1 Reaction Control by Molecular Recognition - A Survey from the Photochemical Perspective Cheng Yang1, Chenfeng Ke2, Yu Liu2, and Yoshihisa Inoue1 1 PRESTO (JST) and Department of Applied Chemistry, Osaka University, Suita 565-0871, Japan department of Chemistry, Nankai University, Tianjing, China 1.1 Introduction Molecular recognition through non-covalent interactions between two or more molecules has attracted much attention from a broad spectrum of chemists for a long period of time and has already found many applications in various areas of science and technology. The concept of molecular recognition was first developed for biomolecular systems such as enzyme, antibody and DNA, which can selectively bind the specific target molecules through non-covalent weak interactions, including hydrogen bonding, van der Waals, dipole-dipole, charge-dipole and hydrophobic interactions.1"3 Recent studies on artificial host-guest systems have revealed that molecular recognition is the essential conceptual basis for supramolecular chemistry and nanotechnology.4,3 Reaction control through complexation of substrate by supramolecular host is a relatively new idea compared to the conventional approaches that involve simple collisional attack or coordination of substrate to metal. Multiple non-covalent interactions in supramolecular assembly bind and locate a site-specific substrate in the right position, orientation and conformation near the catalyst or active site, stabilize the high-energy transition state, and eventually make the reaction faster and more selective. Typical examples are found in enzymatic reactions, which proceed with high specificity and efficiency in aqueous solutions under mild conditions. These observations in natural systems have inspired Molecular Encapsulation: Organic Reactions in Constrained Systems Edited by Udo H. Brinker and Jean-Luc Mieusset © 2010 John Wiley & Sons, Lid 2 Molecular Encapsulation researchers to develop novel research areas such as supramolecular chemistry, biomimetic chemistry and bio-inspired materials science and technology.6,7 Contrary to the thermal counterpart, photochemical reactions in supramolecular system have been less investigated and therefore of current interest. Photochemistry is a powerful tool in synthetic chemistry as a complementary method for achieving compounds that are difficult to obtain through thermal reactions due to high strain, low stability, and orbital symmetry reasons. Unlike thermal reactions, photo reactions deal with excited-state molecules that are usually short-lived but experience much lower energy barriers and exhibit high reactivities even at low temperatures. As a consequence of these features, the precise control of a photoreaction is more difficult to achieve than that of thermal one. This is one of the reasons why most asymmetric photoreactions result in only relatively low enantioselectivities. In this context, supramolecular approaches to the photochemical asymmetric synthesis enable the more precise control of the orientation and conformation of substrates and, as a result, the enantioselectivity of photoproducts, by utilizing the non-covalent interactions in both ground and excited states. Supramolecular photochemistry is a relatively new interdisciplinary area of science and may be tracked back to the work in early 1980s, where the spectroscopic properties of ions were manipulated by crown ethers.8"10 The rapid development of supramolecular chemistry in the last two decades accelerated the application of supramolecular systems to organic photochemistry1'''2 and more recently to asymmetric synthesis,13,14 leading to a great number of publications on reaction control by molecular recognition. Consequently, not all of these areas will be covered, but the concentration will be rather on the representative supramolecular photoreactions conducted primarily in solution. This will help idenitify the crucial concepts, strategies and conclusions as well as the major factors and mechanisms that govern the supramolecular photochemistry in different systems, and also provide the possible applications and future perspectives of this interesting area of supramolecular chemistry. 1.2 Photochemical Reactions Mediated by Macrocyclic Compounds 1.2.1 Supramolecular Photoreactions with Crown Ethers Crown ethers, a family of cyclic oligomers of ethylene oxide, are artificial macrocyclic hosts which have been synthesized and utilized since the early days of supramolecular chemistry.13,16 Besides various metal ions that are complexed by crown ethers mainly through ion-dipole interaction, primary and secondary organic ammonium ions also form stable complexes with larger sized crown ethers through ion-dipole and hydrogen-bonding interactions. Stoddart and co-workers used crown ethers that can simultaneously bind two organic ammonium guests to facilitate photodimerization,'7 As illustrated in Scheme 1.1, /ram-stilbene derivative 2 forms a doubly encircled, doubly threaded 2:2 complex with bis-/?-pheny[ene-34-crown-10 1 to give a centrosymmetric [4)pseudorotaxane in the solid state. In addition to the hydrogen-bonding interactions between 1 and 2, the complex is also stabilized by n-n stacking interactions between the two rra/u-stilbene units with mean interplanar and centroid-centroid separations of 3.57 and 4.33 A, respectively. The close arrangement of stilbenes accelerates the photodimerization upon irradiation to Reaction Control by Molecular Recognition 3 5 6 dication form radical cation form Scheme 1.2 exciusively give a single cyclobutane isomer 4 with a syn-onti-syn conformation, as confirmed by X-ray crystallographic analysis. A control experiment showed that no pho-todimerization but only trans-to-cis isomerization took place in the absence of crown ether 1. The photochrome behavior of viologens is greatly affected upon complexion with crown ether. Viologens show photoinduced colour change in the absence of any additional reagents when dispersed in isotropic thin polymer films.18 Irradiation of benzylviologen 5 (Scheme 1.2) incorporated in a polymer matrix caused a colour change from colourless to blue as a result of the reduction of 5 from dication to radical cation, which was reverted to dication within 2 h in the dark. Crown ether 1 forms a 1:1 complex with 5 and also with 6 in acetone with association constants of ca. 200M"1. The charge-transfer (CT) interaction between viologen 5 or 6 and 1 led to the formation of yellow-coloured CT complex with a CT absorption band at 453nm and 421nm for 5 and 6, respectively. The crown ether complexes of photoreduced viologens showed much accelerated bleaching rates than the corresponding free viologen radical cations. A similar phenomenon was observed also for 2 c 1 complex in a polymer matrix. 1.2.2 Supramolecular Photoreactions with Calixarenes Calix[n]arenes are a class of macrocycles that are normally made up of phenol units linked with methylene bridges and possess cavities of various sizes that can accommodate small organic molecules primarily driven by hydrophobic interactions. Water soluble p-suIfonatocalix[6]arene (SCA[6]) and [SJarene (SCA[8]) (Scheme 1.3) Have dimensions of 15.9 X 11.8 A and 20.4 x 16.7 A at the upper rim and 6.5 x 3.3 A and 4 Molecular Encapsulation Type I o Ph Ph1 „R. Ph Rj 7a, R, = B2 = H 7b, R, = H; HE = CH3 7C. R, = n2 = CH3 O 0 M Ph Ph 8 Ph H—I— OCHR,R2 RiR2HCO-|—H Ph Ph..,OH PhCHO 10 SCA[n](n = 6,B, Type|| pjkjl — PhA^ * 11 HO R, Ph 12 Scheme 1.3 8.6 x 5.9 A at the lower rim, respectively,19,20 and provide suitable cavities for accommodating quaternary ammonium ions,21,23 native amino acids,23 and small neutral organic molecules.24 Using SCA[6] and SCA[8]:5 as supramolecular hosts, Ramamurthy et al. investigated the photochemistry of benzoin alkyl ethers 7a-c.26""28 These SCAs formed the corresponding 1:1 complexes with 7a-c in aqueous solution, and 7a showed modest association constants of 137M"1 and 386M"1 with SCA[6] and SCA[8], respectively. Upon photolysis, these benzoin alkyl ethers underwent both the Norrish type I (a-cleavage) and type II (/-hydrogen abstraction) reactions to give photoproducts 8-12 (Scheme 1.3). In the absence of SCAs, pinacol ether 9 was obtained as in 92% relative yield in aqueous solution at pH 7, along with deoxybenzoin 11 (8% relative yield), for which the a-cleavage (ka ~ 10,0s_1) faster than the /-hydrogen abstraction (kY ~ 109s_I) is responsible. However, when the photoreaction was performed in the presence of SCA, product 11 became the major product. The relative yield of the type II products 11 and 12 depends critically on the cavity size of hosts and association constants. Photoirradiation of 7a in the presence of an 8-fold excess amount of SCA[8] or SCA[6] gave 11 and 12 in 96% or 70% combined yield, respectively. The dominant formation of type II products suggests that 7 adopts a conformation favourable for /-hydrogen absorption in the cavity. Choosing a suitable substrate with higher binding affinity for SCA is likely to be crucial in improving the stereoselectivity of photoreaction. Photoreaction of stilbazoles 13a-f (Scheme 1.4) has also been investigated in the presence of SCA[n]. Upon irradiation in dilute aqueous HCI solution without a host, trans-stilbazoles 13a-f gave predominantly czs-isomers 16a-f, along with only small amounts of anti-head-to-tail (HT) dimers 14a-f and anti-head-to~head (HH) diraers 15a-f.29 In aqueous solution, stilbazoles were found to form 2:1 complexes with SC A[8] and SCA[6], irradiation of which afforded the corresponding tm/7-HT dimer in 66-86% yield in the presence of SCA[8] and in 60-76% yield in the presence of SCA[6]. The anti-EB dimer was given in only 16% yield, which was attributed to the electrostatic repulsion between two pyridinium components. The hydrophobic nature of SCA cavity should be responsible for the inclusion of stilbazoles. It is thus concluded that SCAs control the orientation of stilbazoles through complex formation to eventually enhance the distribution of HT dimer. Ar" hv 13a-f Reaction Control by Molecular Recognition 5 Ar Py Ar I Py Py Ar 14a-f I Ar Py 15a-f Py 16a-f a: At = phenyl; Py = 4-pyridyl b- Ar = 4'CI-phenyl Py = 4-pyridyl c. Ar = 4'-OCH3- phenyl; Py = 4-pyridyl &. Ar = 1-naphthyl; Py - 4-pyridyl e; Ar = phenyl; Py = 2-pyridyl (. Af = phenyl' Py = 3-pyridy! Scheme 1.4 y + 17a-c, 17e-f a R = H, X = CH, Y = CH, Z = N b;R = CI,X=CH, Y = CH.Z = N c: R = OCH3l X = CH, Y = CH, Z = N e; R = H,X = N, Y= CH,Z = CH f: R = H, X = CH, Y= N.Z^CH 13d 23 Scheme 7.5 Unlike water-soluble callxarenes that encapsulate guests by hydrophobic, electrostatic and van der Waals interactions, amphiphilic calixarenes in solid state form container- or capsule-like structures and include guest molecules predominantly through van der Waals interactions. Photochemical behavior of stilbenes included in amphiphilic molecular capsules of ;?-hexanoyicalix[4]arene 19 (Scheme 1.5) in the solid state was studied by Ananchenko et al.i0 Possessing diverse urn- and bimolecular reaction routes, including geometrical isomerization, cyclization and cyclodimerization, stilbenes are good model compounds for examining the effects of calixarene capsules on photoreactivity. In the solid state, two molecules of 19 self-assemble in a head-to-head fashion to form a hydrophobic capsule, which can accommodate two cw-stilbene molecules to give a 2:2 complex. This 2:2 complex is not very stable and can release one ds-stilbene molecule. On the other hand, irans-sti\ben& 20 is co-included with an ethanol molecule in the capsule to give a 1:1:2 complex. Irradiation of the complex of ds-stilbene first gave rise to trans-stiibene, and then to [2+2] dinners 21 and 22 in 5:1 ratio upon prolonged irradiation. Irradiation of/rans-stilbene complex gave cis- and trans-stiibene in 1:1 ratio, along with a trace amount of dimers 21 and 22, confirming that the initial capsule is occupied primarily by only one frans-stilbene molecule. Notably, calixarene 19 readily forms solid lipid nanoparticles (SLNs), which can serve as a potential carrier system.31 2-Ethylhexy! rrans-4-methoxycinnamate 23 can be loaded 6 Molecular Encapsulation by a solvent displacement method into the SLNs based on 19. Comparison of the powder X-ray diffraction (XRD) patterns of unloaded SLN and SLN loaded with 23 ([23]/ [19] - 0.6) with that of crystalline complex 23 cz 192 revealed that the complexation pattern of the SLN loaded with 23 is similar to that of the crystalline complex. No dimeri-zation product was obtained upon irradiation of 23 loaded in SLN of 19, and only pho-toisomerization occurred to give a 4:6 mixture of cis- and trans-isomev. However, when the stoichiometry was changed to [23]/[19] = 1.2, photolysis of 23 loaded in SLN yielded HH dimers 24 and 25 in a combined yield of ca. 10%. This regioselectivity of cyclodimer-ization of 23 is attributed to the fact that two 23 molecules preferably align in the 19's cavity in HH orientation. These results suggest that one can efficiently manipulate the photochemical behavior of 23 by simply adjusting the molar ratio of 23 loaded to the SLNs of amphiphilic 19. 1.2.3 Supramolecular Photo reactions with Cyclodextrins Cyclodextrins (CDs) are most frequently employed hosts for supramolecular photoreac-tions by virtue of the fact that they are readily available, UV-transparent, water-soluble and capable of accommodating a wide range of organic guests in their hydrophobic cavities. Organic guests can form inclusion complexes with a-, j3- and y-CDs in various stoichiometrics both in solution and in the solid state. Unimolecidar Reactions The cavity of {3-CD is smaller than that of ^CD, and normally includes one organic molecule of suitable size to form 1:1, 2:2 or 2:1 host-guest complexes. Asymmetric intramolecular me/a-photocycloaddition of phenoxyalkenes (Scheme 1.6) has been studied in the presence of /3-CD by Eycken and co-workers32. The inclusion complexes of 26, 28, 30 and 32 with /3-CD were collected from the deposit formed in a warm aqueous solution containing /3-CD and substrates by centrifugation and decantation. For the complexes of 26a, 28b, 30a and 30b with /3-CD, the host-guest stoichiometries were determined as 2:1 by UV spectroscopy, while the rest of the substrates formed 1:1 complexes. Irradiation of the solid complexes for 24 h led to ca, 55-82% conversion, which are appreciably lower than that obtained in the solution-phase photoreactions. In all cases, meto-photocycloaddidon led exclusively to only one regioisomer of 1,5-bridged dihydrosemibuhvalenes 27, 31 and 33 respectively from 26, 30 and 32. On the contrary, irradiation of complex 28 c CD afforded two meta adducts 29a,b and 29c,d. The regioselectivity of adducts 29a and 29c is about 1:3 in the presence of /3-CD against 1:1 in the absence of /3-CD. Photocyclization of 'linear' photos ubstrates 26a,b gave insignificant enantiomeric excess (ee) of less than 3%, which is probably due to the less restricted orientation of p-substituted substrate in the cavity. Photocyclization of 28a afforded minor product 29a in much better 17% ee but the major product 29c in only 2% ee. These results may indicate the trade-off relationship between chemical and optical yield: thus, largei steric hindrance leads to low chemical but high optical yield, and vice versa. It is well documented that direct or sensitized photolysis of (Z)-cyclooctene 34Z leads to geometrical isomerization to planar chiral (F)-isomer 34E (Scheme 1.7).33 Due to the comprehensive work by Inoue et al, the enantiodifferentiating photoisomerization of 34Z sensitized by optically active benzenecarboxylates has become a benchmark reaction for evaluating chiral photosensitizing system.""1-36 The first supramolecular enantiodifferentiating photoisomerization of 34Z was examined in direct photolysis of its /3-CD complex Reaction Control by Molecular Recognition tlV MeOOCn(H2C)—/(^ 26a: n = 1 ^ —--* 32 26b: n = 2 I J , \ 27a: n = 1 (CHa^COOMe 27b: n = 2 28a: n = 1 X---— + \j£> 28b: n = 2 jf 1 MeOOCn(H2C) N ^ >j:*;^jCHj)ricooys 29a: n = 1 29c: n = 1 29b: n = 2 29d: n = 2 hv 30a: n = 1 ^4^(CHz)ncooMe 30b: n = 2 (CH2)nC00Me 31a: n = 1 31b: n = 2 hv Scheme 1.6 o-S-% 34Z (R)-34E (SJ-34E 35a-n a, R, = H ; R2 = OH c, R, = m-C02Me; R2 = OH d, R1 =p-C02Me; R2 = OH e, R, = H ; R2 = OMe f, = 0-CO2Me; R2 = OMe g, Ri = m-C02Me; R2 = OMe h, R, = p-C02Me; R2 = OMe i, Rj = o-Me; R2 = OH j, R, =m-Me; R2 = OH k, Rt = p-Me; R2 = OH I, Rt =o-OMe; R2 = OH m, Rt =m-OMe; R2 = OH n, Rt = p-OMe; R2 = OH Scheme 7.7 8 Molecular Encapsulation in the solid state. Photoproduct obtained from this complex was almost racemic with only 0.247c ee, demonstrating that the cavity interior of native /J-CD does not possess sufficient enantiodifferentiating ability for the photoisomerization of 34Z. A more sophisticated strategy for achieving higher levels of enantiodifferentiation has been established by performing the photolysis of 34Z with sensitizing chiral hosts 35 (Scheme 1.7), in which a chromophore is introduced to the primary rim of fi-CD. A clear merit of this supramolecular photos ens itization system is that the energy of excited sensitizer can be efficiently transferred to 34Z included in CD cavity, while the undesirable, less-enantiodifferentiating sensitization outside the CD cavity can be prevented. Furthermore, this sensitizing host strategy allows the asymmetric photoreaction to occur with only a catalytic amount of chira! host, achieving photochemical chirality amplification. In contrast to the small EIZ ratios around 0.25 reported for non-supramolecular photo sensitizations by conventional alkyl ben2oates>37 an EIZ ratio of up to 0.8 were obtained at the photostationary state in 1:1 methanol-water mixture by using 35. By adjusting the solvent composition, good enantiomeric excesses of up to 24% were obtained upon photosensitization with 35a-d. The enantio selectivity of 34E obtained in the photoisomerization of 34Z with non-methylated CD is in general insensitive to the temperature variations as a result of the insignificant role of entropy in the /3-CD-based supramolecular photochirogenesis system. However, the photoisomerization of 34Z in permethylated CD derivatives 35e-h turned out to be highly temperature dependent, frequently leading to a switching of the product chirality by changing the reaction temperature.38 The more flexible skeleton of permethylated CD due to the lack of hydrogen-bonding net at the secondary rim is responsible for the temperature-dependent enantioselectivity. Recently, further efforts were done to elucidate the effects of chromophore substitution on the ee of 34E,39 and much better enantiomeric excesses of up to 46% were reported upon photosensitized isomerization mediated by 35m. Analogous hosts 35a, 351 and 35n afforded only modest ee's in a range of 4%-10% under optimized conditions.40 The ee value falls drastically to 1.7% when the m 320 nm H02C co2h 43 anti-HT H02C CO;H 44* syn-HT 45* antt-HH Scheme 1.9 ■CO,H 46 syn-HH hn—(CH^p—n ; ■■ 91b > 91a. A cis-syn [2+2] adduct was given in 89% yield after the photolysis of 91c at 366 nm for 6 h at room temperature in the presence of the template. The same reaction performed at 70 °C, where 91c was decomplexed from the template, afforded no photoligated product, indicative of the importance of preorientation of photosubstrate by supramolecular host. On the other hand, photoirradiation of the isolated adduct in the absence of the template at 366 nm for 6 h afforded 91c in 90% yield as a result of the photosensitized split. In order to improve the photo reactivity of template-directed photochemical synthesis of branched oligodeoxynucleotides, the 5-vinyldeoxyuridine component was replaced by 5-carboxyvinyldeoxyuridine 92, which has a much higher extinction coefficient (Bm ~ 76).™ Photoirradiation of 92 for 1 h in the presence of a template gave a cis-syn [2+2] adduct in good yield of 93%. Similar [2+2] photocycloaddition between an a-5-cyanovmyldeoxyuridine 93 at the 3'-end and a thymine at the 5'-end also occurred smoothly in the presence of a template.71 A single mismatch in oligodeoxynucleotide chain led to a great decrease of reaction rate, indicating a critical dependence of photoli-gation on sequence specificity. Using 94 as a template DNA, Ihara ex ai. investigated the photodimerization of anthracene tethered to complementary oligodeoxynucleotides 95 and 96 (Scheme 1.18).77 The reactivity of the photodimerization mediated by 94 was found to be dependent on the distance between oligodeoxynucleotides and anthracene, and decrease in an order of 95a/96a > 95a/95b > 95b/96b > 96a/96b. The reaction efficiency is also significantly affected by the introduction of an additional or mismatched nucleotide, indicating that this DNA-templated photoligation is highly position- and distance-dependent. Photodimerization of 1-substituted anthracene derivatives 97a and 97b (Scheme 1.19) templated by a full-match DNA 98 selectively afforded only two isomeric dimers among the eight dimers that are possibly formed from the dimerization of 97a and 97b. Photoreaction with the full-match template was found to be much more efficient than those with mismatch templates.78"79 There are two kinds of grooves in DNA helixes, i.e. major and minor grooves, which can interact with metal ions or organic guests. Since these grooves are well-structured 18 Molecular Encapsulation S CAGTCGTATGCAGGGGGGACGTATGCTGAC 3' 98 Scheme 1.19 and chiral in nature, they can be used as ideal stereodifferentiating binding sites. Inoue et oi. performed the enantiodifferentiating photoisomerization of 34Z (Scheme 1.7) com-plexed and sensitized by calf thymus DNA (ctDNA).80 Photosensitized isomerization of 34Z with pyrimidine nucleosides as chiral sensitizers afforded 34E in 5.2% ee at the photostationary state. However, much better ee of up to 15.2% was obtained when the photolysis was carried out in the presence of ctDNA in aqueous solution. Supramolecular interaction of 34Z with hydrophobic minor groove of ctDNA evidently plays an important role in the photochirogenesis, as only negligible ee was obtained for 34E when the pho-tosensitization was performed in 50% aqueous methanol, in which the supramolecular interaction of 34E with ctDNA was significantly reduced. 1.3.2 Photochemical Reactions Mediated by Proteins Proteins, the most abundant and versatile macromolecules in living organisms, are polymers built from about twenty essential L-or-amino acids. Driven by a variety of non- Reaction Control by Molecular Recognition 19 Scheme 1.20 covalent interactions, such as ionic, hydrogen binding, van der Waals and hydrophobic interaction, these biopolymers fold into specific conformations to achieve various biological functions. The binding sites of defined shape and size, as well as the chiral nature, render proteins excellent supramolecular hosts for specific binding and recognition. A series of photochemical reactions have been investigated with various proteins, mainly targeting the photochemical chiral discrimination and generation based on the inherently chiral character of binding sites in protein. Serum albumin is the most abundant protein in plasma which binds and transports not only endogenous but also exogenous compounds, and has therefore been most frequently employed as biosupramolecular host for photochemical reactions. McDonagh and co-workers investigated the photoisomerization of bilirubin-HIa 99a,b (Scheme 1.20) in the presence of human serum albumin (HSA). The E-Z photoisomerization between (Z,Z)-99a and (E,Z)-99b is not inhibited even in the binding cavity of HSA. Bilirubin-IIla shows intense bisignate circular dichroism spectra in the chiral pocket of HSA.81,82 The negative exciton coupling signal, which was observed upon irradiation of (Z,Z)-biIirubin-IUa/HSA complex with a broad-band blue light of /C, - 430nm, was dramatically switched to a positive exciton coupling signal after irradiation with green light at 544nm.S3 This signal switching, which is controllable by changing the irradiation wavelength, renders the system a potential chiroptical switch. Zandomeneghi et at. reported the enantioselective photoinduced decomposition of l,l'-binaphthol 100 (Scheme 1.21) included in bovine serum albumin (BSA). Complexation of (R)-(+)- and (S)-(-)-100 with BSA revealed a remarkable difference in stability between the two diastereomeric complexes, and the BSA complex of (5)-(-)-100 exhibited a significantly bathochromic shift in the absorption spectrum. By selectively irradiating the (S)-(-)-100 complex at longer wavelengths, (i?)-(+)-100 of up to 99.5% ee was obtained after 77% of the starting material (racemic 100) were decomposed.84"86 Miranda et at. studied the excited-state behavior of chiral_drugs bound to BSA and HSA.87"89 Inclusion of carprofen 101 (Scheme 1.22) in HSA significantly lengthened the triplet-state lifetime of 101 as a result of more rigid surroundings and the suppression of self-quenching of 101. The complexation of enantiomeric 101 with HSA caused a significant difference in triplet lifetime, and the lifetime of (S)-lOl-HSA complex is 4 times shorter than that of (fl)-lOl-HSA complex. Irradiation of 101 alone in aqueous buffer solution led to a polymerization of 101. However, dechlorinated carprofen 102 was 20 Molecular Encapsulation R-(+)-100 S-(-)-100 R-(+)-100 Scheme 1.21 formed in the presence of HSA, and (5)-101 was 1.5 times more efficient than (#)-101 in producing the corresponding (S)- and (^)-102. The complexation behavior of organic substrates with proteins is usually very complicated as a consequence of the diversified binding sites with distinctive size, shape, hydro-phobicity and binding affinity. Since these binding sites differ in reactivity and selectivity, elucidation of binding behaviour is essential for understanding and manipulating the photoreaction performed in the binding sites of proteins. Inoue and co-workers have comprehensively studied the binding behaviour of 2-anthracenecarboxylate (AC) (Scheme 1.9) to the hydrophobic pockets of BSA and HSA by a combined use of spectroscopic techniques, i.e. UV/Vis, fluorescence and circular dichroism spectroscopy.90"92 Although HSA and BSA share more than 95% of amino acid residues in common (i.e., 26 out of co. 600 amino acids), the two albumins display entirely different binding, photophysical and photochemical behavior. BSA possesses four binding sites, which accommodate 1, 3,2 and 3 AC molecules with individual binding constants of 5.3 x 107,1.3 x 105, 1.4 x" 10* and 3 X 103]Vrl, respectively. In contrast, HSA provides five binding sites that accommodate 1, I, 3, 5 and >10 AC molecules in the order of reducing binding ability.93"97 Although multiple AC molecules are bound to sites 2-4 of BSA and sites 3-5 of HSA. they do not appear to be very closely located to each other, since no exciton coupling was seen in the circular dichroism spectrum and no static quenching of fluorescence was detected. AC bound to site 1 of BSA shows highly structured fluorescence with dual lifetimes of 4.8 and 2.1 ns, which are assignable to two kinds of AC that differ in position or orientation in highly hydrophobic environment. However, ACs in site 2 of BSA gave a much longer lifetime of 13.3 ns and the fluorescence spectra became broader; the lifetimes of AC in sites 3 and 4 are practically indistinguishable from that in bulk water (15.9 ns). Almost the same is true for HSA, except for the fact that not only the first but also the second site bind only one AC and are highly'hydrophobic. Reaction Control by Molecular Recognition 21 Each binding site in BSA and HSA exhibits very different photochemical behaviour. Thus, the HTVHH ratio and enantioselectivity obtained in albumin-mediated AC photo-cyclodimerization are dynamic functions of the AC/BSA or AC/HSA ratio. For example, the HT dimers are produced as the major products in the photodimerization of AC in host-free bulk water and also in the presence of HSA, whereas the HH dimers become the dominant products in the BSA-mediated photodimerization. In the presence of BSA (AC/BSA = 1.3), chiral HT and HH dimers, 44 and 45, were obtained in 29% and 41% ee, respectively. Interestingly, the ee's for 44 and 45 were further improved up to 38% and 58% by adding nitromethane as a site-selective quencher of AC located in such binding sites that are more accessible but less enantioselective. In the case of HSA, much higher 79% and 88% ee were reported for 44 and 45, respectively, at 25 °C and AC/HSA = 3. Temperature was found to have a modest effect on the enantioselectivity to give better ee's of 82% and 90% for 44 and 45, respectively, by decreasing the temperature to 5 °C. 1.4 Photochemical Reactions with Confined Cages Based on Inorganic and Organic-Inorganic Hybrid Materials 1.4.1 Photochemical Reactions with Zeolites Besides the natural and artificial molecular hosts that are primarily based on organic compounds, photochemical reactions have also been investigated in the confined spaces of inorganic nano- or mesoarchitecture. Zeolites, which are porous crystalline alumino-silicates composed of tetrahedral A104 and Si04 building blocks and usually possess cages and channels of 4-14 A, have been extensively used as hosts for mediating photochemical reactions. The ratio of Si04 to A104 can be changed from 1 to infinite, and metal cations are commonly introduced to balance the negative charge of A104 units. The fau-jasite and pentasil family of zeolites, which form roughly spherical supercages of ca. 13 A and tubular channels with lengths of ca. 50 A, are most commonly used zeolites for catalyzing chemical reactions. Zeolites have a wide UV/Vis transparent region as a result of Al-O-Si framework that is similar to glass and quartz, and therefore are compatible with most organic compounds. The size and free volume zeolite supercages are adjustable by the number and sort of countercations. By virtue of these properties, zeolites have attracted much attention of photochemist as confining media in the last two decades. 103 105 106 107 a: R,=H; R2= CH3 b: R,=H; R2= (CH,)jCH3 c:R,= CH3;R,= CH3 Scheme 1.23 22 Molecular Encapsulation Scheme 1.24 Studies on photochemical reactions within zeolites have already been summarized in several reviews.98"102 The earliest work in this field appeared in 1980s.103"106 Turro and co-workers investigated Norrish type I and type II photoreactions of phenyl alkyl ketones 103 in the supercage of faujasite-type zeolites. Photolysis of 103 in solution or solid state was known to give a variety of photoproducts 104-108, depending on the molecular mobility, conformation and orbital overlap in the excited state. Inclusion of 103 in zeolites can significantly modify the above factors and lead to a switching of reaction selectivity. Photolysis of 103 in supercages of NaY zeolite gave a mixture of products with modest selectivities; 105/(107 + 108) = 0.72-0.83. The ratio was improved to 3.2-3.8 by using NaX zeolite, and was dramatically enhanced up to >50 by using silicalite (S-115) zeolite,103 suggesting that this photoreaction is highly dependent on the cavity size of zeolite. Photooxygenation of (Z)-enecarbamate 109 (Scheme 1.24) in solution gave methyl deoxybenzoin 112 in only a modest enantioselectivity even at a very low temperature, while a much better optical yield was obtained by starting from the (£)-isomer 110.107"1" The confinement in zeolite supercage greatly restricts the orientation and conformation of photosubstrate and leads to a significant switching of reaction selectivity from that observed in isotropic media. Thus, singlet oxygenation of (Z)-109 in NaY zeolite loaded with cationic dye sensitizer methylene blue (which is readily introduced into zeolite supercage through cation exchange and generates 'O, from 302 upon irradiation) gave 112 in up to 80% ee. This is possibly due to the restricted space of zeolite supercage that aligns the substrate in an orientation suitable for ^-face-selective attack of the C=C bond by 102. Compared to the high ee obtained in methylene-blue-exchanged NaY, the same reaction performed in LiY zeolite gave 112 in only 35% ee, for which the larger available volume in the supercage of LiY zeolite is possibly responsible. Besides the well-confined and rigid framework of zeolites, cation species also plays an important role in manipulating photochemical reaction occurring in the cavity.112'12' The free volume in zeolite cavity relies on the number and sort of cations located in the cavity. Differing from isotropic media, in which the direction and magnitude of electric field fluctuate around a solvated molecule, cations in zeolite cavity generate a stronger, anisotropic and more stable electric field. Such an electric field can polarize the included Reaction Control by Molecular Recognition 23 zeolite hv + 113 114 115 Scheme 1.25 o'- hv 116 H 118 H 119 Scheme 1.26 molecules, distort their electron density, and even facilitate heterolytic bond cleavage. Indeed, it has been observed that the intensity and wavelength of absorption and emission of included aromatic compounds were significantly changed in the cavity of zeolite. m~12:> Ramamurthy et al. reported that photoreaction of dibenzobarrelene 113 (Scheme 1.25) in Lif and Na+ exchanged zeolites resulted in triplet photoproduct 115 in 67% and 62% yield, respectively. This observation indicates that the intersystem crossing is significantly accelerated even by light atoms. However, this effect disappeared when the zeolites were equilibrated with water before use. The electric field of the cations in the cavity, which perturbs the symmetric nature of photosubstrate and facilitates the intersystem crossing, may be responsible for this 'light atom' effect. On the other hand, the heavy atom effect is clearly seen even for hydrated cations, and >99% triplet photoproduct was observed with Tl+-incorporated zeolite.126^2" Photoreactivity of androstenedione 116 (Scheme 1.26) was demonstrated to be dramatically affected by the electric field of zeolite.130 The epimerization of 116 to yield 117 is the major reaction in isotropic solution such as hexane, methylene chloride, methanol and cyclohexane. The reduction of the cyclohexenone A-ring can be observed in only propa-nol, with 118 and 119 being given in 14% combined yield. However, irradiation of 116 in NaY afforded exclusively the reduction products in >85% yield, and no product due to the reaction at the D-ring was observed. This reactivity change observed for the androstenedione included in zeolite cavity was ascribed to the lowering of the n,n excited state of the A-ring due to the electric field in zeolite cavity. Interactions between cation and photosubstrate, such as cation-7T, cation-dipole and cation-lone pair interactions, may restrict the mobility and conformation of photosubstrate, and therefore endow the cation with versatile roles in manipulating the reactivity and selectivity of photoreaction in zeolite cavity.131"'42 Ramamurthy and co-workers have studied stereoselective photoisomerization of diphenylcyclopropane derivatives in zeolite supercage. It was found that the photoisomerization of rram-diphenylcyclopropane 121a occurred in the cavity of alkali cation-exchanged Y zeolite to give dj-120a in high 24 Molecular Encapsulation efficiency, while the photolysis of tis-120a failed to give any trans-isomsT.m This is ascribed to the formation of cation-TT complex in which two phenyl groups of ciy-121a sandwich an alkali metal ion. The cK-isomer is thus stabilized and the isomerization reaction is inhibited. However, /ra/w-isomers can be given upon photoirradiation of zeolite-mediated cis-diphenylcyclopropane derivatives 120b-e due to the stronger cation-dipole interaction between cation and carboxamide group than cation-^ interaction. Photolysis of amide 120b-e in hexane-methylene chloride solution afforded the corresponding toms-isomers in diastereomeric excess (de) less than 2%. In sharp contrast to the result obtained in isotropic solution, photoreaction of 120b~e adsorbed in zeolite MY gave frans-isomers in 20-83% de. The dramatic improvement of de is believed to occur as a result of cation-carbonyl and cation-nitrogen dipolar interactions that fix the conformation of reactants, with asymmetric centres of the chiral amide moiety being located closer to the chirogenic center.114'132-'3'1'138'143 Chiral photochemistry in zeolite is an intriguing topic that has attracted intensive attention. Although theoretically zeolites can be chiral, until now no chiral zeolite has been separated in an enantiomerically pure form. Chiral photochemistry in zeolite is conducted primarily through two strategies: the first one is to introduce a chiral auxiliary to photo-substrate and the diastereodifferentiating photoreaction is conducted in intact zeolite, as exemplified in the diastereoselective photoisomerization of diphenylcyclopropane derivatives mentioned above, and the second one is to immobilize optically active compound to chirally modify the zeolite sxipercage and the enantiodifferentiating photoreaction of prochiral substrate is conducted in this chiral supercage. Zeolites modified with norephedrine, ephedrine and pseudoephedrine as chiral inductors have been employed for the enantioselective photocyclization of a series of tropolone derivatives 122.1 l3'1+4-U;> Photocyclization of 122b conducted in NaY zeolite modified with {-)-ephedrine gave 123b in up to 78% ee. The enantioselectivity of the photoreaction was found to be critically controlled by the cationic species and water content in zeolites. The optical yield of photoreaction in chirally modified zeolite relies on several factors such as cation, chiral inductor and its loading level, which is usually kept at a high level to maximize the number of chiral inductors located around the photosubstrate. An exceptional example may be found in the enantiodifferentiating photoisomerization of 34Z (Scheme 1.7) sensitized by optically active (poly)alkyi benzoate derivatives immobilized Reaction Control by Molecular Recognition 25 o ■OR hv OR 122 123 a. R=CH3 b. R-CH2CH2Ph c. R=CH2COOCH3 d. R = CH?CH3 e. R=CH2CH2CH3 f. R=CH2Ph g. R=CH?CH2CH2Ph Scheme 1.28 in NaY zeolite reported by Inoue and co-workers.146 The photoreaction was allowed to occur in the presence of a catalytic amount of sensitizer, and 34E was obtained in a modest ee of 4.5% upon photosensitization with (-)-methylheptyl benzoate-immobilized NaY zeolite. In contrast, the same sensitizer gave racemic 34E in homogenous solution. 1.4.2 Photochemical Reactions in Mesoporous Materials Mesoporous materials have recently attracted considerable attention for the use in photochemical reactions. As defined by the IUPAC nomenclature rules, mesoporous materials have a pore diameter in the range of 2.0-50.0 nm, which, is much larger in general than that of zeolite and is certainly beyond the size of normal organic substrates. Therefore, photoreactions can freely proceed without suffering any restriction. In fact, studies on photochemical reaction in mesoporous materials focus more on construction of functional materials rather than the chemical selectivity. For example, azobenzene, which is structurally rigid and has a van der Waals volume of 144 A3,147 requires a large extra volume of 127 A3 for the photoisomerization to occur. Taking advantage of this property, azobenzene was loaded into nanocomposite films to be used for and showed a potential application in adjusting the cavity volume of mesoporous materials.148 Mai et al. constructed a pho-tochemically controlled system by anchoring coumarin to the pore openings of MCM-41 for taking up or releasing organic guests by controlling the reversible photodimerization of coumarin.1''9 The size of mesoporous silica MCM-41 can be adjusted by changing the number of carbon atoms in surfactant micelles used in the hydrothermal synthesis. Iwamoto and co-workers have reported photocyclization of diarylethenes 124 in different-sized MCM-41. Only the anti-parallel conformation of open form 124 can undergo cyclization upon irradiation to give closed form 125. The reaction rate of 124 was found to be remarkably dependent on the amount of 124 loaded as well as the pore diameter of MCM-41s, but be independent of the organic groups on the surface of MCM-41 s.130 Recently, Inoue and co-workers studied the enantiodifferentiating photocyclodimeriza-tion of AC in the channel of mesoporous silica that is modified with y-CD.131 Photocyclodimerization of AC with mesoporous without y-CD gave HH photodimers 26 Molecular Encapsulation closed-form 125 Scheme 1.29 with a low conversion and enantioselectivity. In remarkable contrast to the )^CD-mediated photoreaction performed in aqueous solution, the photocyclodimerization of AC in y-CD-modified mesoporous silica led to the major formation of HH photodimers, in particular ctnti-HH dimer 45 in 45% yield and 24.1% ee. 1.4.3 Photochemical Reaction with Self-Assembled Molecular Cages Organic ligands bearing two or more coordinating sites can form well-structured aggregates upon coordination to metals. Some of these ligand-metal self-assemblies form structurally well-confined cavity that can accommodate organic guests of suitable size. These cages generally have polyhedron structure with rigid skeleton, and the motion of guest(s) included in the cavity is greatly inhibited. Thermal and photochemical reactions conducted in these molecular cages often show remarkably accelerated rates and significantly high selectivities.153,153 Compounds 126 and 127 shown in Scheme 1.30 represent two typical coordination cages that are self-assembled from six palladium ions and four tridentate ligands. These coordination cages are well soluble in water and can selectively encapsulate organic substrates in the nano-sized cavity in a well-arranged fashion, mainly through hydrophobic and aromatic interactions. So far, a number of different types of photoreactions have been examined within the cavities of these molecular cages.15"1"160 As shown in Scheme 1.31, four stereoisomers 129a-d are theoretically possible to be formed upon photocyclodimerization of 128. Strikingly, photocyclodimerization of 0.5 mM 128 in the cavity of 126a gave the HT yyn-isomer 129a as a sole product in >98% yield after 3 n irradiation. On the contrary, photoirradiation of 128 in benzene in the absence of host 126a gave no adducts even at a high concentration of 150mM. In the presence of 127a as a host, photocyclodimerization of 130 in aqueous solution exclusively afforded jyn-dimer 131a. This is in sharp contrast to the same photoreaction conducted in benzene without any host, where anfi-dimer 131b (21% yield) was favored over yy«-dimer 131a (2% yield). Reaction Control by Molecular Recognition 27 Pd 130 131a 131b Scheme 1.31 The remarkable reactivity and selectivity observed with these molecular vessels are attributed to the greatly increased concentration and the strictly regulated orientation of substrates in the well-confined cavity. The cavity of molecular cage 126a is achiral in origin. Interestingly, a chiral cavity can be constructed simply by replacing the peripheral ethylenediamine with optically active diamines, with the original electronic nature, size and T symmetry element being 28 Molecular Encapsulation a: R=H b: R=CB3 Scheme 1.32 maintained on the whole. Cross addition of 132 and 133 {Scheme 1.32) in the cavity of 126b-e (Scheme 1.30) gave a single product 134, which is ascribed to steric control arising from the confined cavity rather than orbital control.158 The optical yields of this photoaddition reaction increased upon increasing the steric bulk of the /V-substituent on the chiral diamine and finally gave 134b in 50% ee with 126c. This observation is indicative that peripheral chiral auxiliaries, which locate far away from the reaction center and induce only a slight deformation of the triazine panel, are possible to produce considerable asymmetric induction for the photoreaction occurring in the coordinated cages. 1.5 Photochemical Reactions with other Artificial Hosts 1.5.1 Photochemical Reactions with Dendrimers Dendrimers are highly branched globular molecules which are generally well-defined, effectively monodispersed and highly symmetric.161"163 A dendrimer is composed of three arcfhtectural region: a core moiety, branched repeating units derived from the core and end groups on the periphery of the molecule. Properly designed high-generation dendrimers possess a distinct interior space that is stericaliy protected from solvent molecules, and therefore dendrimers can serve as container molecules. An elegant 'dendritic box' that can accommodate small organic molecules and control their release by modifying the steric crowding of the dendritic periphery has been described by Meijer et a/.164 Polyfalky aryl ether) dendrimers 135 (Scheme 1.33), possessing carboxylic acid or hydroxyl group at their periphery, were synthesized and used as hosts for several photo-reactions.165 Both 135a and 135b are water soluble under the base condition and capable of including organic molecules mainly through hydrophobic interaction. Photolysis of I-phenyl-3-p-tolyl-2-propanone 136 led to a-cleavage to form radical pairs, which after decarbonylation recombine to give diarylethanes 137a, 137b and 137c. The photolysis of 136 in hexane solution gave the product 137a, 137b and 137c in a ratio 2.4:1.0:1.4, indicating a zero 'cage effect,' where the 'cage effect' was defined as ([137a]-[137b]-[137c])/([137a] + [137b] + [137c]). Interestingly, photoreaction of 136 mediated by Gl, G2 and G3 acid dendrimers 135b showed the gradually increasing cage effects of 0.09, 0.18 and 0.50, respectively, suggesting stronger confinement with increasing dendrimer Reaction Control by Molecular Recognition 29 ,R (H2cf5 6 6 -O. --h. (Hap) 0 -0 R (H2C)S --O ^ '0'(ch2]5 (CH^ V./ R M O (H2C)S ^ O H' R 135a: R=OH,b: R=COOH o 136 o hv Ph' .0--/ hv Ph 138 137a 137b \ ,0- Ph Ph' Ph Ph Ph Ptt 139a 139b 139c Scheme 1.33 PK Ph 139d generation. Photolyses of 136 encapsulated by G3 of 135a gave a larger cage effect of 0.77, revealing that the phenolic dendrimer 135a is more strongly confining than the acid dendrimer 135b. Photolysis of benzoin ethyl ether 138 was demonstrated to be sensitive to the reaction media employed. It affords Norrish type I products 139c and 139d in more than 94% combined yield in hexane but type II products 139a and 139b in 73% yield in aqueous alkaline solution. Photoreaction of 138 with dendrimer 135b predominantly gave the type II products, particularly 139a in 95% yield. However, when the photoreaction was mediated by 135a, 139a and 139b were produced in 21% and 57% yield, respectively, suggesting that the end group plays an important role in dictating the interior character of the dendrimers. 30 Molecular Encapsulation 1.5.2 Photochemical Reactions with Hydrogen-Bonding Templates Hydrogen bonding interaction plays vital roles in regulating biochemical processes of proteins and deoxyribonucleic acids, and has been widely utilized for constructing supramolecular architectures. This is due to the largest interaction energy (S^OkJmoT1) among the non-covalent weak interactions as well as the ability to assemble molecules at right distance and angle. As a result of these advantages, a series of photochemical reactions have been investigated using hydrogen-bonding templates. Bassani and co-workers investigated the complexation behavior of melamme and barbituric acid derivatives, and examined the photodimerization of styrene, stilbene and cinnamate mediated by hydrogen bonding templates.166-170 Melamine derivatives 140 (Scheme 1.34), which have a hydrogen-bonding motif complementary to barbituric acid derivatives such as 141, are possible to sequentially form 1:1 and 1:2 hydrogen-bonded complexes with 141. As illustrated in Scheme 1.35, 140 and 141 can form two kinds of 1:1 complexes and three kinds of 1:2 complexes, among which only complex C is expected to accelerate the photodimerization of 140. Each of the binding constants K, and K2 should be a sum of these binding constants weighted by their population. A positive cooperativity (K2 > KJ was observed upon complexation of 141b with 140a,b, presumably as a combined result of allosteric and electronic effects. Photoirradiation of 140 without any template led to a fast E-to-Z isomerization to give the TIE ratio of 1.1-5.5 at the photostationary state, although elongated irradiations resulted in a formation of dimers. The existence of barbiturate 141 considerably improved the efficiency and selectivity of the photoreaction. The quantum yields of 142a and 142b were increased respectively from 0.7 x 10"3 and 0.1 x 10~3 in the absence of a template to 2.3 x 10~3 and 0.8 x 10"3 in the presence of 141a.170 The same strategy was applied to a barbituric acid derivative of fullerene to give a photodimer of fullerene, which could not been obtained without the hydrogen-bonding template.169 Bach and co-workers investigated a series of chiral photoreactions that were mediated by Kamp's triacid derivatives 143 working as chiral hydrogen-bonding templates.171-177 As illustrated in Scheme 1.37, these chiral templates possess an amide (lactam) group to bind an amide substrate through dual hydrogen bonds and also a bulky substituent to shield one of the enantiofaces of substrate when bound to the template. Although these Ynynh2 NH a: R= Me, X=H 140a-e b:R=Me,X=C02Me c: R= Pri, X=C6H5 Me02C 0YNYNH NH 0 1 HN NH A ^m-l^n CnH; ;0 141 a: 11=2 Scheme 1.34 Reaction Control by Molecular Recognition 31 COJvle CO,Me COaMe Scheme 1.35 MeO:C C02Me Y a: Ar= i iJH b:Ar = # J n T T Ar Ar 142a,b Scheme 1.36 143a 143b Scheme 1.37 143c templates can form hydrogen-bonded homodimers, the association constants are low in general due to the sterlc repulsion between the bulky moieties. The intramolecular photocycloaddition of prochiral 2-quinolone 144 (Scheme 1.38) was examined in the presence of chiral templates 143a,b.m The amide group of chiral templates forms dual hydrogen bonds with the quinolone moiety of 144, with the bulky tetrahydronaphthalene moiety preventing the approach of dermic double bond from the 32 Molecular Encapsulation hv 144 145 Scheme 1.38 { N H PET catalyst, hv H H 146 147 Scheme 1.39 facing side. Increasing me amount of chiral template or lowering the reaction temperature, by which the ratio of bound photosubstrate is greatly increased, significantly improved the enantioselectivity in the photocycloaddition of 144. By performing the photoreaction in the presence of 143b at -60 °C, 145 was given in up to 93% ee. In contrast, the same reaction sensitized by a chiral sensitizer lacking the hydrogen-bonding site gave only racemic photoproducts.179 Since photoexcitation of free substrate existing in the bulk solution will give racemic photoproducts, at least an equimolar amount of chiral template is necessary in order to obtain photoproduct with good enantioselectivity. A recent report by Bach et al. presented a good solution for this shortcoming by covalently grafting a sensitizer to a chiral template. Thus, sensitizing template 143c (Scheme 1.37) bearing a photoinduced electron transfer sensitizer was synthesized for the use in photosensitized cycloaddition of 146. Photolysis of 146 in the presence of 0.1 equivalent amount of 143c afforded 147 in 52-64% yield with up to 70% ee (Scheme 1.39).180 1.5.3 Photochemical Reactions Templated by Cationic Ion Metal ion can form complex through coordination with unsaturated compounds such as olefin. Through coordination with metal ion, two olefins can be positioned in close proximity, and olefin photochemistry may be caused upon irradiation at longer wavelengths by exciting the charge-transfer band of the resultant complex. Evers and Mackor investigated the intramolecular [2+2] photocycloaddition of diene 148, which is photochemi-cally catalyzed by copper(I) trifluorometbanesulphonate.181 In the presence of the copper Reaction Control by Molecular Recognition 33 Scheme 1.42 catalyst, irradiation of 148 efficiently gave the exo- and e/2c/o-3-bicyclo[3.2.0]heptanol 149 and 150 in a ratio of 3; 2 (Scheme 1.40). Mattay etal. examined the intramolecular [2+2] photocycloadditions of 1,6-dienes 152 catalyzed by copper© coordinated to chiral ligands 151 (Scheme 1.41). IS3PhotocycIoaddifion of 152 catalyzed by 151c gave 153 in up to 5% ee. Bassani and co-workers studied the photodimerization of 154 using a synergistic effect of hydrogen bonding and metal ion complexation.183 Photodimerization of 154 was accelerated by a factor of 2 in the presence of one equivalent of KPF6, and a factor of 5 in the coexistence of KPF6 and 155. Among the metal ions examined, Ba2+ showed the most significant cooperative effect. While 155 enhanced the photodimerization by a factor of K4-1.8, a simultaneous use of 155 and Ba^ gave the quantum yield for the formation of 156 and 157 in more than three orders of magnitude greater than that obtained in the absence of template, and the ratio of 156/157 was greatly improved from 1 to 3.7. 34 Molecular Encapsulation 1.6 Photoreaction Control by External Variants While most studies on supramolecular photochemistry have focused on the design and synthesis of suitable hosts that provide desirable interaction or environment for aimed photosubstrates, recent studies by Inoue et ol. suggest that the external factors, such as temperature, solvent and pressure, may also play a crucial role in controlling the reactivity and selectivity of photoreactions in supramolecular systems. Changing environmental variants, which is much easier to practice than the optimization of host structure involving tedious syntheses, can provide not only a convenient, yet useful, tool for controlling photochemical outcomes, but also important information regarding the mechanism of supramolecular photochemical reaction. The effect of temperature has been well established in the photosensitized isomerization of cycloalkenes with conventional sensitizers.'^187 The change of optical yield upon temperature variation is ascribed to the non-zero differential entropy change for the formation of enantiomeric photoproducts. The entropy effect on supramolecular photochi-rogenesis systems was found to be closely related to the structural properties of supramolecular hosts. The enantioselectivity shows only small changes with the variation of temperature in photoisomerization of 34Z sensitized by /J-CD-based chromophores.37 This insignificant effect of temperature is attributed to the low entropy environment in the cavity of /J-CD due to its rigid skeleton arising from the hydrogen-bonding network at the secondary rim. On the contrary, photoisomerization of 158ZZ with sensitizer-appended y-CD, which has a more flexible framework than y-CD, is more sensitive to the temperature alternation. An inversion of product chirality was observed by lowering the temperature in the photoisomerization of 158ZZ mediated by 159.188 Similar phenomenon was observed in photocyclodimerization of AC (Scheme 1.9) included in the cavity of y-CD derivatives.'89 The enantioselectivity for HH dimer in the photocyclodimerization of AC with diamino- y -CDs 48 in aqueous methanol solution decreased greatly by lowering the reaction temperature and even showed a dramatic inversion to give the antipodal product. When y-CD derivatives 50a-d with flexible caps were used, the ee values obtained for 44 were highly dependent on the temperature. However, in the presence of y-CD derivatives 57a-c, which possess a rigid aryldisulfonate cap, the enantiodifferentiation become much less temperature-dependent.32 On the other hand, when photoisomerization of 34Z was carried out oh Scheme 1.43 Reaction Control by Molecular Recognition 35 with permethylated /3-CD sensitizers 35e-h, in which the hydrogen bonding network is broken by methylation to give a flexible skeleton, the temperature effect became pronounced to afford a chirality inversion by changing the temperature. These observations suggest that the entropy effect is a function of the flexibility/rigidity of the skeleton of supramolecular hosts, and is significant for hosts with flexible framework but is insignificant with rigid hosts. Indeed, works of the other research groups have also demonstrated that hosts bearing rigid skeleton such as zeolite show only slight temperature-dependence. Solvation and desolvation are of paramount importance for molecular recognition in solution. Solvent influences the binding strength of host-guest equilibrium in a diverse way for various host-guest systems. For example, the complexation strength between 18-crown-ó and potassium ion decreases by a factor of >104 on going from propylene carbonate to water.190 This significant solvent dependence mainly comes from the difference in desolvation energy of the metal cation in different solvent. In some cases, solvent may play a role of filler upon co-inclusion with the guest substrate to significantly modify the orientation of substrate in the host cavity. It is known that CD bind organic guests mainly through hydrophobic interactions, and addition of methanol to the aqueous solution greatly reduces the binding constant as a result of increased solvation to both of substrate and host. The plot of log Ks for the complexation of 35 and 34Z against the methanol content showed good straight lines, suggesting that no selective solvation by water or methanol to CD derivatives occurs and water-methanol mixture behaves as a bulk solvent of continuously changing hydrophilicity. The enantioselectivity in photo-isomerization of 34Z with 35 decreases with increasing content of methanol, and appears to be a nice function of host occupancy. On the other hand, addition of methanol decreases the solvent polarity and thus increases the electrostatic interaction of ion pairs. In aqueous solution, the photodimerization of AC mediated by 48a-d shows only subtle effect of the ammonium cations introduced to the primary rim of y-CD, but the electrostatic interaction dominates the photodimerization to give the chiral HH dimer as the major product with a greatly enhanced enantioselectivity. Hydrostatic pressure is also known to play crucial roles in conventional chiral photo-sensitization of 34Z, as demonstrated by the fact that product chirality can be manipulated or even inverted by simply changing the pressure when the differential activation volume for the formation of the enantiomeric or diastereomeric pair is not equal to zero. Under high pressure, less volume-demanding structures and processes are absolutely favoured and hence the host-guest association process is advantageous in principle. If there are two or more possible complex structures in a supramolecular system, dramatic equilibrium and selectivity shifts may occur from a shallow, loose and/or bulky complex to a deeper, tighter and compact ones under high pressure. In other words, we acquire an additional tool, that is pressure as an environmental variant, for manipulating the recognition ability and selectivity of a given guest. Another somewhat unexpected great advantage of high pressure applied to supramolecular systems performed in aqueous solutions is the significant lowering of the melting temperature of water, which goes down to -25 °C at 2 lOMPa, which enables us to perform photochemical reactions below zero Celsius even in water. Thus, the chemical yield and ee of HT dimer 44 were greatly enhanced in the photocy-clodimerization of AC mediated by 7-CD derivatives to reach 53% yield and 71% ee by using host 54 in water at -22 °C at 210MPa. 36 Molecular Encapsulation More recently, the effect of pH was investigated in the supramolecular photochirogenic dimerization of AC with p-cresolbisbenzimidazole-capped 7-CDs 160a,b.191 Thus, pho-todimerization of AC with AE-capped 7-CD 160b gave anti-HH dimer in 5% ee at pH 11 but the antipodal product in 28% ee at pH 6. The conformational change of the ioniz-able capping moiety upon the pH variation is responsible for the pH-dependent enantioselectivity. 1.7 Conclusions Controlling photochemistry through molecular recognition has drawn significant interest from a broad spectrum of scientists and met great progress in recent decades. A number of supramolecular hosts have been successfully exploited for conducting various types of photochemical reactions to reveal the distinct advantages and disadvantages peculiar to each supramolecular system. The multiple rton-covalent interactions and the confinement effect operating in host cavity are two major factors that control the supramolecular photochemistry. Successful supramolecular photoreaction requires reasonable design and synthesis of host molecules and a careful selection of suitable photoreaction and substrate. The complementary fitting of size, shape and interaction motif between host and guest substrate are crucially important in choosing a host-guest pair for specific supramolecular photochemistry. In general, supramolecular hosts that have more confined binding sites usually show specific complexation ability and significant reaction selectivity, while those with flexible binding sites are susceptive to the external control by environmental factors. The supramolecular approach to photochemistry is undoubted a smart efficient way to manipulate and enhance its reactivity and selectivity. In addition to the electronic and orbital properties governing the conventional photoreactions in isotropic media, the steric and conformational effects play heavier roles in supramolecular photochemistry. As a result, photoreactions in supramolecular systems often show unique behavior distinctively different from that of conventional one. On the other hand, the confinement effect of supramolecular hosts can hold two or more photosubstrates in close proximity and consequentially promote bi- and multimolecular photoreactions that are silent in conventional photochemistry under normal conditions. Reaction Control by Molecular Recognition 37 Despite that supramolecular complexation can crucially affect the steric and/or electronic properties of photosubstrates in both ground and excited state, the stereochemical control of photochemical reaction in supramolecular systems is often considered to be dominated by the prearrangement of photosubstrate in the ground state. A photosubstrate is captured by a host for a period of time that is much longer than the excited-state lifetime. It has been demonstrated that the rate constant for a photosubstrate to get into the cavity of host with a sufficiently large opening is normally in the order Kr7-10~8M_1 S"'.'93 An organic guest may stay in the cavity for much longer than 1 jj.s if it has a binding constant of 1000M~' with the host, which is significantly longer than the lifetime of excited molecules commonly encountered. Therefore, the complexation behaviour of photosubstrate in the ground state is of significant importance in supramolecular photochemistry. Optimizing the structure and interactions of a supramolecular system still requires sophisticated design, synthesis, and experimental feedback even in the ground state, and should be much more difficult for supramolecular photochemical reactions. In this context, the combined use of external factors, such as temperature, solvent and pressure, provides a versatile and convenient tool for manipulating photochemical reactions in supramolecular system. The role of these external factors is closely correlated with the properties, in particular rigidity, of supramolecular host employed, and the outcomes are often significantly different from those observed in conventional photoreactions, which would be another reason for performing photochemical reaction in supramolecular system. The number and quality of publications on supramolecular photochirogenesis are rapidly growing in the last decade. Laying in the interdisciplinary area of supramolecular chemistry, photochemistry and asymmetric synthesis, this new area of science is still challenging but appears promising, proposing a novel concept and methodology for overcoming the relatively weak and short-lived interactions in the excited state through multiple supramolecular interactions in both ground and excited states. 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