25a], these substances were perceived as co mbining the co mplexing ability of the macrocyclic antibiotics with the che mical stability of ether functions. Mean while, it had also beco me clear that co mpounds containing a three-di mensional, spheroidal cavity sur- rounding entirely the bound ion, should for m stronger co mplexes than the rather flat shaped macrocycles; thus e merged the idea of designing macrobicy- clic li ga n ds. Work started in October 1967 yielded the first such ligand [2.2.2] 3 i n Septe mber of 1968; its very strong binding of potassiu m ions was noted at once and a cryptate structure was assigned to the co mplex obtained, allo wing also to envisage its potential use for anion activation and for cation transport [29a] [ b]. O t h er li g a n ds s u c h as 1 a n d 2 or lar ger o nes w ere s y nt hes ize d a n d nu merous cryptates were obtained [29b]. Their structure was confir med by crystal structure deter minations of a nu mber of co mplexes, such as the rubi- di u m cr y ptate of 3, 4 b [ 2 9 c ] and their stability constants were measured [28]. The proble m of spherical recog nitio n is t h at of s el e cti n g a gi v e n s p h eri c al i o n a mong a collection of different spheres of sa me charge. Thus, the macrobicyclic cryptands l- 3 for m highly stable and selective cryptatcs [ M n + (cr y pta n d)] s u c h as 4 , wit h t h e c ati o n w h os e si z e is c o m pl e m e nt ar y t o t h e si z e of t h e c a vit y i. e. Li + , N a + a n d K + f or 1, 2 a n d 3 respectively [28a, 29a]. Others display high selectivity for alkali versus alkaline-earth cations [28b]. Thus, recognition features equal to or higher than those of natural macrocyclic ligands may be achieved. The spherical macrotricyclic cryptand 5 binds strongly and selective- l y t he lar ger s p herical cati o ns, gi vi n g a str o n g Cs + c o m pl e x, a s i n 6 [ 3 0].

[a] Earlier observations had suggested that polyethers i nt er a ct wit h al k ali c ati o ns. S e e f or i nst a n c e i n H. C. Br o w n, E.J. M e a d, P. A. Ti er n e y, J. A m. C h e m. S o c. 7 9 ( 1 9 5 7) 5 4 0 0; J. L. D o w n, J. L e wis, B. M o or e, G. Wil ki ns o n, J. C h e m. S o c. 1 9 5 9, 3 7 6 7; s u g g esti o ns h a d als o b e e n m a d e f or th e d esi g n of or g a ni c li g a n ds, se e in R.J. P. Willi a ms. T h e A n al yst 7 8 ( 1 9 5 3) 5 8 6. Q u art erl y R e v. 2 4 ( 1 9 7 0) 3 3 1. [ b] T o n a m e t his n e w cl ass of c h e mi c al e ntiti es, a ter m r o ot e d i n gr e e k a n d lati n, a n d w hi c h w o ul d als o b e e q u all y s u g g esti v e i n Fr e n c h, E n glis h. G er m a n a n d p ossi bl y (!) ot h er la n g u a g es w as s o u g ht; “ cr y pt at es ” a p p e ar e d p arti c ul arl y s uit a bl e f or d esi g n ati n g a c o m pl e x i n w hi c h t h e c ati o n w as c o nt ai n e d i nsi d e t h e m ol e c ul ar c a vit y, t h e cr y pt, of t h e li g a n d t er m e d “ cr y pt a n d ”. 4 5 0 Che mistry 1987

5 6 7 ( Z = H )

A nio n cryptates are for med by the protonated polya mines 7 [ 3 1] a n d 5 [ 3 2] with the spherical halide anions F - a n d C l - r e s p e c t i v e l y . 5 - 4 H + b i n d s C l - v er y str o n gl y a n d v er y s el e cti v el y wit h r es p e ct t o Br - a n d ot her t y pes of a ni o ns, gi vi n g t h e [ Cl- ( 2- 4 H + )] cr y ptate 8 . Quaternary a m moniu m derivatives of such type of macrotricycles also bind spherical anions [33]. Thus, cryptands 1 -3 a n d 5 as well as related co mpounds display s p h e r i c a l recog nitio n of appropriate cations and anions. Their co mplexation properties result fro m their macropolycyclic nature and define a c r y pt at e eff e ct c haracter- i z e d b y hi g h st a bilit y a n d s el e cti vit y, sl o w e x c h a n g e r at es a n d effi ci e nt s hi el di n g of the bound substrate fro m the environ ment. As a consequence of these features, cryptate for mation strongly influences physical properties and che mical reactivity. Nu merous effects have been brought about and studied in detail, such as: stabilization of alkalides and electrides [34], dissociation of ion pairs, anion activation, isotope separation, toxic metal binding, etc. These results will not be described here and revie ws m a y b e f o u n d i n [ 6, 3 5- 3 8].

2.4. Tetrahedral Recog nitio n Selective binding of a tetrahedral substrate requires the construction of a receptor molecule possessing a tetrahedral recognition site, as realized in the m a cr otri c y cl e 5 t h at c o nt ai ns f o ur nitr o g e n a n d si x o x y g e n bi n di n g sit es l o c at e d respectively at the corners of tetrahedron and of an octahedron [30].

+ Indeed, 5 for ms an exceptionally stable and selective cryptate [ N H 4 5], + 9 , with the tetrahedral N H 4 cati o n, d ue t o t he hi g h de gree of str uct ural a n d + energetical co mple mentarity. N H 4 h as t h e si z e a n d s h a p e f or fitti n g i nt o t h e c a vit y of 5 and for ming a tetrahedral array of hydrogen bonds with A th e fo u r n itro g e n site s [3 9 ]. s a r es ult of its v er y str o n g bi n di n g, t h e p K a of t h e + + N H 4 cryptate is about six units higher than that of free N H 4 indicating ho w m u c h str o n g bi n di n g m a y aff e ct t h e pr o p erti es of t h e s u bstr at e. It als o i n di c at es that si milar effects exist in enzy me active sites and in biological receptor- substrate binding.

The unusual protonation features of 5 in aqueous solution (high p K a f o r double protonation, very slo w exchange) and 1 7 O- N M R studies led to the J.- M. Le h n

+ for m ulatio n of a water cry ptate [ H 2 O (5-2 H )] 1 0 wit h t he di proto nate d macr otric ycle [2, 6, 40]. T he facilitati o n of t he sec o n d pr ot o nati o n of 5 re pre- s e nt s a positi ve coo perati vit y, i n w hic h t he first pr ot o n a n d t he effect or m olec ule water set t he sta ge bot h str uct urall y a n d e ner geticall y for t he fixatio n of a seco n d proto n.

+ + Co nsi deri ng toget her t he t hree cry ptates [ N H 4 5] 9, [ H 2 O (5-2 H )] 1 0 a n d [ Cl- (5-4 H + )] 8 , it is see n t hat t he s p herical macr otric ycle 5 i s a m olec ular rece pt or p ossessi n g a tetr a he dr al rec o g niti o n site i n w hic h t he s u bstrates are b o u n d i n a tetra he dral arra y of h y dr o ge n b o n ds. It re prese nts a state of t he art ill ustr ati o n of t h e m ol e c ul ar e n gi n e eri n g i n v ol v e d i n a bi oti c r e c e pt or c h e m-

+ istr y. Si nce it bi n ds a tetra he dral cati o n N H 4 , a be nt ne utral m olec ule H 2 O or a s p h eri c al a ni o n Cl - when res pectively un protonate d, di protonate d an d tetra- proto nate d, t he macrotricyclic cry pta n d 5 be ha ves like a sort of molec ular c h a m el e o n r es p o n di n g t o p H c h a n g es i n t h e m e di u m!

+ T he macrobicycle 3 also bi n ds N H 4 for ming cry ptate 1 1. The dyna mic pr o perties of 1 1 wit h r es p e ct t o 9 reflect t he rece ptor-s ubstrate bi n di ng co m ple-

+ mentarity: whereas N H 4 i s fir ml y h el d i n si d e t h e c a vit y i n 9, it u n dergoes i nt er n al r ot ati o n i n 1 1 [ 4 1].

2. 5. Recognition of A m moniu m Ions and Related Substrates I n vi e w of t h e i m p ort a nt r ol e pl a y e d b y s u bstit ut e d a m m o ni u m i o ns i n c h e mis- try a n d i n biology, t he de velo p me nt of rece ptor molec ules ca pable of recog niz- i ng s uc h s ubstrates is of s pecial i nterest. Macrocyclic polyet hers bi n d pri mary + i nt o t heir circ ular ca vit y via t hree a m moniu m ions by anchoring the - N H 3 + N- H . . O hy droge n bo n ds as s ho w n i n 1 2 a [12-15,25,42]; ho wever they

+ + co m plex alkali catio ns s uc h as K more stro ngly. Selective bi n di ng of R- N H 3 + may be ac hieve d by exte n di ng t he res ults obtai ne d for N H 4 co mplexation by 5 a n d m a ki n g us e of t h e a z a- o x a m a cr o c y cl es [ 1 5, 4 3 1 d e v el o p e d i n t h e c o urs e of t he sy nt hesis of cry pta n ds. I n dee d, t he triaza- macrocycle [18]- N 3 O 3 w hic h + + for ms a co m ple me ntary array of t hree N- H . . . N b o n ds 1 3 , selects R- N H 3 o ver K + a n d is t h us a r e c e pt or u nit f or t his f u n cti o n al gr o u p [ 4 3]. 4 5 2 Che mistry 1987

+ A great variety of macrocyclic polyet hers have bee n s ho w n to bi n d R- N H 3 molec ules wit h str uct ural a n d c hiral selecti vity [12,13,42]. Partic ularly stro ng bi n di ng is s ho w n by t he tetracarboxylate 1 2 b w hic h co nserves t he desirable

basic [18]-0 6 ri n g a n d a d ds electrostatic i nteractio ns, t h us for mi n g t he most stable metal ion an d a m moni u m co m plexes of any polyether macrocycle [44]. Very marke d ce ntr al discri mi n ati o n is observe d in favo ur of pri mary a m moni u m i o ns wit h res pect t o m ore hi g hl y s u bstit ute d o nes; it all o ws prefere ntial bi n di n g of biologically acti ve io ns s uc h as nora dre nali ne or nore p he dri ne wit h res pect to t heir N- met hylate d derivatives a dre nali ne a n d e p he dri ne [44]. Mo d ulatio n of t he co m plexatio n feat ures of 1 2 b y var yi n g t he si de gr o u ps X so as to ma ke use of s pecific i nteractio ns (electrostatic, H- bo n di n g, c har ge

+ tra nsfer, li po p hilic) bet wee n X a n d t he R gro u p of t he ce ntrally bo u n d R- N H 3 s u bstrate, bri n gs a b o ut l ater al discri mi n ati o n effects. T his als o re prese nts a ge ner- al way of mo deli ng i nteractio ns prese nt i n biological rece ptor-s ubstrate co m- plexes, s uch as that occ urring bet ween nicotina mi de an d try pto phane [45]. O n e m a y t h us att a c h t o 1 2 a mi n o- a ci d r esi d u es, l e a di n g t o “ p ar all el p e pti d es ” [ 4 4] as i n 1 2 c, n ucleic bases or n ucleosi des, sacc hari des, etc.

m + Binding of metal-a mine co mplexes M( N H 3 )n to macrocyclic polyethers

vi a N- H... O i nt er a cti o ns wit h t h e N H 3 gr o u ps, lea ds t o a variet y of s u pra m ole- c ular s pecies of “s u perco m plex ty pe” by seco n d s p here coor di natio n [46]. As + s ubstrate, bi n di ng to aza-oxa or polyaza macrocycles (see 13) wit h R- N H 3 may also be ex pecte d. Strong co m plexation by macrocycles bearing negative c h ar g es (s u c h as 1 2 b or t h e h e x a c ar b o x yl at e i n 1 4 [ 4 7]), s h o ul d all o w t o i n d u c e vario us processes bet ween centrally bo un d metal-a mine s pecies an d lateral gr o u ps X i n 1 2 ( e ner g y a n d electro n tra nsfer, c he mical reactio n, etc.). Rece ptor sites for seco n dary a n d tertiary a m mo ni u m gro u ps are also of + i o ns bi n d t o t he [12]- N- O macrocycle via t wo hy drogen i nterest. R 2 N H 2 2 2 bo n ds [48]. T he case of q uater nary a m mo ni u m io ns will be co nsi dere d belo w.

T he g ua ni di ni u m catio n bi n ds to [27]- O 9 macrocycles t hro ug h a n array of six H- bo n ds [49] yiel di n g a partic ularl y sta ble co m plex 1 4 wit h a hexacarboxy- l at e r e c e pt or, t h at als o bi n ds t h e i mi d a z oli u m i o n [ 4 9 a]. J.- M. Le h n 4 5 3

3. Anion Coordination Che mistry and the Recognition of Anionic Sub- str ates Alt ho ug h a nio nic s pecies play a very i m porta nt role i n c he mistry a n d i n biology, t heir co m plexatio n c he mistry we nt u nrecog nise d as a s pecific fiel d of researc h, w hile t he co m plexatio n of metal io ns a n d, more rece ntl y, of catio nic molec ules was exte nsively st u die d. T he coor di natio n c he mistry of a nio ns may be ex pecte d t o yiel d a great variet y of n o vel str uct ures a n d pr o perties of b ot h c he mical a n d bi ol o gical si g nifica nce [2, 6, 32). T o t his e n d, a ni o n rece pt or molec ules a n d bi n di ng s ub u nits for a nio nic f u nctio nal gro u ps have to be de vise d. Researc h has bee n i ncreasi n gl y acti ve al o n g t hese li nes i n rece nt years a n d a nio n coor di natio n c he mistr y is pro gressi vel y b uil di n g u p [8, 9, 50]. Positi vel y c har ge d or ne utral electro n deficie nt gro u ps ma y ser ve as i nterac- tion sites for anion bin ding. A m moni u m an d g uani dini u m units which for m + N- H... X - bon ds have mainly been use d, b ut ne utral polar hy drogen bon ds (e.g. wit h - N H C O- or - C O O H f u nctio ns), electro n deficie nt ce ntres (boro n, ti n, et c.) or m et al i o n c e ntr es i n c o m pl e x es, als o i nt er a ct wit h a ni o ns. Polya m moniu m macrocycles and macropolycycles have been studied most exte nsi vel y as a nio n rece ptor molec ules. T he y bi n d a variet y of a nio nic s pecies (i nor ga nic a nio ns, car box ylates, p hos p hates, etc.) wit h sta bilities a n d selecti vi- ties res ulti n g fr o m b ot h electr ostatic a n d str uct ural effects. Stro ng a n d selective co m plexes of t he s p herical h ali de a ni o ns are for me d by macrobicyclic an d by spherical macrotricyclic polya m moniu m receptors such as t he proto nate d for ms of 5 [ 3 2] (s e e 8 ), of bis-tr e n 1 5 [51] a n d of relate d co m po un ds [50, 52]. T he hexa proto nate d for m of bis-tre n, 1 5 - 6 H + co mplexes various monoato- mic a n d pol yato mic a nio ns [51]. T he cr ystal str uct ures of fo ur s uc h a nio n

1 6 4 5 4 C he mistry 1987

cry ptates provi de a u niq ue series of a nio n coor di natio n patter ns [51b]. T he s p herical hali de io ns are not co m ple me ntary to t he elli psoi dal rece ptor ca vity a n d distort t he str uct ure, F - being bo un d in a tetrahe dral array of H-bon ds a n d C l- a n d B r - havi ng octa he dral coor di natio n. T he li near triato mic a nio n

- + N 3 has a s ha pe a n d size co m ple me ntary to t he ca vity of 1 5 - 6 H a n d is bo u n d i nsi de by a pyra mi dal array of t hree H-bo n ds to eac h ter mi nal nitroge n,

- + + for mi ng t he cry ptate [ N 3 ( 1 5 - 6 H )], 1 6 ( Fi g ure 1). T h us, 1 5- 6 H i s a - molec ular rece ptor recog nizi ng li near triato mic s pecies s uc h as N 3 , w hi c h is in dee d bo un d m uch more strongly than other singly charge d anions. Carboxylates a n d phosphates bin d to polya m moni u m macrocycles with stabili- ties a n d selecti vities deter mi ne d by str uct ure a n d c harge of t he t wo part ners [50, 51, 53-57]. T he desi g n of rece pt or u nits f or t hese f u ncti o nal gr o u ps is of m uc h i nterest si nce t hey ser ve as a nc hori ng sites for n u mero us biological s ubstrates. Th us, strong co m plexes are obtaine d with macrobicyclic polya m- mo ni u m pockets i n w hic h carboxylate (for mate, acetate, oxalate, etc.) a n d phos phate gro u ps interact with several a m moni u m sites [51]. The g uani dini u m gro u p, w hic h ser ves as bi n di ng site i n biological rece ptors, may for m t wo H- bo n ds wit h carboxylate a n d p hos p hate f u nctio ns a n d has bee n i ntro d uce d i nto acyclic [58] a n d macrocyclic [59] str uct ures. Bi n di ng u nits mi micki ng t hat of va nco myci n are bei ng so ug ht [60]. Co m plexatio n of co m plex a nio ns of tra nsitio n metals s uc h as t he hexacya n-

n - i d e s M ( C N ) 6 yiel ds secon d coor dination s phere co m plexes, superco mplexes [53a] an d affects marke dly their electroche mical [61, 62] an d photoche mical [63] pr o perties. Of s pecial i nterest is t he str o n g bi n di n g of a de n osi ne m o n o-, di- and triphosphate ( A MP, A DP and ATP) a n d relate d co m po u n ds t hat play a very i m porta nt biological role [55-57]. Cascade type bi ndi ng a n d recog nitio n [64] o f a nio nic s pecies occ urs w he n a li ga n d first bi n ds metal i o ns w hic h t he n ser ve as i nteracti o n sites f or a n a ni o n. S uc h processes occ ur for i nsta nce i n li po p hilic catio n /a nio n pairs [65] a n d wit h C u(II) co m plexes of bis-tre n 1 5 a n d of macrocyclic polya mi nes [66]. Hetero n uclear N M R st u dies give i nfor matio n abo ut t he electro nic effects i n d uce d by a nio n co m plexatio n as fo u n d for c hlori de cry ptates [67]. J.- M. Le h n 4 5 5

Co m plexatio n of vario us molec ular a nio ns by ot her ty pes of macrocyclic liga n ds have bee n re porte d [50], i n partic ular wit h cyclo p ha ne ty pe co m- po u n ds. T wo s uc h rece ptors of defi ne d bi n di ng geo metries are re prese nte d by t he proto nate d for ms of t he macro polycycles 1 7 [68] a n d 1 8 [ 6 9]. Anion coor dination che mistry has th us ma de very significant progress in recent years. The develo p ment of other rece ptor molec ules possessing well defi ne d geo metrical a n d bi n di ng feat ures will allo w to f urt her refi ne t he re- q uire ments for anion recognition, s o as t o yiel d hi g hl y sta ble a n d selecti ve a nio n co m plexes wit h c haracteristic coor di natio n patter ns. T heoretical st u dies ma y be of m uc h hel p i n t he desi g n of a ni o n rece pt ors a n d i n t he a pri ori esti mati o n of bi n di n g feat ures, as rece ntl y ill ustrate d b y t he calc ulati o n of t he relati ve affi nit y of 5-4 H + for c hlori de a n d bro mi de io ns [70].

4. Coreceptor Molecules and Multiple Recognition O nce bi n di ng u nits for s pecific gro u ps ha ve bee n i de ntifie d, o ne may co nsi der co mbi ni ng several of t he m wit hi n t he sa me macro polycyclic arc hitect ure. T h us are for me d polyto pic corece ptor molec ules co ntai ni ng several discrete bi n di ng s ub units which may coo perate for the si m ultaneo us co m plexation of several s ubstrates or of a m ulti ply bo u n d ( poly ha pto) polyf u nctio nal s pecies. S uitable mo dificatio n wo ul d yiel d cocatalysts or cocarriers perfor mi ng a reactio n or a tra ns port o n t he bo u n d s ubstrate(s). F urt her more, beca use of t heir ability to perfor m m ulti ple reco g nitio n a n d of t he m ut ual effects of bi n di n g site occ u pa- tio n, s uc h corece ptors pro vi de e ntries i nto hig her for ms of molec ular be ha vio ur s uc h as coo perati vit y, alloster y, re g ulatio n as well as co m m u nicatio n or si g nal tra nsfer, if a s pecies is release d or ta ke n u p. Basic i deas a n d defi niti o ns co ncer ni ng corece ptor molec ules have bee n prese nte d i n more detail else w here [ 7] . T he si m plest class of corece ptors are t hose co ntai ni n g t wo bi n di n g s ub u nits, dito pic corece ptors, w hic h may belo ng to differe nt str uct ural ty pes. Co mbi na- tio n of c helati ng, tri po dal a n d macrocyclic frag me nts yiel ds macrocyclic, axial or lateral, macro bic yclic, or c yli n drical macrotric yclic str uct ures ( Fi g. 2). De pe n di ng o n t he nat ure of t hese u nits t he res ulti ng corece ptors may bi n d metal i o ns, or ga nic m olec ules or b ot h. 4 5 6 Che mistry 1987

Fi g. 2. C o m bi n ati o n of c h el ati n g, tri p o d al a n d c y cli c s u b u nits i nt o dit o pi c c or e c e pt ors of m a cr o c y c- li c, a xi al a n d l at er al m a cr o bi c y cli c a n d c yli n dri c al m a cr otri c y cli c t y p e s (fr o m l eft t o ri g ht).

4.1. Di n uclear a nd Poly n uclear Metal-Io n Cryptates Corece ptor molec ules co ntai ni ng t wo or more bi n di ng s ub u nits for metal io ns for m di n uclear or poly n uclear cry ptates i n w hic h t he arra nge me nt of t he metal ions is deter mine d by the macro polycyclic str uct ure. S uch co m plexes may prese nt a m ultit u de of ne w pro perties, s uc h as i nteractio ns bet wee n catio ns, electroche mical an d photoche mical processes, fixation of bri dging s ubstrates etc., t hat are of i nterest bot h for bioi norga nic mo deli ng a n d for m ultice nter m ul- tielectr o n reacti o ns a n d catal ysis. Di n u cl e ar cr y pt at es of li g a n ds b el o n gi n g t o all str u ct ur al t y p es s h o w n i n Fi g. 2 ha ve bee n obtai ne d. T his vast area will o nl y be ill ustrate d here b y a fe w rece nt exa m ples, (f or m ore details a n d refere nces see earlier re vie ws [64, 71]. Axial macrobicyclic liga n ds give di n uclear cry ptates s uc h as t he bis C u(I) co m plex 1 9 for me d b y a lar ge hexai mi ne str uct ure obtai ne d i n a o ne ste p m ulti ple c o n de nsati o n reacti o n; its cr ystal str uct ure is s h o w n i n 2 0 [ 7 2]. Lateral macrobicycles are dissy m metric by co nstr uctio n a n d allo w to ar- ra n ge metal ce ntres of differe nt pro perties i n t he sa me li ga n d. T h us, co m plexes of t y p e 2 1 c o m bi ne a re d ox ce ntre a n d a Le wis aci d ce ntre f or acti vati o n of a bo u n d s ubstrate [73]. J.- M. Le h n 4 5 7

2 3

“ Cl uster cryptates” may be for me d by asse mbli ng of metal io ns a n d bri dgi ng s pecies i nsi de t he molec ular ca vit y of pol yto pic rece ptors. T h us, i n t he tri n u- clear C u(II) co m plex 2 2 (cr ystal str uct ure 2 3 ) a [tris C u(II), bis µ 3 -hy droxo] gr o u p is b o u n d i n t he ca vit y of a trit o pic macr oc ycle [74]. M o deli n g of biological iro n-s ulf ur cl uster sites may e m ploy i ncl usio n i nto a p pro priate macr oc yclic ca vities [75]. T his i n or ga nic as pect of s u pra m olec ular s pecies re prese nts i n itself a fiel d of researc h i n w hic h ma ny novel str uct ures a n d reactivitics a wait to be discov- er e d.

4.2. Li near Recog nitio n of Molec ular Le ngth by Ditopic Coreceptors Rece ptor molec ules possessi ng t wo bi n di ng s ub u nits locate d at t he t wo poles of the str uct ure will co m plex preferentially s ubstrates bearing t wo a p pro priate f u nctio nal gro u ps at a dista nce co m patible wit h t he se paratio n of t he s ub u nits. T his dista nce co m ple me ntarity a mo u nts to a recog nitio n of molec ular le ngt h of t he s u bstrate b y t he rece pt or. S uc h li near molec ular recog nitio n of dicati o nic a n d dia nio nic s ubstrates corres po n ds to t he bi n di ng mo des ill ustrate d by 2 4 a n d 2 5.

+ Incorporation of macrocyclic s ub units that bin d - N H 3 gro u ps (see abo ve) i nt o c yli n drical macr otric yclic [76] a n d macrotetracyclic [77] str uct ures, yiel ds

2 4 2 5 4 5 8 Che mistry 1987

dito pic corece ptors t hat for m molec ular cry ptates s uc h as 2 6 wit h t er mi n al

+ dia m moniu m cations + H 3 N - ( C H 2 ) n - N H 3 . I n t he res ulti n g s u per molec ules t he s ubstrate is locate d i n t he ce ntral molec ular ca vity a n d a nc hore d by its t wo

+ - N H 3 i n t he macrocyclic bi n di ng sites, as s ho w n by t he crystal str uct ure 2 7

(2 6 with R= N A and A=( C H 2 )5 ) [ 7 8]. C h a n gi n g t h e l e n gt h of t h e bri d g es R i n 2 6 mo difies t he bi n di n g selecti vit y i n fa vo ur of t he s u bstrate of co m ple me ntar y length. N M R relaxation data have also sho wn that o pti mal partners present si milar molec ular motio ns i n t he rece ptor-s ubstrate pair. T h us, co m ple me ntar- it y i n t he s u pra m olec ular s pecies ex presses itself i n b ot h steric a n d d y n a mi c fit [ 7 9]. - Di a ni o nic s u bstr ates, t he dicarboxylates - O 2 C-( C H 2 )n - C O 2 , are bo u n d wit h le ngt h discri mi natio n by dito pic macrocycles s uc h as 2 8 . T hese rece ptors contain t wo tria m moni u m gro u ps as bin ding s ub units interacting with the ter mi nal carboxylate f u nctio ns, via a patter n sc he matically s ho w n i n 2 9 [ 8 0]. Th us, for both the ter minal dia m moni u m an d dicarboxylate s ubstrates, selective bi n di ng by t he a p pro priate rece ptors describes a li near recog nitio n J.- M. Le h n 4 5 9 process base d o n le ngt h co m ple me ntarity i n a dito pic bi n di ng mo de. I m porta nt biological s pecies s uch as polya mines, a mino-aci d an d pe pti de dia mines or dicar box ylates, etc. ma y also be bo u n d selecti vel y. N u mer o us variati o ns i n t he nat ure of t he bi n di n g s u b u nits or of t he bri d ges linking the m, are conceavable an d may be tailore d to s pecific co m plexation pr o perties (see f or i nsta nce [15, 81]). T he d evelop ment of heterotopic receptors m a y all o w t o bi n d i o n p airs [ 8 2] or z witt eri o ni c s p e ci es [ 8 3]. St u di es o n d y n a mic c o u pli n g [79, 84] bet wee n a rece pt or a n d a s u bstrate are of m uc h i nterest. Dy na mic feat ures of s u per molec ules corres po n d o n t he i nter mo- l e c ul ar l e v el t o t h e i nt er n al c o nf or m ati o n al m oti o ns pr es e nt i n m ol e c ul es t h e m- sel ves a n d defi ne molec ular reco g nitio n processes b y t heir d y na mics i n a d ditio n t o t heir str uct ural as pects.

4.3. Heterotopic Coreceptors. Spelea nds, A mphiphilic Receptors Co mbi natio n of bi n di ng s ub u nits of differe nt nat ure yiel ds heteroto pic rece p- tors t hat may bi n d s ubstrates by i nteracti ng si m ulta neo usly wit h catio nic, a ni o nic or ne utral sites, ma ki n g use of electr ostatic a n d Va n der Waals f orces as w ell as of s ol v o p h o bi c eff e cts. T he nat ural cyclo dextri ns were t he first rece ptor molec ules w hose bi n di ng pro perties to war ds orga nic molec ules, yiel de d a wealt h of res ults o n p hysical a n d c he mical feat ures of molec ular co m plexatio n [21, 85]. N u mero us ty pes of sy nt hetic macrocyclic rece ptors t hat co ntai n vario us orga nic gro u ps a n d polar f u nctio ns, ha ve bee n de velo pe d i n rece nt years. T hey co m plex both charge d an d uncharge d organic s ubstrates. Altho ugh the res ults obtai ne d ofte n describe mere bi n di ng rat her t ha n act ual recog nitio n, t hey ha ve pr o vi de d a lar ge b o d y of data t hat all o w t o a nal yze t he basic feat ures of molec ular co m plexatio n a n d t he pro perties of str uct ural frag me nts to be use d i n rece ptor desig n. We describe here mai nly so me of o ur o w n res ults i n t his ar e a, r ef erri n g t h e r e a d er t o s p e cifi c r e vi e ws of t h e s u bj e ct [ 2 0, 8 6] Sy nergetical o peratio n of electrostatic a n d hy dro p hobic effects may occ ur i n a m p hi p hilic rece pt ors co mbi ni ng c harge d polar sites wit h orga nic resi d ues w hic h s hiel d t he polar sites fro m solvatio n a n d i ncrease electrostatic forces. S uc h macro polycyclic str uct ures containing polar bin ding s ub units maintaine d by a polar sha ping co m ponents, ter me d s pele a n ds, yiel d molec ular cr y ptates, ( s pe- le ates), b y s u bstrate bi n di n g [87]. T h us, macrocycle 3 0 i ncor porati ng fo ur carboxylate gro u ps a n d t wo di p he n- yl met ha ne u nits [88], not o nly for ms very stable co m plexes wit h pri mary a m moni u m ions, b ut also strongly bin ds secon dary, tertiary an d q uaternary a m mo ni u m s ubstrates. I n partic ular, it co m plexes acet ylc h oli ne, givi ng i nfor ma- ti o n a b o ut t h e t y p e of i nt er a cti o ns t h at m a y pl a y a r ol e i n bi ol o gi c al a c et yl c h o- li ne rece ptors, s uc h as t he co mbi natio n of negative c harges wit h hy dro p hobic walls. Si milar effects o perate i n ot her a nio nic rece ptors co m plexi ng q uater nary a m moni u m cations [86a, 89]. Extensive st u dies have been con d ucte d on the co mplexation of heterocyclic a m moniu m ions such as diquat by macrocyclic pol yet her rece ptors [90].

+ T h e C H s - N H 3 cati o n f or ms a selecti ve s peleate 3 1 b y bi n di n g t o t h e [ 1 8]- 4 6 0 Che mistry 1987

3 1

N 3 O 3 s ub unit of a macro polycycle maintaine d by a cyclotriveratrylene sha ping co m po ne nt. T he tig ht i ntra molec ular ca vity efficie ntly excl u des larger s ub- str ates [ 8 7, 9 1]. A m p hi p hili c t y p e of bi n di n g als o o c c urs f or m ol e c ul ar a ni o ni c s u bstr at es [ 2 0, 86, 92]. C harge d heterocyclic ri ngs syste ms s uc h as t hose derive d fro m t he pyri di ni u m gro u p re prese nt a n efficie nt way to i ntro d uce si m ulta neo usly elec- trostatic i nteractio ns, h y dro p ho bic effects, str uct ure a n d ri gi dit y i n a molec ular rece ptor; i n a d ditio n t hey may be electroacti ve a n d p hotoacti ve [93]. E ve n si ngle pla nar u nits s uc h as diaza- pyre ni u m dicatio ns bi n d flat orga nic a nio ns re mar ka bl y well i n a q ueo us sol utio n, usi n g electrostatic i nteractio ns as well as hy dro p hobic stacki ng [93]. A macrocycle co ntai ni ng fo ur pyri di ni u m sites was fo u n d to stro ngly co m plex orga nic a nio ns [94]. Rece pt ors of cycloi ntercala nd t y pe, t hat i nc or p orate i ntercalati n g u nits i nt o a macr oc yclic s yste m, are of i nterest f or b ot h t he bi n di n g of s mall m olec ules a n d t heir o w n (selecti ve) i nteractio n wit h n ucleic aci ds. A c ycl o- bis-i nterc al a n d h a s b e e n f o u n d t o f or m a n i nt er c al ati v e m ol e c ul ar cr y pt at e 3 2 i n w hic h a nitr o be n- z e n e m ol e c ul e is i ns ert e d b et w e e n t h e t w o pl a n ar s u b u nits of t h e r e c e pt or [ 9 5]. S uc h rece pt ors are well s uite d f or t he rec o g niti o n of s u bstrates prese nti n g flat s ha pes a n d beco me of s pecial i nterest if i ntercalati ng dyes are i ncor porate d [ 9 6]. Fitti ng t he macrocyclic polya mi ne 3 3 wit h a si de c hai n beari n g a 9a- mi noacri di ne gro u p yiel ds a corece ptor t hat may dis play bot h a nio n bi n di ng via the polya m moni u m s ub unit an d stacking interaction by the intercalating d ye. It i nteracts wit h b ot h t he tri p h os p hate a n d t he a de ni ne gr o u ps of A T P a n d pr o vi d es i n a d diti o n a c at al yti c sit e f or its h y dr ol ysis (s e e b el o w) [ 9 7]. Flat aro matic heterocyclic u nits beari ng lateral aci d a n d a mi d f u nctio nal gro u ps, f u nctio n as rece ptors t hat perfor m size a n d s ha pe recog nitio n of co m- ple me ntary s ubstrates wit hi n t heir molec ular cleft [17b]. Rece ptor u nits co n- tai ni ng heterocyclic gro u ps s uc h as 2,6- dia mi no pyri di ne [98a] or a n ucleic base co mbi ne d wit h a n i ntercalator [98b] may lea d to recog nitio n of n ucleoti des via b as e p airi n g [ 9 8 c]. J.- M. Le h n 4 6 1

T he s p hericall y s ha pe d cryptopha nes allo w to st u dy recog nitio n bet wee n ne u- tral rece ptors a n d s ubstrates, a n d i n partic ular t he effect of molec ular s ha pe a n d vol u me co m ple me ntarity o n selectivity [99].

4.4. M ultiple Recog nitio n i n Metallo- Receptors Metallorece ptors are heteroto pic corece ptors t hat are able to bi n d bot h metal io ns a n d orga nic molec ules by mea ns of s ubstrate-s pecific u nits. Por p hyri n a n d α, α ’-bi pyri di ne (bi py) gro u ps have bee n i ntro d uce d as metal ion bin ding units in macro polycyclic corece ptors containing also macrocyclic

+ sites for a nc hori ng - N H 3 gro u ps [64, 71, 100]. T hese rece ptors for m mixe d- s ubstrate s u per molec ules by si m ultaneo usly bin ding metal ions an d dia m mon- i u m cations as sho wn in 3 4 [101]. Metallorece ptors an d the s u per molec ules w hic h t he y for m, t h us o pe n u p a vast area for t he st u d y of i nteractio ns a n d reactio ns bet wee n co-bo u n d orga nic a n d i norga nic s pecies. I n vie w of t he n u mber of metal io n co m plexes k no w n a n d of t he vario us pote ntial molec ular s ubstrates to t he bo u n d, n u mero us ty pes of metallorece ptors may be i magi ne d w hic h w o ul d be of i nterest as a bi otic c he mical s pecies or as bi oi n or ga nic m o del syste ms. 4 6 2 Che mistry 1987

5. S u pra molec ular Reactivity a n d Catalysis Reacti ve a n d catal ysis re prese nt major feat ures of t he f u nctio nal pro perties of s u pra molec ular syste ms. Molec ular rece ptors bearing a p pro priate reactive gro u ps i n a d ditio n to bi n di ng sites, may co m plex a s ubstrate ( wit h give n st a bilit y, s el e cti vit y a n d ki n eti c f e at ur es), r e a ct wit h it ( wit h gi v e n r at e, s el e c- ti vit y, t ur no ver) a n d release t he pro d ucts, t h us re ge nerati n g t he rea ge nt for a n e w c y cl e ( Fi g. 3). S u pr a m ol e c ul ar r e a cti vit y a n d c at al ysis t h us i n v ol v e t w o m ai n st e ps: bi ndi ng w hic h selects t he s u bstrate, f oll o we d b y - tr a nsf or m ati o n of t he bo u n d s pecies i nto pro d ucts wit hi n t he s u per molec ule for me d. Bot h ste ps take part i n t he m ol e c ul ar rec o g niti o n of the prod uctive s ubstrate a n d re q uire t he correct molec ular i nfor matio n i n t he reactive rece ptor [1]. Co m pare d to molec ular catalysis, a bi n di ng ste p is i n vol ve d t hat selects t he s ubstrate a n d prece des t he reactio n its elf. T he desig n of efficie nt a n d selecti ve s u pra molec ular reage nts a n d catalysts may gi ve mec ha nistic i nsig ht i nto t he ele me ntary ste ps of catalysis, pro vi de ne w t y pes of c he mical rea ge nts a n d effect reactio ns t hat re veal factors co ntri- b uti ng to e nzy matic catalysis. T his le d to n u mero us i n vestigatio ns, t hat ma de use mai nly of reage nts base d o n f u nctio nalize d α - cyclo dextri n, macrocyclic pol yet hers a n d c yclo p ha nes [84, 85, 102, 103]

5.1. Catalysis by Reactive Catio n Receptor Molec ules Ester cleavage processes ha ve bee n most freq ue ntly i n vestigate d i n e nzy me mo del st u dies. Macrocyclic polyet hers fitte d wit h si de c hai ns beari ng t hiol gro u ps cleave activate d esters wit h marke d rate e n ha nce me nts a n d c hiral discri mi na- tio n bet wee n o ptically active s ubstrates [104-106]. T he tetra-( L)-cystei nyl deri vati ve of macrocycle 1 2 c bi n ds ( P N P) esters of a mi no-aci ds a n d pe pti des, a n d reacts wit h t he bo u n d s pecies, releasi ng a s s h o w n i n 3 5 [ 1 0 5]. T h e r e a cti o n dis pl a ys i) s u bstr at e s el e cti vit y wit h ii) m ar k e d rate e n ha nce me nts i n favo ur of di pe pti de ester s ubstrates, iii) i n hibitio n by co m plexable metal catio ns t hat dis place t he bo u n d s ubstrate, iv) hig h c hiral recog nitio n bet wee n e na ntio meric di pe pti de esters, v) slo w b ut defi nite catalyt- i c t ur n o v er. 4 6 3

Bi n di ng of pyri di ni u m s ubstrates to a macrocycle of ty pe 1 2 c beari n g 1,4- di hy dro pyri dyl si de c hai ns le d to e n ha nce d rates of hydroge n tra nsfer fro m dihy dro pyri dine to pyri dini u m within the s u pra molec ular s pecies 3 6 f or m e d. T he first or der i ntraco m plex reactio n was i n hibite d a n d beca me bi molec ular o n dis place me nt of t he bo u n d s ubstrate by co m plexable catio ns [107]. Activatio n a nd orie ntatio n by bi n di ng was obser ve d for t he hy drolysis of 0- + for ms s uc h a stable co m plex wit h t he acetylhydroxyla mine. C H 3 COO N H 3 macroc yclic tetracarbox ylate 1 2 b [44], t hat it re mai ns proto nate d a n d bo u n d e ve n at ne utral p H, des pite t he lo w p K a , of t h e fr e e s p e ci es ( ~ 2. 1 5). As a consequence, its hy drolysis is accelerate d a n d excl usively gives acetate a n d hy droxyla mi ne, w hereas i n prese nce of K + io ns, w hic h dis place t he s ubstrate, t he latter rearra nges to acetyl hy droxa mic aci d C H 3 C O N H- O H (~ 50 %) [108]. T h us, stro ng bi n di ng may be s ufficie nt for marke dly accelerati ng a reacti o n a n d affecti n g its c o urse, a res ult t hat als o bears o n e nz y me catal yze d reacti o ns.

5.2. Catalysis by Reactive A nio n Receptor Molec ules T he develo p me nt of a nio n coor di natio n c he mistry a n d of a nio n rece ptor mole- c ules has ma de possi ble to perfor m molec ular catal ysis o n a nio nic s u bstrates of c he mical a n d bioc he mical i nterest [50], s uc h as a de nosi ne tri p hos p hate ( A T P). A T P hy drolysis was fo u n d to be catalyze d by a n u mber of proto nate d macrocyclic polya mines. In partic ular [24]- N 6 O 2 , 3 3, strongly bin ds A T P an d marke dly accelerates its hy drolysis to A D P a n d i norga nic p hos p hate over a wi de p H ra n ge [109]. T he reactio n prese nts first-or der ki netics a n d is catalytic wit h t ur no ver. It procee ds via i nitial for matio n of a co m plex bet wee n A T P a n d proto nate d 3 3, follo we d by a n i ntraco m plex reactio n w hic h may i nvolve a 4 6 4 Che mistry 1987

3 7 3 8 co mbi natio n of aci d, electrostatic, a n d n ucleo p hilic catalysis. Str uct ure 3 7 re presents one possible bin ding mo de of the A T P- 3 3 co m plex an d in dicates ho w clea vage of t he ter mi nal p hos p horyl gro u ps mig ht take place. A tra nsie nt inter me diate i dentifie d as phos phora mi date 3 8, is for me d by phos phorylation of the macrocycle by A T P an d is s ubseq uently hy drolyze d. St u dies with a nalog ues of A T P i n dicate d t hat t he mec ha nis m was dissociative i n c haracter wit hi n a pre-associative sc he me res ulti ng fro m rece ptor-s ubstrate bi n di ng [110]. I n t his pr ocess catal yst 3 3 prese nts prototy pical A T Pase activity, i.e. it behaves as a proto- A T Pase.

5. 3. C oc at al ysis: C at al ysis of s y nt hetic re acti o ns A f urt h er st e p li es i n t h e d esi g n of s yst e ms c a p a bl e of i n d u ci n g bond for mation rat her t ha n bo n d cleavage, t h us effecti ng s y nt hetic reactions as co m pare d to degra dative o nes. To t his e n d, t he prese nce of several bi n di ng a n d reactive gr o u ps is ess e nti al. S u c h is t h e c as e f or c or e c e pt or m ol e c ul es i n w hi c h s u b u nits may coo perate for s ubstrate bi n di ng a n d tra nsfor matio n [7]. T hey s ho ul d be a bl e t o p erf or m c oc at al ysis by bri ngi ng toget her s ubstrate(s) a n d cofactor(s) a n d me diating reactions bet ween the m within the s u pra molec ular str uct ure (Fig. 4) . A process of t his ty pe has bee n realize d rece ntly [111]. I n dee d, w he n t he sa me macrocycle 3 3 use d i n t he st u dies of A T P hy drolysis was e m ploye d as

2- catalyst for the hy drolysis of acetyl phos phate ( Ac P = C H 3 C O OP O 3 ), it w as f o u n d t o m e di at e t h e sy nthesis of pyrophosphate fro m AcP. Substrate consu mption was accelerate d a n d catal ytic wit h t ur no ver. T he res ults o btai ne d a gree wit h a catalytic cycle i n vol vi ng t he follo wi ng ste ps: i) s ubstrate Ac P bi n di ng by t he proto nate d molec ular catalyst 3 3; ii) p hos p hor ylatio n of 3 3 wit hi n t he s u pra- m ol e c ul ar c o m pl e x, gi vi n g t h e p h os p h or yl at e d i nt er m e di at e P N 3 8; iii) bi n di n g

2- of t he s ubstrate H P O 4 ( P); i v) p hos p horyl tra nsfer fro m P N to P wit h for matio n of pyro p hos p hate P P (Fig. 5); v ) release1 of t he pro d uct a n d of t he free c at al yst f or a n e w c y cl e. T h e f a ct t h at 3 3 is a dito pic corece ptor co ntai ni ng t wo dict hyle netria mi ne s ub u nits is of s pecial si g nifica nce for bot h P N a n d P P for matio n. T hese s ub u n- its ma y coo perate i n bi n di n g Ac P a n d acti vati n g it for p hos p hor yl tra nsfer via J.- M. Le h n 4 6 5

Fig. 4. Sche matic illustration of cocatalysis processes: group transfer and ligation reactions occur- ring within the supra molecular co mplex for med by the binding of substrates to the t wo macrocyclic s u b u nit s of a m a cr otri c y cli c c or e c c pt or m ol e c ul e. t he a m mo ni u m sites, i n provi di ng a n u n proto nate d nitroge n site for P N for ma- ti o n, as w ell as i n m e di ati n g p h os p h or yl tr a nsf er fr o m P N t o P. T h us 3 3 wo ul d co m bi ne electrostatic a n d n ucleo p hilic catal ysis i n a defi ne d str uct ural arra n ge- me nt s uita ble f or P P s y nt hesis via t w o s uccessi ve p h os p h or yl tra nsfers, dis pla y- i ng protoki nase ty pe activity (Fig. 5). T his bo n d- maki ng process exte n ds s u pra molec ular reacti vity to cocatalysis, me diati ng sy nthetic reactio ns wit hi n t h e s u pra molec ular entities for me d by corece ptor molec ules. The for mation of P P w he n A T P is hy drolyze d by 3 3 i n prese nce of di vale nt metal i o ns has als o bee n re porte d [112].

Fi g. 5. C o c at al y si s: p yr o p h o s p h at e s y nt h e si s b y p h o s p h or yl tr a n sf er m e di at e d m a cr o c y cl e 3 3 vi a the phosphorytated inter mediate 38. 4 6 6 C he mistry 1987

F u nctio nalize d macrocyclic polyet hers were use d for pe pti de bo n d for matio n i n t wo s uccessive i ntra-co m plex ste ps [113] a n d a t hiazoli u m beari ng macrobi- cyclic cyclo p ha ne was s ho w n to effect s u pra molec ular catalysis of t he be nzoi n con densation of t wo benzal dehy de molec ules [114]. T he syste ms describe d above possess t he pro perties t hat defi ne s u pra molec u- lar reacti vit y a n d catal ysis: s u bstrate reco g nitio n, reactio n wit hi n t he s u per mo- lec ule, rate acceleratio n, i n hibitio n by co m petitively bo u n d s pecies, str uct ural a n d c hiral selecti vit y, catal ytic t ur n o ver. Ma n y ot her t y pes of pr ocesses ma y be i magi ne d. T h us, s u pra molec ular catalysis of t he hy drolysis of u nactivate d esters a n d of a mi des prese nts a c halle n ge [115] t hat c he mistr y has met i n nat ural e nz y matic rea ge nts b ut not yet i n abiotic catal ysts. Desi g ni n g mo difie d enzy mes by che mical m utation [116], or by protei n e ngi neeri ng [117] a n d pro d ucing catalytic proteins by antibo dy in d uction [118] re present bioche mi- cal a p proac hes to artificial catal ysts. Of partic ular i nterest is t he de velo p me nt of s u pra molec ular catalysts perfor mi ng sy nt hetic reactio ns t hat create ne w bo n ds rat her t ha n cleave t he m. By virt ue of t heir m ulti ple bi n di ng feat ures c orece pt ors o pe n t he wa y t o t he desi g n of c ocatal ysts f or li gati o n, metall ocata- lysis, cofactor reactio ns, t hat act o n t wo or more co-bo u n d a n d s patially orie nte d s u bstrates. S u pra molec ular catalysts are by nat ure a bi otic reage nts, c he mical catalysts, t hat may perfor m t he sa me o ver all processes as e nzy mes, wit ho ut follo wi ng t he d et ail e d w a y i n w hi c h t h e e n z y m e s a ct u all y r e ali z e t h e m. T hi s c h e mi str y m a y de velo p reage nts t hat effect hig hly efficie nt a n d selecti ve processes t hat e n- z y m es d o n ot p erf or m or r e ali z e e n z y m ati c o n es i n c o n diti o ns i n w hi c h e n z y m es d o n ot o perate.

6. Tra ns port Processes a n d Carrier Desig n The organic che mistry of me mbrane trans port processes an d of carrier mole- c ules has o nly rece ntly bee n develo pe d, alt ho ug h t he p hysico-c he mical feat ures an d the biological i m portance of trans port processes have long been recog- nize d. T he desig n a n d sy nt hesis of rece ptor molec ules bi n di ng selectively orga nic a n d i norga nic s ubstrates ma de available a ra nge of co m po u n ds w hic h, if ma de me mbrane sol uble, co ul d beco me carrier molec ules an d in d uce selec- tive tra ns port by re n deri ng me mbra nes per meable to t he bo u n d s pecies. T h us, tra ns port re prese nts o ne of t he basic f u nctio nal feat ures of s u pra molec ular s pecies t o get her wit h rec o g niti o n a n d catal ysis [2, 103]. T he c he mistry of tra ns port syste ms co m prises t hree mai n as pects: to desig n tra ns port effecters, to de vise tra ns port processes, to i n vesti gate t heir a p plica- tions in che mistry an d in biology. Selective me mbrane per meability may be i n d u c e d eit h er b y carrier molec ules or b y trans me mbrane channels ( Fi g. 6).

6.1. Carrier- mediated Tra nsport Carrier- mediated tra nsport c o nsists i n t he tra nsfer of a s u bstrate acr oss a me m- bra ne, facilitate d b y a carrier molec ule. T he fo ur ste p c yclic process (associ- atio n, dissociatio n, for war d a n d back- diff usio n) (Fig. 6) i s a p h ysic al c at al ysis o perati n g a tra nsl ocati o n o n t he s u bstrate li ke c he mical catal ysis effects a J.- M. Le h n

Membrane

tra nsfor matio n i nto pro d ucts. T he carrier is t he tra ns port catal yst a n d t he acti ve s pecies is t he carrier-s u bstrate s u per molec ule. Tra ns port is a t hree- p hase process, whereas ho mogeneo us che mical an d phase transfer catalyses are re- s pectively si ngle p hase a n d t wo- p hase. Carrier desig n is t he major feat ure of t he orga nic c he mistry of me mbra ne tra ns p ort si nce t he carrier deter mi nes t he nat ure of t he s u bstrate, t he p h ysic o- c he mical feat ures (rate, selecti vit y) a n d t he t y pe of process (facilitate d diff u- sio n, co u pli ng to gra die nts a n d flo ws of ot her s pecies, acti ve tra ns port). T he carrier m ust be hig hly selecti ve, prese nt a p pro priate exc ha nge rates a n d li po- p hilic / hy dro p hilic bala nce, bear f u nctio nal gro u ps s uitable for flo w co u pli ng. T he tra ns port process de pe n ds also o n t he nat ure of t he me mbra ne, t he co nce ntratio ns i n t he t hree p hases, t he ot her s pecies prese nt. More detaile d co nsi deratio ns o n t hese i nter nal a n d exter nal factors t hat affect tra ns port pr o c ess es m a y b e f o u n d i n e arli er r e p orts [ 1, 1 0 3, 1 2 0, 1 2 1]. O ur i niti al w or k o n t h e tra nsport of a mi no-acids, di pe pti des an d acetylcholine thro ugh a liq ui d me mbrane e m ploye d si m ple li po philic s urfactant ty pe carri- ers. It was ai me d at t he p hysical orga nic c he mistry of tra ns port processes, ex pl ori n g vari o us sit uati o ns of tra ns p ort c o u ple d t o fl o ws of pr ot o ns, cati o ns or a nio ns i n co nce ntratio n a n d p H gra die nts [122]. S el e cti v e tra nsport of metal catio ns, mai nl y of al kali cati o ns, has bee n a maj or fiel d of i n vestigatio n, s p urre d by t he n u mero us catio n rece ptors of nat ural or s y nt hetic ori gi n t hat are a ble t o f u ncti o n as cati o n carriers [24, 103, 120, 121, 1 2 3, 1 2 4]. It w as o n e of t h e i niti al m oti v ati o ns of o ur w or k [ 2 9 a]. Cr y pta n ds of t y pe l- 3 a n d deri vati ves t here of carr y al kali cati o ns [125], e ve n u n der co n ditio ns i n w hic h nat ural or s y nt hetic macroc ycles are i nefficie nt. T he selecti vities o bser ve d de pe n d o n t he str uct ure of t he li ga n d t he nat ure of t he catio n a n d t he ty pe of co-tra ns porte d co u nter a nio n. Desig ne d str uct ural c ha n ges all o w t o tra nsf or m a cati o n rece pt or i nt o a cati o n carrier [120, 125]. 4 6 8 Che mistry 1987

T he res ults obtai ne d wit h cry pta n ds i n dicate d t hat t here was a n o pti mal co m plex stability a n d p hase tra nsfer eq uilibri u m for hig hest tra ns port rates [125]. Co mbi ne d wit h data for vario us ot her carriers a n d catio ns, t he y ga ve a bell-s ha pe d de pe n de nce of tra ns port rates o n extractio n e q uilibri u m (see Fi g. 3 i n [120]), wit h l o w rates f or t w o s mall or t o o lar ge (carrier sat urati o n) extrac- ti o n a n d hi g hest rates f or half-fille d carriers [120, 125]. Ki netic a nal yses all o w e d t o r el at e t h e e x p eri m e nt al r es ults t o t h e d e p e n d e n c e of tr a ns p ort r at es a n d selecti vities o n carrier pro perties [124, 126, 127] Detaile d st u dies of t he tra ns p ort of K + an d Na + b y li p o p hili c d eri v ati v es of 2 a n d 3 i n v esi cl es b or e o n t he efficie nc y, t he selecti vit y a n d t he mec ha nis m of t he pr ocesses [128]. M o dif yi n g t h e n at ur e of t h e bi n di n g sit es all o ws t o s el e cti v el y tr a ns p ort ot h er catio ns s uc h as toxic metal io ns. Macrocyclic polyet hers carry orga nic pri mary a m mo ni u m catio ns, i n partic ular p hysiologically active o nes [129]. T he nat ure of t he co u nterio n a n d t he co nce ntratio ns of s pecies stro n gl y i nfl ue nce rates of tra ns p ort a n d ma y affect its selecti vit y [120, 125]. A nio n tra nsport may be effecte d by li po p hilic a m mo ni u m io ns or by metal co m plexes [130] acti ng as a nio n rece ptors. Progress i n a nio n coor di natio n c h e mistr y s h o ul d pr o vi d e a r a n g e of a ni o n c arri ers t h at will h el p t o d e v el o p t his area of tra ns port c he mistry. T he selecti ve tra ns port of carboxylates a n d p hos- p hates is of great i nterest. So me res ults, refere nces a n d s u g gestio ns ha ve bee n gi v e n e arli er [ 1 2 0]. Catio n-a nio n cotra nsport was effecte d b y a c hiral macr otric yclic cr y pta n d t hat carrie d si m ulta neo usly a n alkali catio n a n d a ma n delate a nio n, see 3 9 [ 8 2]. E m pl o yi n g t o g et h er a c ati o n a n d a n a ni o n c arri er s h o ul d gi v e ris e t o s y ner getic tra nsport wit h d o u bl e s el e cti o n, b y f a cilit ati n g t h e fl o w of b ot h c o m p o n e nts of a salt (see t he electro n-catio n s y m port, belo w). Selecti ve tra ns p ort of a mi n o- aci ds occ urs wit h a macrotricycle co ntai ni ng a n i nter nal p hos p horic aci d gro u p [83b] a n d wit h a co n verge nt dicarboxylic aci d rece pt or [83c]. Ne utr al molec ules are carrie d bet ween t wo organic phases t hro u g h a water la yer b y water sol u ble rece ptors co ntai ni n g a li po p hilic ca vit y [ 1 3 2].

3 9 4 0 J.- M. Le h n 4 6 9

It is clear t hat n u mer o us facilitate d tra ns p ort pr ocesses ma y still be set u p, es p e ci all y f or a ni o ns, s alts or n e utr al m ol e c ul es a n d t h at t h e a cti v e r es e ar c h i n rece pt or c he mistr y will ma ke a vaila ble a variet y of carrier m olec ules. Of s pecial i nterest are t hose tra ns port effectors deri ve d fro m corece ptors, t hat allo w c o u pl e d tr a ns p ort, cotra nsport to be perfor me d.

6.2. Co upled Tra nsport Processes A major goal i n tra ns port c he mistr y is to desi g n carriers a n d processes t hat i n v ol v e t h e c o u pl e d fl o w of t w o ( or m or e s p e ci es) eit h er i n t h e s a m e (s y m p ort) or i n o p p osite (a nti p ort) directi o n. S uc h parallel or a nti parallel vect orial pr o- cesses allo w to set u p p u m pe d syste ms i n w hic h a s pecies is carrie d i n t he pote ntial create d by p hysico-c he mical gra die nts of electro ns (re dox gra die nt), proto ns ( p H gra die nt) or ot her s pecies (co nce ntratio n gra die nt). To t his e n d, eit h er t w o or m or e i n di vi d u al c arri ers f or diff er e nt s p e ci es m a y b e us e d si m ult a- neo usl y or t he a p pro priate s u b u nits ma y be i ntro d uce d i nto a si n gle s pecies, a cocarrier.

6.2.1. Electro n Co upled Tra nsport i n a Redox Gradie nt Electro n- Catio n sy mport has bee n realize d i n a d o u ble carrier pr ocess w here t he co u ple d parallel tra ns port of electro ns a n d metal catio ns was me diate d by a n electr o n carrier a n d a selecti ve cati o n carrier [133]. T he tra ns p ort of electr o ns b y a ni c k el c o m pl e x i n a r e d o x gr a di e nt w as t h e el e ctr o n p u m p f or dri vi n g t h e selecti ve tra ns p ort of K + io ns b y a macroc yclic pol yet her ( Fi g. 7). T he process h as t h e f oll o wi n g f e at ur es: - acti ve K + tra ns port a n d co u ple d electro n flo w; - t wo coo perati ng carriers acti ng sy nergetically; - a re dox p u m p; - a selectio n

Fig. 7. Electron-cation coupled transport: redox driven electron-cation sy mport via an electron carrier (nickel co mplex) and a selective cation carrier ( macrocyclic polyether) R E D: potassiu m dithionite. O X potassiu m ferricyanide [133). 4 7 0 Che mistry 1987 pr ocess b y t he cati o n carrier; - reg ulatio n by t he catio n /carrier pair. T his syste m re presents a prototy pe for the design of other m ulticarrier co u ple d tra ns port processes. Electro n tra ns port wit h q ui no ne carriers i nvolves a (2e -, 2 H + ) s y m p ort [134, 135]. Electr o n- a ni o n a nti p ort has bee n realize d for i nsta nce wit h carriers s uc h as ferroce ne or alklylviologe ns [136]. T he latter have bee n use d exte nsively i n li g ht dri v e n s y st e m s a n d i n st u di e s o n s ol ar e n er g y c o n v er si o n.

6.2.2. Proto n Co upled Tra nsport i n a p H Gradie nt Carriers beari ng negatively c harge d gro u ps may effect catio n a nti port across m e m br a n es s o t h at if o n e c ati o n is a pr ot o n, a pr ot o n p u m p m a y b e s et u p i n a p H gra die nt. T his has bee n realize d f or al kali cati o ns wit h nat ural or s y nt hetic carboxylate bearing iono phores [137]. A case of s pecial i nterest is t hat of t he tra ns p ort of di vale nt i o ns s uc h as calci u m, vers us mo no vale nt o nes. T he li po p hilic carrier 40 co ntai ni ng a si n gle cati o n rece pt or site a n d t w o ionizable carboxylic aci d gro u ps, was fo un d to tra ns port selecti vely Ca 2 + i n t he dicarboxylate for m a n d K + when monoion- i z e d, t h us all o wi n g p H c o ntr ol of t h e pr o c ess. T his stri ki n g c h a n g e i n tr a ns p ort feat ures i n vol ves p H re g ul ati o n of C a 2 + / K + selecti vit y i n a c o m petiti ve ( Ca 2 + , K + ) sy m port co u ple d to ( Ca 2 + , 2 H + ) a n d ( K + , H + ) a nti port i n a p H gra die nt, w hic h pro vi des a proto n p u m p ( Fi g. 8) [138]. J.- M. Le h n 4 7 1

This syste m de monstrates ho w carrier design allo ws to en do w transport pr ocesses wit h re g ulati o n of rates a n d selecti vit y as well as c o u pli n g t o e ner g y s o urces, f or tra ns p ort of a s pecies a gai nst its o w n c o nce ntrati o n gra die nt.

6.2.3. Light Co upled Tra nsport Processes Lig ht drive n tra ns port may be bro ug ht abo ut by p hotoge neratio n of a s pecies t h at will i n d u c e t h e pr o c ess or p ert ur b it. T his has bee n ac hieve d i n a li g ht i n d uce d electr o n tr a ns p ort pr o c ess i n v ol vi n g t h e proflavine sensitized photogeneration of reduced methylviologen M V + w hic h tra nsfers electro ns to a q ui no ne ty pe carrier co ntai ne d i n t he me mbra ne [135]. Light driven (electron, cation) sy m port occ urs when co mbining this syste m wit h t he ( nickel co m plex, macrocycle) process describe d above [139]. T he i ncrease d li po p hilicit y of re d uce d violo ge ns facilitates electro n a n d p hase tra ns- fer [140]. S uc h pr ocesses are als o of i nterest f or s olar e ner g y st ora ge s yste ms where electron per meable me mbranes separate the re ductive an d oxi dation co m ponents. Photocontrol of ion extraction an d trans port has been realize d with macrocyclic ligan ds un dergoing a str uct ural change un der irra diation, b et w e e n t w o f or ms h a vi n g diff er e nt i o n affi niti es [ 1 4 1]. T he res ults o btai ne d o n co u ple d tra ns port processes stress t he role of cocar- rier syste ms ca pable of tra ns porti ng se veral s ubstrates wit h co u pli ng to p hys- ical a n d c he mical e nergy so urces.

6.3. Tra nsfert via Tra ns me mbra ne Cha n nels Tra ns me mbra ne c ha n nels re prese nt a s pecial ty pe of m ulti ple- u nit effector allo wi ng t he passage of io ns or of molec ules t hro ug h me mbra nes by a flo w or site-to-site ho p pi ng mec ha nis m. T he y pla y a n i m porta nt role i n biolo gical trans port. Nat ural an d synthetic pe pti de channels (gra mici dine A, ala methi- ci n) f or cati o ns ha ve bee n st u die d [142, 143]. Artifi ci al catio n cha n nels wo ul d provi de f un da mental infor mation on the m e c h a nis m of c ati o n fl o w a n d c h a n n el c o n d u cti o n. A s oli d st at e m o d el of c ati o n tra nsfert i nsi de a c ha n nel is pr o vi de d b y t he cr ystal str uct ure of t he K Br co m plex of 1 2 c (Y=Y’=C H 3 ) w hic h co ntai ns stacks of macrocycles wit h cati o ns l ocate d alter nati vel y i nsi de a n d a b o ve a macr oc yclic u nit, li ke a fr oze n pict ure of catio n pro pagatio n t hro ug h t he “c ha n nel” defi ne d by t he stack [ 1 4 4]. A pol y meric stac k of macroc ycles has bee n s y nt hesize d [145] a n d a c yclo dex- tri n base d mo del of a half-c ha n nel has bee n re porte d [146]. A derivative of mo ne nsi n, a n acyclic polyet her io no p hore, for ms lit hi u m c ha n nels i n vesicles [147] w hic h may be seale d by dia m mo ni u m salts [148]. C yli n drical macrotric ycles s uc h as 2 6 (s ubstrate re move d) re prese nt t he basic u nit of a cati o n c ha n nel base d o n stac ks of li n ke d macr oc ycles; t he y bi n d alkali catio ns [149] a n d catio n j u m pi ng processes bet wee n t he to p a n d botto m ri ngs ha ve bee n obser ve d [150]. T heoretical st u dies gi ve i nsig ht i nto t he molec ular dy na mics [151] of io n tra ns port a n d t he e nergy profiles [152] i n catio n c ha n nels. Electro n cha n nels, as tra ns me mbra ne wires, re prese nt t he c ha n nel ty pe co u n- 4 7 2 Che mistry 1987 ter part to t he mobile electro n carriers disc usse d abo ve a n d will be co nsi dere d b el o w. A ni o n c h a n nels m a y al s o b e e n vi s a g e d. T h us, se veral t y pes of st u dies directe d to war ds t he de velo p me nt of artificial ion channels an d the un derstan ding of ion motion in channels are engage d. T hese effecters deser ve a n d will recei ve i ncrease d atte ntio n, i n vie w also of t h eir p ot e nti al r ol e i n m ol e c ul ar i o ni cs (s e e b el o w). A f urt her ste p i n c ha n nel desig n m ust i n vol ve t he i ntro d uctio n of ( proto n, i o n, r e d o x or li g ht a cti v at e d) g ates a n d co ntr ol ele me nts for reg ulati ng o pe ni ng a n d cl osi n g, rates a n d selecti vit y. I n t his res pect, o ne ma y n ote t hat i o niza ble gro u ps o n mo bile carriers (as i n 40, see a bo ve) are, for t hese effecters, t he co u nter part of gati ng mec ha nis ms i n c ha n nels. I n co ncl usio n, tra ns port st u dies o pe n ways to n u mero us develo p me nts of t his c he mically a n d biologically most i m porta nt f u nctio n: effector desig n, a nalysis of ele mentary ste ps an d mechanis ms, co u pling to che mical potentials, energy a n d sig nal tra ns d uctio n, mo dels of biological tra ns port processes, co nstr uctio n of vesic ular micr oreact ors a n d artificial cells, etc., wit h a variet y of p ossi ble a p plicatio ns, for i nsta nce i n se paratio n a n d p urificatio n or i n batteries a n d s yste ms for artificial p hotos y nt hesis. By t he i ntro d uctio n of polyto pic feat ures, w hic h may i ncl u de selecti ve bi n d- i ng s ub u nits as well as gati ng co m po ne nts for flo w reg ulatio n, t he desig n of cocarriers a n d of artificial molec ular c ha n nels s ho ul d a d d a not her di me nsio n to t he c he mistry of t he effecters a n d mec ha nis ms of tra ns port processes.

7. Fro m Endo-receptors to Exo-receptors. Exo-Supra molecular C he mistry T he desig n of rece ptor molec ules has mai nly relie d o n macrocyclic or macro po- l yc yclic arc hitect ures (see a bo ve) a n d /or o n ri gi d s pacers or te m plates (see for i nsta nce [17 b, 26, 76-79, 81 b, 83 b] t hat all o w t o p ositi o n bi n di n g sites o n t he walls of m olec ular ca vities or clefts i n s uc h a wa y t hat t he y c o n ver ge t o war ds t he bo u n d s ubstrate. T he latter is more or less co m pletely s urro u n de d by t he r e c e pt or, f or mi n g a n i ncl usi o n c o m pl e x, a cr y ptate. T his wi d el y us e d pri n ci pl e of co nverge nce defi nes a co nverge nt or endo-supra molecular che mistry wit h e n dorece p- t ors effecti n g e n d o-rec o g niti o n. Bi ol o gical a nal o gies are f o u n d i n t he acti ve sites of e nzy mes w here a s mall s ubstrate bi n ds i nsi de a ca vity of a large protei n m ol e c ul e. T he o p p osite p oi nt of vie w w o ul d be t o ma ke use of a n exter nal s urface wit h protuberances an d depressions, rat her t ha n a n i nter nal ca vit y, as s u bstrate recei vi ng site. T his wo ul d a mo u nt to t he passage fro m a co n verge nt to a di ver ge nt or exo-s upra molec ular che mistry an d fro m en do- to e xo-rece ptors. Rece pt or- s ubstrate bi n di ng t he n occ urs by s urface-to-s urface i nteractio n, t hat may be ter me d affi xi o n a n d sy mbolize d by / / or by t he mat he matical sy mbol of i nter- s e cti o n (if t h er e is n ot a bl e i nt er p e n etr ati o n of t h e s urf a c es) [ 1 5 3], a n d n σ] r es p e cti v el y. Exo-recog nitio n wit h stro n g a n d selecti ve bi n di n g re q uires a large e no ug h co ntact area a n d a s ufficie nt n u mber of i nteractio ns as well as geo metrical an d site (electronic) co m ple mentarity bet ween the s urfaces of a n d σ. S uc h a mo de of bi n di ng fi n ds biological a nalogies i n protei n- protei n J.- M. Le h n 4 7 3

pl a n ar tetra he dral octa he dral

Fi g. 9. Sc he matic re prese ntatio n of t h e arra nge me nt of exter nal i nteractio n sites (re prese nte d by arro ws) aro un d a metal ion of given coor dination geo metry in monon uclear metallo-exorece ptors.

i nteractio ns, for i nsta nce at t he a ntibo dy-a ntige n i nterface w here t he i m m u no- logical recog nitio n processes occ ur [154]. O ne may note t hat exo-recog nitio n i ncl u des recog nitio n bet wee n (rat her lar ge) bo dies of si milar size as well as reco g nitio n at i nterfaces wit h mo no- l a y ers, fil ms, m e m br a n es, c ell w alls, et c.

7. 1, Metallo-exoreceptors. Metallo n ucleates I n or der to rei nforce t he bi n di n g stre n gt h o ne ma y t hi n k of i ntro d uci n g o ne or m or e i nt er a cti o n p oles, f or i nsta nce electrical c har ges, ge nerati n g str o n g electr o- static forces. S uc h co ul d be t he case for a metal co m plex w hose ce ntral catio n wo ul d be t he electrostatic pole a n d w hose exter nal s urface co ul d bear f u nctio n- al gro u ps containing the molec ular infor mation req uire d for recognizing the part ner. I n a d diti o n, t he metal cati o n pr o vi des a f urt her wa y of or ga nizi n g t he str uct ure by virt ue of its coor di natio n geo metry (tetra he dral, sq uare- pla nar, octa he dral, etc.) w hic h lea ds t o a gi ve n arra n ge me nt of t he exter nal i nteracti o n sit es ( Fi g. 9). As a first a p proac h to rece ptor desig n alo ng t hese li nes, s pecific gro u ps, selecte d for t heir i nfor matio n co nte nt, have bee n attac he d to f u nctio nalize d gi vi n g li ga n ds of t y pe 4 1 t hat for m metal co m plexes of define d geo metry an d physico-che mical pro perties. With n ucleosi des, s pecies s uc h as t he bis-a de nosi ne deri vati ve 4 2 are o btai ne d [155]. T he res ulti n g p ositi v el y c h ar g e d, metallo n ucleate co m plexes s ho ul d i nteract stro ngly a n d selec- ti vely wit h t he negati vely c harge d oligo n ucleoti des a n d n ucleic aci ds, t he fixatio n site de pe n di ng o n t he nat ure a n d dis positio n of t he exter nal n ucleo- si des. Do uble helical metallo n ucleates [155] m a y b e d eri v e d fr o m t h e h eli c at es describe d belo w. N u mero us variatio ns may be i magi ne d for t he exter nal gro u ps (i ntercalators, a mi no-aci ds, oligo- pe pti des, reactive f u nctio ns) so as to yiel d metal co m plexes dis playi ng selective fixatio n a n d reactivity (c he mical, p hoto- c he mical) deter mi ne d b y t he nat ure of t he attac he d sites. 4 7 4 Che mistry 1987

4 1

4 2

7.2. Molec ular Morphoge nesis T he desig n of exo-rece ptors req uires mea ns of ge nerati ng defi ne d exter nal molec ular s ha pes. T his may be ac hieve d i n a n u mber of ways, na mely by ste p wise sy nt hesis of molec ular arc hitect ures or by asse mbli ng o n metal te m- plates t hat i m pose a gi ve n coor di natio n geo metry, as note d abo ve. Another a p proach to s uch controlle d molec ular mor phogenesis, is provi de d by the generation of glob ular molec ules s uch as the “starb urst den dri mers” [156] an d the “arborols” [157], base d o n bra nc he d str uct ures for me d via casca de processes. Starti n g fro m a gi ve n core, it ma y be possi ble to pro d uce a m ol e c ul e of gi v e n si z e a n d e xt er n al s h a p e. O n t h e p ol y m ol e c ul ar le v el, t his m a y be relate d to t he ge neratio n of s ha pes a n d str uct ures i n t wo- di me nsio nal li pi d mo nolayers [158] a n d i n aggregates of a m p hilic molec ules [159] (see also b el o w).

8. Fro m S uper molec ules to Poly molec ular Asse mblies Molec ular c he mistry is t he do mai n of ( more or less) i n de pe n de nt si n gle m ol e- c ul es. S upra molec ular che mistry m a y b e di vi d e d i nt o t w o br o a d, p arti all y o v erl a p- pi n g ar e a s: - s uper molec ules ar e w ell- d efi n e d oli g o m olec ular s pecies t hat res ult fro m t he i nter molec ular associatio n of a fe w co m po ne nts (a rece ptor a n d its s ubstrate(s)) follo wi ng a b uilt-i n A ufba u sc he me base d o n t he pri nci ples of molec ular reco g nitio n; - molec ular asse mblies are poly molec ular syste ms that res ult fro m the s pontaneo us association of a non- define d n u mber of co m po- ne nts i nt o a s pecific p hase ha vi n g m ore or less well- defi ne d micr osc o pic or ga ni- zatio n a n d macrosco pic c haracteristics de pe n di ng o n its nat ure (layers, me m- br a n es, v esi cl es, mi c ell es, m es o m or p hi c p h as es. . . [ 1 6 0]). Co nti n uo us progress is bei ng ma de i n t he desig n of sy nt hetic molec ular asse mblies, base d on a gro wing un derstan ding of the relations bet ween the feat ures of t he molec ular co m po ne nts (str uct ure, sites for i nter molec ular bi n d- J.- M. Le h n 4 7 5 i n g, etc.), t he c haracteristics of t he processes w hic h lea d to t heir associatio n a n d t he s u pra molec ular pro perties of t he res ulti ng poly molec ular asse mbly. Molec ular orga nizatio n, self-asse mbli ng a n d coo peratio n, co nstr uctio n of m ultilayer fil ms [161-164], ge neratio n of defi ne d aggregate mor p hologies [159], etc. allo w to b uil d u p s u pra molec ular arc hitect ures. T he poly merizatio n of t he m olec ular s u b u nits has bee n a maj or ste p i n i ncreasi n g c o ntr ol o ver t he str uct ural pro perties of t he poly molec ular syste m [165, 166]. I ncor porati ng s uitable gro u ps or co m po ne nts may yiel d f u nctio nal asse mblies ca pable of perfor ming o perations s uch as energy, electron or ion transfer, infor mation stora ge, si g nal tra ns d uctio n, etc. [160, 162, 167, 168]. T he co m bi natio n of rece pt ors, carriers a n d catal ysts, han dling electrons an d ions as disc usse d abo ve, wit h poly molec ular orga nize d asse mblies, o pe ns t he way to t he desig n of what may be ter med m olec ul ar a n d s upra molec ular devices, a n d to t he elaboratio n of c he mical microreactors a n d artificial cells. O ne may also note t hat poly molec ular asse mblies defi ne s urfaces o n w hic h a n d t hr o u g h w hic h pr ocesses occ ur, a feat ure t hat a gai n stresses t he i nterest of desi g ni n g exorece ptors o perati n g at t he i nterfaces, i n a d ditio n to e n dorece ptors e m b e d d e d i n t h e b ul k of t h e m e m br a n es.

9. Molecular and Supra molecular Devices Molec ular devices may be define d as str uct urally organize d an d f unctionally integrate d che mical syste ms b uilt into s u pra molec ular architect ures. The de- velo p me nt of s uc h devices req uires t he desig n of molec ular co m po ne nts (effec- tors) perfor mi ng a gi ve n f u nctio n a n d s uitable for i ncor poratio n i nto a n orga- nize d arra y s uc h as t hat pro vi de d b y t he differe nt t y pes of pol y molec ular asse mblies (see above). T he co m po ne nts may be p hoto-, electro-, io no-, mag ne- to-, ther mo-, mecano-, che mo-active de pen ding on whether they han dle pho- to ns, electro ns or io ns, res po n d to ma g netic fiel ds or to heat, u n der go c ha n ges i n mec ha nical pro perties or perfor m a c he mical reactio n. A major req uire me nt w o ul d b e t h at t h es e c o m p o n e nts a n d t h e d e vi c es t h at t h e y bri n g a b o ut, p erf or m t h eir f u n cti o n(s) at t h e m olec ul ar a n d s u pr a m olec ul ar le vels as disti nct fr o m t he b ul k m at eri al. Molec ular rece ptors, rea ge nts, catal ysts, carriers a n d c ha n nels are pote ntial effecters t hat ma y ge nerate, detect, process a n d tra nsfer si g nals b y ma ki n g use of the three- di mensional infor mation storage an d rea d-o ut ca pacity o perating i n molec ular recog nitio n a n d of t he s ubstrate tra nsfor matio n a n d tra nslocatio n processes co nveye d by reactivity a n d tra ns port. Co u pli ng a n d reg ulatio n may occ ur if t he effecters c o ntai n se veral s u b u nits t hat ca n i nteract, i nfl ue nce eac h ot her a n d res p o n d t o exter nal sti m uli s uc h as li g ht, electricit y, heat, press ure, et c. T he nat ure of t he me diator (s ubstrate) o n w hic h molec ular devices o perate defi nes fiel ds of molec ular p hoto nics, molec ular electro nics a n d molec ular io nics. T heir de velo p me nt re q uires to desig n effecters t hat ha n dle t hese me dia- tors a n d to exa mi ne t heir pote ntial use as co m po ne nts of molec ular de vices. We s hall n o w a nal yze s pecific feat ures of m olec ular rece pt ors, carriers a n d rea ge nts fr o m t his p oi nt of vi e w. 4 7 6 Che mistry 1987

ENERGY TRANSFER

9.1. Supra molecular Photoche mistry and Molecular Photonics T he for matio n of s u pra molec ular e ntities fro m p hotoactive a n d /or electroactive co m ponents may be ex pecte d to pert urb the gro un d state an d excite d state pr o p erti es of t h e i n di vi d u al s p e ci es, gi vi n g ris e t o n o v el pr o p erti es t h at d efi n e a supra molecular photoche mistry a n d electroche mistry. T h us, a n u mber of processes may take place wit hi n s u pra molec ular syste ms, mo d ulate d by t he arra nge me nt of t he bo u n d u nits as deter mi ne d by t he organizing rece ptor: photoin d uce d energy migration, charge se paration by electro n or proto n tra nsfer, pert ur batio n of o ptical tra nsitio ns a n d polarisa bili- ties, mo dificatio n of re dox pote ntials i n gro u n d or excite d states, p hotore g ula- tio n of bi n di n g pro perties, selecti ve p hotoc he mical reactio ns, etc. S u pra molec ular p hotoc he mistry, like catalysis, may i nvolve t hree ste ps: bi n di ng of s ubstrate a n d rece ptor, me diati ng a p hotoc he mical process follo we d b y r est or ati o n of t h e i niti al st at e f or a n e w c y cl e or b y a c h e mi c al r e a cti o n [ 1 6 9] (Fig. 10). T he p hoto p hysical a n d p hotoc he mical feat ures of s u pra molec ular e ntities f or m a vast area of i n vesti gati o n i nt o pr ocesses occ urri n g at a le vel of inter molec ular organization.

9.1.1. Light Co nversio n by E nergy Tra nsfer A light co nversio n molec ular device may be realized by an Absorption Energy Trans- fer- E missio n A- E T- E process i n w hic h lig ht absor ptio n by a rece ptor molec ule is follo we d by i ntra molec ular e nergy tra nsfer to a bo u n d s ubstrate w hic h t he n e mits. T his occ urs i n t he e uro pi u m(III) a n d terbi u m(III) cry ptates of t he m a cr o bi c y cli c li g a n d [ bi p y. bi p y. bi p y] 4 3 [170]. U V lig ht absorbe d by t he bi py gro u ps is tra nsferre d to t he la nt ha ni de catio n bo u n d i n t he molec ular ca vity, a n d r el e as e d i n t h e f or m of visi bl e l a nt h a ni d e e missi o n vi a a n A- E T- E pr o c ess, as s h o w n i n 4 4 [171]. T hese E u(III) a n d Tb(III) co m plexes dis play a brig ht l u mi n es c e n c e i n a q u e o us s ol uti o n, w h er e as t h e fr e e i o ns d o n ot e mit i n t h e s a m e con ditions. N u mero us a p plications may be envisage d for s uch s ubstances, in J.- M. Le h n 4 7 7

partic ular as l u mi nesce nt probes for mo noclo nal a ntibo dies, n ucleic aci ds, me mbra nes, etc. P hoto p hysical processes occ urri ng i n macrocyclic [172], cry ptate [173] a n d molec ular [174, 175] co m plexes ha ve bee n i n vestigate d.

9.1.2. Photoi nd uced Electro n Tra nsfer in Photoactive Coreceptor Molec ules T he p hoto ge neratio n of c har ge se parate d states is of i nterest bot h for i n d uci n g p h ot ocatal ytic reacti o ns (e. g. f or artificial p h ot os y nt hesis) a n d f or t he tra nsfer of p h ot o-si g n als, f or i nst a n c e t hr o u g h a m e m br a n e. It m a y b e r e ali z e d i n D- P S- A s yst e ms i n w hi c h e x cit ati o n of a p h ot os e nsiti z er P S, f oll o w e d b y t w o el e ctr o n tra nsfers fro m a do nor D a n d to a n d to a n acce ptor A, yiel ds D + - PS- A -. N u m er o us s yst e ms of t his t y p e ar e b ei n g st u di e d i n m a n y l a b or at ori es fr o m t h e sta n d poi nt of mo delli ng p hotosy nt hetic ce ntres. T he D, A u nits may be metal coor di natio n ce ntres. T h us, bi n di ng of silver io ns to t he lateral macrocycles of corece ptors co ntai ni ng por p hyri n gro u ps as p hotose nsitizers, i ntro d uces electro n acce ptor sites, as s ho w n i n 45. T his 4 7 8 Che mistry 1987 res ults i n q ue nc hi n g of t he si n glet excite d state of t he Z n- por p h yri n ce ntre b y a n efficie nt i ntra-co m plex electro n tra nsfer, lea di ng to c harge se paratio n a n d ge nerati n g a p hor p h yri ni u m catio n of lo n g half-life [176]. Syste ms perfor ming photoin d uce d electron transfer processes re present co m- p o ne nts f or light to electro n co nversio n devices. T h e li g ht a cti v at e d el e ctr o n tr a ns p ort m e nti o n e d a b o v e [ 1 3 5] als o b el o n gs t o t his g e n er al t y p e.

9.1.3. Photoinduced Reactions in Supra molecular Species T he bi n di n g of a s u bstrate to a rece ptor molec ule ma y affect t he p hotoc he mical reacti vit y of eit her or b ot h s pecies, orie nti n g t he c o urse of a reacti o n or gi vi n g ris e t o n o v el tr a nsf or m ati o ns. Co m plexation of coor dination co m po un ds may allo w to control their photo- che mical behavio ur via the str uct ure of the s u pra molec ular s pecies for me d.

3- T h us, t he p hotoaq uatio n of t he Co( C N) 6 a nio n is mar ke dl y affecte d b y bin ding to polya m moni u m macrocycles. The res ults agree with the for mation of s u pra molec ular s pecies, i n w hic h bi n di ng to t he rece ptor hi n ders so me C N - gro u ps fro m esca ping when the Co- C N bon ds are te m porarily broken follo wing lig ht excitatio n [63]. It t h us a p pears possible to orie nt t he p hotos ubstit utio n reactions of transition metal co m plexes by using a p pro priate rece ptor mole- c ules. S uc h effects ma y be ge neral, a p pl yi n g to co m plex catio ns as well as to co m plex anions, an d provi ding an a p proach to the control of photoche mical reactio ns via for matio n of defi ne d s u pra molec ular str uct ures [169, 177, 178]. Str uct ural or confor mational changes photo pro d uce d in rece ptor molec ules affect t heir bi n di n g pr o perties t h us ca usi n g release or u pta ke of a s pecies, as occ urs i n macroc yclic li ga n ds co ntai ni n g li g ht se nsiti ve gro u ps [141, 172]. S uc h effects ma y be use d t o ge nerate pr ot o nic or i o nic p h ot osi g nals i n li g ht-to- io n co nversio n de vices.

9.1.4. No n-li near Optical Properties of S upra molec ular Species S u bsta nces prese nti n g a lar ge electr o nic p olarisa bilit y are li kel y t o yiel d materi- als dis playi ng large macrosco pic o ptical no n-li nearities. T his is t he case for p us h- p ull co m po u n ds possessi ng electro n do nor a n d acce ptor u nits. T he pote n- tial no n-li near o ptical ( N L O) pro perties of materials base d o n metal co m plexes a n d s u pra molec ular s pecies have bee n poi nte d o ut rece ntly [179a]. T he D- PS- A s yste m i n vesti gate d f or t heir a bilit y t o yiel d c har ge se parate d states p ossess s uc h feat ures; t hey may be metallic or molec ular co m plexes. Ion de pen dent o ptical changes pro d uce d by in dicator ligan ds [180] might lea d t o cati o n c o ntr ol of n o n-li near o ptical pr o perties. Molec ular electron- donor-acce ptor co m plexes co ul d present N L O effects si nce t hey possess polarize d gro u n d states a n d u n dergo ( partial) i nter molec ular c h ar g e s e p ar ati o n o n e x cit ati o n. It is p ossi bl e t o m or e or l ess fi n el y t u n e t h eir p olarizati o n, p olariza bilit y, exte nt of c har ge tra nsfer, a bs or pti o n ba n ds, etc. b y ma n y variatio ns i n basic str uct ural t y pes as well as i n s u bstit ue nts (see for i nsta nce [174, 179 b]). T he res ults disc usse d abo ve pro vi de ill ustratio ns a n d i nce nti ves for f urt her J.- M. Le h n 4 7 9 st u dies of p hoto-effects bro ug ht abo ut by t he for matio n of s u pra molec ular s p e ci es. I n a broa der pers pecti ve, s uc h i n vestigatio ns may lea d to t he de velo p me nt of photoactive molec ular devices, base d on photoin d uce d energy migration, electron tra nsfer, s ubstrate release or c he mical tra nsfor matio n i n s u per molec ules. T h us wo ul d be bro ught together molec ular design, inter molec ular bon ding an d supra molecular architectures with photophysical, photoche mical and optical pr o p erti es, b uil di n g u p a ki n d of molec ular photo nics.

9.2. Molec ular Electro nic Devices M ore a n d m ore atte nti o n is bei n g gi ve n t o m olec ul ar electr o nics a n d t o t h e possibilit y of de velo p pi n g electro nic de vices t hat wo ul d o perate at t he molec u- lar le vel [3, 181]. Molec ular rectifiers, tra nsistors a n d p hoto dio des ha ve bee n e n vis a g e d, t h e l att er r e q uiri n g f e at ur es s u c h as t h os e of c h ar g e tr a nsf er st at es i n orga nic molec ules, i n metal co m plexes a n d i n D- PS- A syste ms disc usse d above (s e e r ef. i n [ 1 8 2]). A mo n g t he basic co m po ne nts of electro nic circ uitr y at t he molec ular le vel, a u nit of f u n da me ntal i m porta nce is a co n nector or j u nctio n allo wi ng electro n fl o w t o ta ke place bet wee n differe nt parts of t he s yste m, i.e., a m olec ul ar wire. A n a p pr oac h t o s uc h a u nit is re prese nte d b y t he c ar o vi ol o ge ns, vinylogo us deri vati ves of met hyl viologe n t hat co mbi ne t he feat ures of t he carote noi ds a n d of t he violo ge ns [182]. T he y prese nt feat ures re q uire d for a molec ular wire: a conj ugate d polyene chain for electron con d uction; ter minal electroactive an d hy drosol uble pyri di ni u m gro u ps for reversible electro n exc ha nge; a le ngt h s ufficie nt for s pa n ni ng ty pical molec ular s u p porti ng ele me nts s uc h as a mo no- layer or bilayer me mbra ne.

Fi g. 1 1. Trans me mbrane incorporation of a caroviologen into sodiu m dihexadecylphosphate vesi- cl es. 4 8 0 Che mistry 1987

Caroviologens have been incorporate d into so diu m dihexa decyl phosphate vesicles. T he data o btai ne d a gree wit h a str uct ural m o del i n w hic h t he car o vi o- loge ns of s ufficie nt le ngt h s pa n t he bilayer me mbra ne, t he pyri di ni u m sites bei n g close to t he ne gati vel y c har ge d o uter a n d i n ner s urfaces of t he vesicles a n d t he pol ye ne c hai n crossi n g t he li pi dic i nterior of t he me m bra ne ( Fi g. 11) These an d other f unctionalize d me mbranes are being teste d in processes in which the caroviologen wo ul d f unction as a contin uo us, trans me mbrane elec- tr o n c h a n n el, i.e., a ge n ui ne molec ular wire. Wit h res pect to electro n tra ns port by mea ns of re dox acti ve mobile carrier molec ules (see abo ve), t he caro violo- ge ns re prese nt electro n c ha n nels, li ke t here are cati o n c ha n nels a n d cati o n carriers. T he y p ortra y a first a p pr oac h t o m olec ular wires a n d se veral m o difica- tio ns co ncer ni ng t he e n d-gro u ps a n d t he c hai n may be e n visage d. For i nsta nce, co u pling with photoactive gro u ps co ul d yiel d photores ponsive electron chan- nels, as well as c har ge se paratio n a n d si g nal tra nsfer de vices [183]. Co mbi na- tio n wit h ot her poly molec ular s u p ports, s uc h as poly meric layers or meso mor- p hic p hases, a n d wit h ot her co m po ne nts, mig ht allo w to asse mble na nocirc uits an d more co m plex molec ular electronic syste ms. Re dox mo dificatio n of a n electroacti ve rece ptor or carrier molec ule lea ds to c ha nges i n bi n di ng a n d tra ns port pro perties, t h us ca usi ng release or u ptake of t he s u bstrate, i n a wa y a nalo go us to t he p hoto-effects disc usse d a bo ve. To t his en d re dox co u ples s uch as dis ulfi de / dithiol [184, 185a] an d q uinone /hy dro- q ui no ne [185] have bee n i ntro d uce d i nto rece ptor molec ules a n d s ho w n to mo dify their s ubstrate bin ding feat ures. Co m plexation of metal hexacyani des

n- M ( C N ) 6 by polya m moniu m macrocycles markedly perturbs their redox pro perties [61]. T hese electroc he mical feat ures res ulti ng fro m rece ptor-s ub- strate ass ociati o n defi ne a s u pr a m olec ul ar electr oc he mistr y. T he m ut ual effects bet wee n re dox c ha nges a n d bi n di ng stre ngt h i n a rece ptor-s ubstrate pair, may allo w to ac hie ve electroco ntrol of co m plexatio n a n d, co n versely, to mo dify re dox pro perties b y bi n di n g (see also belo w).

9. 3. M olec ul ar I o nic De vices T he n u mero us rece ptor, reage nt a n d carrier molec ules ca pable of ha n dli ng i norga nic a n d orga nic io ns are pote ntial co m po ne nts of molec ular a n d s u pra- m olec ular i o nic de vices that wo ul d f unction via highly selective recognition, reactio n a n d tra ns port processes wit h co u pli ng to exter nal factors a n d reg ula- ti o n. S u c h c o m p o n e nts a n d t h e d e vi c es t h at t h e y m a y b uil d u p f or m t h e b asis of a fi el d of m olec ul ar i o nics, t he fiel d of syste ms o perati ng wit h io nic s pecies as s u p port for si g nal a n d i nfor matio n stora ge, processi n g a n d tra nsfer. I n vie w of t h e si z e a n d m ass of i o ns, i o ni c d e vi c es m a y b e e x p e ct e d t o p erf or m m or e sl o wl y t ha n electro nic de vices. Ho we ver io ns ha ve a very hig h i nfor matio n co nte nt by virt ue of t heir m ulti ple molec ular (c har ge, size, s ha pe, str uct ure) a n d s u pra mo- lec ular (bi n di ng geo metry, stre ngt h a n d selectivity) feat ures. Molec ular io nics . a p pear a pro mising fiel d of research which may alrea dy dra w fro m a vast a mo unt of kno wle dge an d data on ion processing by nat ural an d synthetic rece ptors a n d carriers. Selecti ve io n rece ptors re prese nt basic u nits for io nic tra ns mitters or detec- J.- M. Le h n 4 8 1 tors, selecti ve io n carriers corres po n d to io nic tra ns d ucers. T hese u nits ma y be fitt e d wit h tri g g ers a n d s wit c h es s e nsiti v e t o e xt er n al p h ysi c al (li g ht, el e ctri cit y, electric or mag netic fiel d, heat, press ure) or c he mical (ot her bi n di ng s pecies, re g ulati n g sites) sti m uli for co n nectio n a n d acti vatio n. Bi n di ng or tra ns port a n d triggeri ng may be perfor me d by se parate s pecies ha vi ng eac h a s pecific f u nctio n, as i n m ulti ple carrier tra ns port syste ms (see above) [133]. T his allo ws a variety of co mbi natio ns bet wee n p hoto- or elec- troactive co m po ne nts a n d differe nt rece ptors or carriers. O n t he ot her ha n d, light an d re dox sensitive gro u ps have been incor porate d into rece ptors an d carriers a n d s ho w n to affect bi n di ng a n d tra ns port pro perties (see [141, 172, 184, 185] a n d refere nces t herei n). Corece ptors a n d cocarriers provi de mea ns for reg ulation via cofactors, co-bo un d s pecies that mo d ulate the interaction wit h t he s ubstrate. T h us, a si m ple io nizable gro u p s uc h as a carboxylic aci d f u nctio n re prese nts a pr ot o n s witc h a n d lea ds to gate d rece ptors a n d carriers res po n di ng to p H c ha nges, as see n for i nsta nce i n t he reg ulatio n of tra ns port s el e cti vit y b y 4 0 [ 1 3 8]. The main proble m is the generally ins ufficient changes bro ught abo ut in most syste ms by t he s witc hi ng process. It is w ort h stressi n g t hat pr ot o n triggere d yes / no or + /- s witc hes are pote ntially co ntai ne d i n t he ability of polya mi ne rece ptors a n d carriers to bi n d a n d tra ns port catio ns w he n u n proto- nate d a n d a nio ns w he n proto nate d; also, z witterio ns s uc h as a mi no-aci ds may change fro m bo un d to unbo un d or conversely when they un dergo charge i n v ersi o n as a f u n cti o n of p H. M ol e c ul ar proto nic de vices t h us re prese nt a partic u- larly i nteresti ng s pecial case of io nic devices. A proto n co n d ucti ng c ha n nel w o ul d b e a proto n wire. F unctional molec ular asse mblies provi de ways of organizing molec ular de- vices a n d of i ntro d uci ng reg ulatio n a n d coo perative processes w hic h may i n d u c e a m u c h st e e p er r es p o ns e of t h e s yst e m t o t h e sti m uli. V esi cl es h a v e b e e n fitte d w ith fu n c tio n a l u n its [1 6 8 ], for i nst a n c e wit h a Li + io n c ha n nel t hat may

4 6 4 7 4 8 2 Che mistry 1987 be seale d [147, 148]. Li q ui d cr ystals co nsisti n g of macroc yclic molec ules bear- i n g m es o g e ni c gr o u ps, s u c h as 4 6, f or m t ub ular mesophases, co m pose d of stacke d ri n gs as i n 4 7, t h at l e a d t o t h e d e v el o p m e nt of p h as e d e p e n d e nt i o n c o n d u cti n g c ha n nels [186, 187]. Coo perativity a n d self-asse mbly may also be desig ne d directly i nto t he molec ular co m po ne nts (see belo w). Biolo gical i nfor matio n a n d si g nals are carrie d b y io nic a n d molec ular s pecies ( N a + , K + , C a 2 + , acetylc holi ne, cyclic A M P, etc.). Polyto pic metallo protei ns s uc h as calci u m bi n di n g protei ns [188] p er f or m co m plicate d tas ks of detecti n g, processi n g a n d tra nsferri n g io nic si g nals. T hese biolo gical f u nctio ns gi ve co nfi- d e n c e a n d i ns pir ati o n f or t h e d e v el o p m e nt of m ol e c ul ar i o ni cs. O ne may note t hat io n rece ptors, c ha n nels, s witc hes a n d gates have bee n consi dere d within a potential E uro pean research progra m me on “Ionic A da p- tative Co m p uters”. A p plications s uch as selective che mical sensors base d on molec ular recog nitio n are alrea dy well a d va nce d [121].

9. 4. M olec ul ar Self- Asse m bl y Self-asse mbli ng a n d m ulti ple bi n di ng wit h positive coo perativity are processes of s po nta neo us molec ular orga nizatio n t hat also allo w to e n visage a m plific ati o n m olec ul ar de vices. Such pheno mena are well docu mente d in biology, but much less so i n c he mistry. By virt ue of t heir m ulti ple bi n di ng s ub u nits, polyto pic corece ptors may dis play self-asse mbli ng if s ubstrate bi n di ng to o ne rece ptor molec ule ge nerates bi n di n g sites t hat i n d uce associatio n wit h a not her o ne. Positi ve coo perati vit y i n s u bstrate bi n di n g is more diffic ult to set u p t ha n negative coo perativity. Ho wever, bot h effects are of i nterest for reg ulatio n pr ocesses. Coo perati vit y is fo u n d i n t he u n us ual facilitatio n of t he seco n d pr ot o nati o n of 5 b y a water effector molec ule as i n 1 0 (see a b o ve) [40]. Allosteric effects o n catio n bi n di n g to macroc yclic pol yet hers ha ve bee n st u die d by i n d uci ng co nfor matio nal c ha nges via a re mote site [17a] a n d s ub u nit coo perati vity occ urs i n a di meric por p hyri n [189]. T he s po nta neo us for matio n of t he do u ble helix of n ucleic aci ds re prese nts t he self-asse mbli ng of a s u pra molec ular str uct ure i n d uce d by t he patter n of i nter- molec ular interactions provi de d by the co m ple mentary n ucleic bases. It in- vol ves recog nitio n a n d positi ve coo perati vity i n base pairi ng [190] S uc h self-asse mbli ng has rece ntly bee n s ho w n to occ ur i n re petitive c hai n liga n ds, acyclic corece ptors co ntai ni ng se veral i de ntical bi n di ng sites arra nge d li nearly. Base d o n earlier work wit h a q uater pyri di ne liga n d, oligo-bi pyri di ne c hai n liga n ds i ncor porati ng t wo to five bi py gro u ps were desig ne d. By treat- ment with C u(I) ions they un der went a s pontaneo us asse mbling into do uble stra nded helicates co ntai ni ng t wo liga n d molec ules a n d o ne C u(I) io n per bi py site of eac h liga n d, t he t wo rece ptor stra n ds bei ng wra p pe d aro u n d t he metal io ns w hi c h h ol d t h e m t o g et h er. T h us, t h e tris- bi p y li g a n d 4 8 f or ms t h e tri n u cl e ar c o m pl e x 4 9 w hose cr ystal str uct ure has bee n deter mi ne d, co nfir mi n g t hat it is i n dee d a n i norga nic do uble helix [191]. T he res ults obtai ne d i n dicate t hat t he process occ urs probably wit h positive coo perativity, bi n di ng of a C u(I) io n wit h t wo liga n ds facilitati ng co m plexatio n of t he next o ne. F urt her more, it a p pears t hat i n a mixt ure of li ga n ds c o ntai ni n g differe nt n u m bers of bi p y u nits, J.- M. Le h n 4 8 3

4 8

pairi n g occ urs prefere ntiall y bet wee n t he s a me liga n ds, t h us perfor mi ng self-self rec o g niti o n. T his s po nta neo us for matio n of a n orga nize d str uct ure of i nter mole- c ular ty pe o pens ways to the design an d st u dy of self-asse mbling syste ms prese nti ng coo perativity, reg ulatio n a n d a m plificatio n feat ures. Catalytic reac- tio ns, gate d c ha n nels, p hases c ha nges re prese nt ot her processes t hat mig ht be us e d f or i n d u ci n g a m plifi c ati o n eff e cts. Vario us f urther develop ments may be envisage d along organic, inorganic a n d bioc he mical li nes. T h us, if s ubstit ue nts are i ntro d uce d at t he para posi- ti o ns of t h e si x p yri di n e u nits i n 4 8 , treat me nt wit h C u(I), s ho ul d for m a n i norga nic do uble helix beari ng t wel ve o utsi de directe d f u nctio nal gro u ps [155]. Designe d self-asse mbling rests on the elaboration of molec ular co m ponents that will s pontaneo usly un dergo organization into a desire d s u pra molec ular ar c hit e ct ur e. S u c h c o ntr ol of s elf- or g a ni z ati o n at t h e m ol e c ul ar l e v el is a fi el d of major i nterrest i n molec ular desig n a n d e ngi neeri ng, t hat may be ex pecte d to beco me s u bject of i ncreasi n g acti vit y.

9. 5. C he mi o nics Co m ponents an d molec ular devices s uch as molec ular wires, channels, resis- tors, rectifiers, dio des, p hotose nsiti ve ele me nts, etc. mig ht be asse mble d i nto nanocirc uits an d co mbine d with organize d poly molec ular asse mblies to yiel d syste ms ca pable ulti mately of perfor mi ng f u nctio ns of detectio n, storage, pro- cessi ng, a m plificatio n a n d tra nsfer of sig nals a n d i nfor matio n by mea ns of vario us me diators ( photons, electrons, protons, metal cations, anions, mole- c ul es) wit h c o u pli n g a n d r e g ul ati o n [ 3, 8, 1 8 1, 1 8 2, 1 9 2]. Molec ular p hoto nics, electro nics a n d io nics re prese nt t hree areas of t his i ntrig ui ng a n d rat her f ut uristic fiel d of c he mistry w hic h may be ter me d “c he- mio nics ” [3,8] - t he desi g n a n d o peratio n of p hoto nic, electro nic a n d io nic co m po ne nts, devices, circ uitry a n d syste ms for sig nal a n d i nfor matio n treat- m e nt at t h e m ol e c ul ar l e v el. S u c h p ers p e cti v es li e, of c o urs e, i n t h e l o n g r a n g e 4 8 4 Che mistry 1987

[193], b ut along the way they co ul d yiel d n u mero us s pin-offs an d they do represent ulti mate goals to war ds which work may alrea dy be planne d an d r e ali z e d.

10. Co ncl usio n T he prese nt text was ai me d at prese nti n g t he sco pe, pro vi di n g ill ustratio n a n d ex ploring pers pectives of s u pra molec ular che mistry. Its conce pt ual fra me work has bee n progressively lai d do w n a n d t he very active researc h o n molec ular recog nitio n, catalysis a n d tra ns port, toget her wit h exte nsio n to molec ular s urfaces a n d poly molec ular asse mblies, is b uil di ng u p a vast bo dy of k no wle dge o n m ol e c ul ar b e h a vi o ur at t h e s u pr a m ol e c ul ar l e v el. It is cl e ar t h at m u c h b asi c c he mistry re mai ns to be do ne o n t he desig n a n d realizatio n of n u mero us ot her s yst e ms a n d pr o c ess es t h at a w ait t o b e i m a gi n e d. T h e r es ults o bt ai n e d m a y als o be a nalyze d i n t he vie w of develo pi ng co m po ne nts for molec ular devices t hat wo ul d perfor m hig hly selecti ve f u nctio ns of recog nitio n, tra nsfor matio n, tra ns- fer, reg ulatio n a n d co m m u nicatio n, a n d allo w sig nal a n d i nfor matio n process- i ng. T his i m plies o peratio n via i nter molec ular i nteractio ns a n d i ncor poratio n of t h e ti me di me nsio n i nto recog nitio n eve nts. O ne may note t hat s uc h f u nctio ns ha ve a nal o gies wit h feat ures of ex pert s yste ms, t h us li n ki n g pr ocesses of artifi- cial i ntellige nce a n d molec ular be havio ur. These develo p ments in molec ular an d s u pra molec ular science an d engineer- i ng offer exciti ng pers pecti ves at t he fro ntiers of c he mistry wit h p hysics a n d biology. Of co urse, eve n wit h past ac hieve me nts a n d prese nt activities, ex- tra p olati o ns a n d pre dicti o ns ca n o nl y be te ntati ve; yet, o n s uc h a n occasi o n f or t he cele bratio n of c he mistr y, it a p pears j ustifie d to tr y loo ki n g o ut i nto t he f ut ur e f or “ H e ( or s h e) w h o sits at t h e b ott o m of a w ell t o c o nt e m pl at e t h e s k y, will fi n d it s m all ” ( Ha n Y u, 768-824). Ackno wledge ments. I wish to thank very war mly my collaborators at the U ni versité Lo uis Paste ur i n Strasbo ur g a n d at t he Colle ge de Fra nce i n Paris w hose s kill, de dicatio n a n d e nt h usias m, allo we d t he wor k describe d here to be realize d. Starti n g wit h B. Dietric h et J.- P. Sa u va ge, t he y are too n u mero us to b e n a m e d h er e, b ut t h e y all h a v e c o ntri b ut e d t o t h e c o m m o n g o al. I als o wis h to ack no wle dge t he fr uitf ul collaboratio n wit h a n u mber of laboratories i n vario us co u ntries, begi n ni ng wit h t he crystal str uct ure deter mi natio ns of cry p- tates by Ray mon d Weiss an d his gro u p an d exten ding over vario us areas of str uct ural an d coor dination che mistry, electroche mistry, photoche mistry, bio- c h e mistr y. Fi n all y, I t h a n k t h e U ni v ersit é L o uis P ast e ur, t h e C oll è g e d e Fr a n c e a n d t h e C e ntr e N ati o n al d e l a R e c h er c h e S ci e ntifi q u e f or pr o vi di n g t h e i nt ell e c- t u al e n vir o n m e nt a n d t h e fi n a n ci al s u p p ort f or o ur w or k.

R E F E R E N C E S

1. J.- M. L e h n, Str u ct. B o n di n g ( B erli n) 1 6 ( 1 9 7 3) 1. 2. J.- M. L e h n, P ur e A p pl. C h e m. 5 0 ( 1 9 7 8) 8 7 1. 3. J.- M. L e h n, Inaugurale, Collège de France, Paris 1980. 4. R. Pfeiffer “ Organische Molekülerverbindungen”, Stuttgart, 1927. 5. K. L. W olf, F. Fr a h m, H. H ar ms, Z. P h ys. C h e m. A bt. B 3 6 (1937) 17: K. L. Wolf, J.- M. Le h n 4 8 5

H. Dunken, K. Merkel, ibid. 46 (1940) 287; K. L. Wolf, R. Wolff, Ange w. Che m. 61 (1949) 191. 6. J.- M. L e h n, A ct. C h e m. R es. 1 1 (1978) 49. 7. J.- M. L e h n, i n Z.I. Y o s hi d a a n d N. I s e ( E d s.): “ Bi o mi m eti c C h e mi str y ”, K o d a n- sha, Tokyo, Elsevier, A msterda m 1983, p. 163. 8. J.- M. Lehn, Science 227 (1985) 849. 9. P. G. Potvin, J.- M. Lehn in R. M. Izatt, J.J. Christensen ( Eds.): “ Synthesis of Macfocycles: The Design of Selective Co mplexing Agents”; Progress in Macrocyc- lic Che mistry vol. 3, Wiley, Ne w York, 1987, p. 167. 10. E. Fischer, Ber. Deutsch. Che m. Gesell. 27 (1894) 2985. 11. F. Cra mer, W. Freist, Act. Che m. Res. 20 (1987) 79. 12. J. F. Stoddart, Che m. Soc. Rev. 8 (1979) 85; A nnual Reports B, Roy. Soc. Che m. (1983) p353 1 3. D.J. Cr a m, J. M. Cr a m, A ct. C h e m. R es. 1 1 (1978) 8. 1 4. R. C. H a y w ar d, C h e m. S o c. R e v. 1 2 (1983) 285. 1 5. I. O. S ut h erl a n d, C h e m. S o c. R e v. 1 5 (1986) 63. 16. G. van Binst ( Ed.) “ Design and Synthesis of organic Molecules based on Molecu- lar Recognition”, Springer, Berlin 1986. 1 7. a) J. R e b e k, Jr., A ct. C h e m. R es. I 7 ( 1 9 8 4) 2 5 8; b) S ci e n c e 2 3. 5 ( 1 9 8 7) 1 4 7 8. 18. a) P. B. Dervan, R. S. Youngquist, J. P. Sluka, in W. Bart mann, K. B. Sharpless ( Eds.) “Stereoche mistry of Organic and Bioorganic Transfor mations” Verlag Che mie, Heidelberg 1987, p.221; b) W. C. Still, ibid. p.235. 19. R. M. Izatt, J.J. Christensen ( Eds.), “ Progress in Macrocyclic Che mistry”, Wiley, N e w Y or k, v ol. 1 ( 1 9 7 9), v ol. 2 ( 1 9 8 1), v ol. 3 ( 1 9 8 7). 20. F. Vogtle ( Ed.) “ Host Guest Che mistry”, Topics Curr. Che m. 98 (1981), 101 ( 1 9 8 2); F. V o gtl e, E. W e b er ( E ds.), i bi d., 1 2 1 (1984). 21. J. L. At wood, J. E. D. Davies, D. D. Mac Nicol, “Inclusion Co mpounds”, Acade mic Pr ess, L o n d o n, v ol. 1, 2, 3 ( 1 9 8 4). 22. G. Wipff, P. K. Koll man, J.- M. Lehn, J. Mol. Struct. 93 (1983) 153; G. Ranghino, S. R o m a n o, J.- M. L e h n, G. Wi pff, J. A m. C h e m. S o c. 1 0 7 ( 1 9 8 5) 7 8 7 3; G. Wi pff, P. Koll man, Nouv. J. Chi m. 9 (1985) 457; “ Structure and Dyna mics of Macro mole- cules”, S. Lifson, M. Levitt ( Eds.) Israel J. Che m. 27 (1986) 2 3. A n i d e a a b o ut t h e r es p e cti v e r ol e of c oll e cti o n a n d ori e nt ati o n m a y b e g ai n e d fr o m

+ exa mining the energies calculated for a series of Li( N H 3 ) n co mplexes and of the + c o r r e s p o n d i n g ( N H 3 ) n units in the identical geo metry. In presence of Li t h e + for mation energies of the co mplexes are obtained at the opti mized Li . . . N H 3 + distances. When Li is re moved and the N H 3 m olec ules are ke pt at t he sa me position the energies calculated are for the for mation of the coordination shell

alone. These energies represent the repulsion bet ween the N H 3 gr o u ps; t he y are a measure of the intersite repulsive energy for bringing together t wo, three or four a mine binding sites into a polydentate ligand of sa me coordination geo metry.

Res ults, ( N H 3 ) n , geo metry (repulsive energy, kcal/ mole): ( N H 3 ) 2 , li near (- 2. 4),

bent (-3.8); ( N H 3 ) 3 , trigonal (-9.1), py ra midal (-10.8); ( N H 3 ) 4 , tetra he dral (- 2 0. 8). T h u s, t h e t ot al c oll e cti o n e n er gi e s ar e a p pr e ci a bl y l ar g er t h a n t h e or g a ni z ati o n energies represented by the changes fro m one geo metry to another, linear to bent (1.4 kcal/ mole) or trigonal to pyra midal (1.7 kcal/ mole). A b i niti o co mputations p erf or m e d wit h a s et of g a ussi a n t y p e b asis f u n cti o ns, c o ntr a ct e d i nt o a d o u bl e s et with polarisation; J.- M. Lehn, R. Ventavoli, unpublished results; see also: R. Ventavoli, 3e Cycle Thesis, Université Louis Pasteur, Strasbourg, 1972. 24. (a) Yu. A. Ovchinnikov, V. T. Ivanov, A. M. Skrob, “ Me mbrane Active Co mplex- ones”, Elsevier, Ne w York (1974); (b) B. C. Press man, Ann. Rev. Bioche m. 4 5 (1976) 501; (c) H. Brock mann, H. Gecren, Annalen 6 0 3 (1957) 217; (d) M. M. She myakin, N. A. Aldanova, E.I. Vinogradova, M. Yu. Feigina, Tetrahedron Lett. 1963, 1921; (e) C. Moore, B. C. Press man, Bioche m. Biophys. Res. Co m mun. 1 5 (1964) 562; (f) B. C. Press man, Proc. Natl. Acad. Sci. U S A 53 (1965) 1077; (g) J. 4 8 6 Che mistry 1987

B e c k, H. G erl a c h, V. Pr el o g, W. V o s er, H el v. C hi m. A ct a 7 4 ( 1 9 6 2) 6 2 0; ( h) Z. St ef a n a c, W. Si m o n, C hi mi a 2 0 (1966) 436 and Microche m. J. 1 2 (1967) 125; (i) K. T. Kil b o ur n, J. D. D u nit z, L. A. R. Pi o d a, W. Si m o n, J. M ol. Bi ol. 3 0 ( 1 9 6 7) 5 5 9; (j) P. Mueller, D. O. Rudin, Bioche m. Biophys. Res. Co m mun. 2 6 (1967) 398; (k) T. E. Andreoli, M. Tieffenberg, D. C. Tosteson, J. Gen. Biol. 5 0 (1967) 2527; (1) M. M. S h e m y a ki n, Y u. A. O v c hi n ni k o v, V. T. I v a n o v, V. K. A nt o n o v, A. M. S kr o b, 1.1. Mikhaleva, A. V. Evstratov, G. G. Malenkov, ibid. 29 (1967) 834; ( m) B. C. Press man, E.J. Harris, W. S. Jagger, J. H. Johnson, Proc. Natl. Acad. Sci. U S A 58 (1967) 1949. 25. (a) C.J. Pedersen, J. A m. Che m. Soc. 89 (1967) 7017; (b) C.J. Pedersen, H. K. Fr e ns d orff, A n g e w. C h e m. I nt. E d. E n gl. 1 1 (1972) 16. 2 6. D.J. Cr a m, A n g e w. C h e m. I nt. E d. E n gl. 2 5 ( 1 9 8 6) 1 0 3 9. 27. D. Parker, Adv. Inorg. Che m. Radioche m. 27 (1983) 1; B. Dietrich, J. Che m. Ed. 62 (1985) 954. For the sepulchrate type of encapsulated metal ions, see: A. M. Sargeson, Pure Appl. Che m. 56 (1984) 1603. 2 8. ( a) J.- M. L e h n, J.- P. S a u v a g e, J. A m. C h e m. S o c. 9 7 ( 1 9 7 5) 6 7 0 0; ( b) B. Di etri c h, J.- M. Lehn, J.- P. Sauvage, J. Che m. Soc., Che m. Co m mun. 1973, 15. 29. (a) B. Dietrich, J.- M. Lehn, J.- P. Sauvage, Tetrahedron Lett. 1969, 2885 and 2889; ( b) B. Dietric h, J.- M. Le h n, J.- P. S auvage, J. Blanzat, Tetrahedron 29 (1973) 1629; B. Dietrich, J.- M. Lehn, J.- P. Sauvage, ibid. 29 (1973) 1647; (c) B. Metz, D. M or as, R. W eiss, J. C h e m. S o c., C h e m. C o m m u n. 1970,217 ; F. M at hi e u, B. M et z, D. Moras, R. Weiss, J. A m. Che m. Soc. 100 (1978) 4412 and references therein. 3 0. E. Gr af, J.- M. L e h n, J. A m. C he m. S oc . 97 (1975) 5022; Helv. Chi m. Acta 64 (1981) 1 0 4 0. 3 1. B. Di etri c h, J.- M. L e h n, u n p u bli s h e d r e s ult s. 3 2. E. Gr af, J.- M. L e h n, J. A m. C h e m. S o c. 9 8 ( 1 9 7 6) 6 4 0 3. 33. F. Sch midtchen, G. Muller, J. Che m. Soc., Che m. Co m mun. 1984, 1115. 34. J. L. Dye, Ange w. Che m. Int. Ed. Engl. 18 (1979) 587; J. L. Dye, M. G. De Backer, Ann. Rev. Phys. Che m. 38 (1987) 271. 35. J.- M. Lehn, Pure Appl. Che m. 52 (1980) 2303. 3 6. A.I. P o p o v, J.- M. L e h n i n G. A. M el s o n( E d.): “ C o or di n ati o n C h e mi str y of M a cr o- c y cli c C o m p o u n d s ” Pl e n u m Pr e s s, N e w Y or k 1 9 7 9. 3 7. I. M. K olt h off, A n al. C h e m. 5 1 (1979) I R. 38. F. Montanari, D. Landini, F. Rolla, Topics Curr. Che m. 1 0 1 (1982) 203; E. Blasius, K.- P. Janzen, ibid. 98 (1981) 163. 3 9. E. Gr af, J.- M. L e h n, J. L e M oi g n e, J. A m. C h e m. S o c. 1 0 4 ( 1 9 8 2) 1 6 7 2. 4 0. E. Gr af, J.- P. Ki nt zi n g er, J.- M. L e h n, u n p u bli s h e d r e s ult s. 4 1. B. Di etri c h, J.- P. Ki nt zi n g er, J.- M. L e h n, B. M et z, A. Z a hi di, J. P h y s. C h e m. 9 1 (1987) 6600. 42. a) D.J. Cra m, K. N. Trueblood, Topics Curr. Che m. 98 (1981) 43; b) F. De Jong, D. N. Reinhoudt in V. Gold, D. Bethel1 ( Eds.) Adv. Phys. Org. Che m. 17 (1980) 219, Acade mic Press, Ne w York. 43. J.- M. Lehn, P. Vierling, Tetrahedron Lett. 1980, 1323. 44. J.- P. Behr, J.- M. Lehn, P. Vierling, J. Che m. Soc., Che m. Co m mun. 1976, 621; Helv. Chi m. Acta 65 (1982) 1853. 4 5. J.- P. B e hr, J.- M. L e h n, H el v. C hi m. A ct a 6 3 ( 1 9 8 0) 2 1 1 2. 46. H. M. Colquhoun, J. F. Stoddart, D.J. Willia ms, Ange w. Che m. Inter. Ed. Engl. 25 (1986) 487. 47. Stability constants of about 800 and 10 5 l m o l - 1 have been obtained for binding of 3 + t o 1 2 b and to the hexacarboxylate in 14, respectively (aqueous R u ( N H 3 ) 6 s ol uti o n, p H = 7. 3); J.- M. L e h n, P. Vi erli n g, u n p u bli s h e d r e s ult s. 48. J. C. Metcalfe, J. F. Stoddart, G. Jones, J. A m. Che m. Soc. 99 (1977) 8317; J. Krane, 0. Aune, Acta Che m. Stand. B 3 4 (1980) 397. 4 9. a) J.- M. L e h n, P. Vi erli n g, R. C. H a y w ar d, J. C h e m. S o c., C h e m. C o m m u n. 1 9 7 9 , 296; b) see also: K. Madan, D.J. Cra m, ibid. 1975, 427; J. W. H. M. Uiter wijk, S. Harke ma, J. Geevers, D. N. Reinhoudt, ibid. 1982, 200. J.- M. L e h n 4 8 7

50. a) F. Vogtle, H. Sieger, W. M. Muller, Topics Curr. Che m. 98 (1981) 107; b) K. Saigo, Kagaku to Kogyo 35 (1982) 90; c) J.- L. Pierre, P. Baret, Bull. Soc. Chi m. Fr. II 1983, 367; d) E. Ki mura, Topics Curr. Che m. 1 2 8 ( 1 98 5) 1 1 3; e) F. P. S c h mi dt c h e n, i bi d. 1 3 2 (1986) 101. 51. a) J.- M. Lehn, E. Sonveaux, A. K. Willard, J. A m. Che m. Soc. 100 (1978) 4914; b) B. Dietrich, J. Guilhe m, J.- M. Lehn, C. Pascard, E. Sonveaux, Helv. Chi m. Acta 6 7 ( 1 9 8 4) 9 1; c) f or ot h er m a cr o bi c y cli c r e c e pt or s s e e al s o M. W. H o s s ei ni, T h e s e d e D o ct or at- e s- S ci e n c e s, U ni v er sit é L o ui s P a st e ur, Str a s b o ur g 1 9 8 3. 5 2. C. H. P ar k, H. Si m m o ns, J. A m. C h e m. S o c. 9 0 ( 1 9 6 8) 2 4 3 1. 5 3. a) B. Di etri c h, M. W. H oss ei ni, J;- M. L e h n, R. B. S essi o ns, J. A m. C h e m. S o c. 1 0 3 (1981) 1282; b) Helv. Chi m. Acta 68 (1985) 289. 5 4. J. C ulli n a n e, R.I. G el b, T. N. M ar g ulis, L.J. Z o m p a, J. A m. C h e m. S o c. 1 0 4 ( 1 9 8 2) 3048; E. Suet, H. Handel, Tetrahedron Lett. 1984, 645 . 55. M. W. Hosseini, J.- M. Lehn, M. P. Mertes, Helv. Chi m. Acta 66 (1983) 2454. 5 6. E. Ki m ur a, M. K o d a m a, T. Y ats u n a mi, J. A m. C h e m. S o c. 1 0 4 (1982) 3182; J. F. Marecek, C.J. Burro ws, Tetrahedron Lett. 1 9 8 6, T 9 4 3. 57. M. W. Hosseini, J.- M. Lehn, Helv. Chi m. Acta 70 (1987) 1312; see also H. R. Wils o n, R.J. P. Willi a ms, J. C h e m. S o c., F ar a d a y Tr a ns. I 8 3 (1987) 1885. 58. B. Dietrich, D. L. Fyles, T. M. Fyles, J.- M. Lehn, Helv. Chi m. Acta 62 (1979) 2763. 59. B. Dietrich, T. M. Fyles, J.- M. Lehn, L. G. Pease, D. L. Fyles, J. Che m. Soc., Che m. Co m mun. 1978,934. 60. M.J. Mann, N. Pant, A. D. Ha milton, J. Che m. Soc., Che m. Co m mun. 1986, 158. 6 1. F. P et er, M. Gr oss, M. W. H oss ei ni, J.- M. L e h n, J. El e ctr o a n al. C h e m. 1 4 4 ( 1 9 8 3) 2 7 9. 62. E. Garcia- Espana, M. Micheloni, P. Paoletti, A. Bianchi, Inorg. Chi m. Acta 1 0 2 (1985) L9; A. Bianchi, E. Garcia- Espana, S. Mangani, M. Micheloni, P. Orioli, P. P a ol etti, J. C h e m. S o c., C h e m. C o m m u n. 1 9 8 7, 7 2 9. 6 3. M. F. M a nfri n, L. M o g gi, V. C a st el v etr o, V. B al z a ni, M. W. H o s s ei ni, J.- M. L e h n, J. A m. C h e m. S o c. 1 0 7 (1985) 6888. 64. J.- M. Lehn, Pure Appl. Che m. 52 (1980) 2441. 6 5. J.- M. L e h n, J. Si m o n, J. W a g n er, A n g e w. C h e m. I nt. E d. E n gl. 1 2 (1973) 578,579. 66. R.J. Motekaitis, A. E. Martell, B. Dietrich, J.- M. Lehn, Inorg. Che m. 23 (1984) 1588; R.J. Motekaitis, A. E. Martell, I. Murase, ibid. 25 (1986) 938; A. Evers, R. D. Hancock, I. Murase, ibid. 25 (1986) 2160; D. E. Whit moyer, D. P. Rille ma, G. F err a u di, J. C h e m. S o c., C h e m. C o m m u n. 1 9 8 6, 6 7 7. 6 7. J.- P. Ki nt zi n g er, J.- M. L e h n, E. K a uff m a n n, J. L. D y e, A.I. P o p o v, J. A m. C h e m. Soc. 10.5 (1983) 7549. 6 8. D. H e y er, J.- M. L e h n, T etr a h e dr o n L ett. 1986, 5869. 69. T. Fujita, J.- M. Lehn, Tetrahedron Lett. 1 9 8 8, 1 7 0 9. 70. T. P. Lybrand, J. A. Mc Ca m mon, G. Wipff, Proc. Natl. Acad. Sci. U S A 83 (1986) 8 3 3. 71. J.- M. Lehn, in K.J. Laidler ( Ed.): “I U P A C Frontiers of Che mistry” Perga mon Press, Oxford 1982, p 265. 72. J. Jaz winski, J.- M. Lehn, D. Lilienbau m, R. Ziessel, J. Guilhe m, C. Pascard, J. C h e m. S o c., C h e m. C o m m u n. 1 9 8 7, 1 6 9 1. 7 3. A. C arr o y, J.- M. L e h n, J. C h e m. S o c., C h e m. C o m m u n. 1 9 8 6, 1 2 3 2. 7 4. J. C o m ar m o n d, B. Di etri c h, J.- M. L e h n, R. L o ui s, J. C h e m. S o c., C h e m. C o m- m u n. 1 9 8 5, 7 4. 75. Y. Okuno, K. Uoto, 0. Yone mitsu, T. To mohiro, J. Che m. Soc., Che m. Co m mun. 1 9 8 7, 1 0 1 8; J. R. H ol m es, J.- M. L e h n, w or k i n pr o gr ess. 76. F. Kotzyba- Hibert, J.- M. Lehn, P. Vierling, Tetrahedron Lett. 1980, 941. 7 7. F. K ot z y b a- Hi b ert, J.- M. L e h n, K. S ai g o, J. A m. C h e m. S o c. 1 0 3 (1981) 4266. 7 8. C. P a s c ar d, C. Ri c h e, M. C e s ari o, F. K ot z y b a- Hi b ert, J.- M. L e h n, J. C h e m. S o c., Che m. Co m mun. 1982, 557. 7 9. J.- P. Ki nt zi n g er, F. K ot z y b a- Hi b ert, J.- M. L e h n, A. P a g el ot, K. S ai g o, J. C h e m. 4 8 8 Che mistry 1987

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