Research Article pubs.acs.org/journal/ascecg
Solid-State Photochemical Reaction of Multisubstituted Thymine Derivatives Akihiro Udagawa,† Priscilla Johnston,§ Hidehiro Uekusa,‡ Hideko Koshima,∥ Kei Saito,*,§ and Toru Asahi*,†,∥ †
Department of Advanced Science and Engineering, Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan § School of Chemistry, Monash University, Clayton, Victoria 3800, Australia ‡ Department of Chemistry and Materials Science, Tokyo Institute of Technology, Ookayama 2-12-1, Meguro-ku, Tokyo 152-8551, Japan ∥ Research Organization for Nano & Life Innovation, Waseda University, 513 Wasedatsurumakicho, Shinjuku-ku, Tokyo 162-0041, Japan S Supporting Information *
ABSTRACT: Solid-state photochemical reactions in crystals, known as topochemical reactions, are solvent-free green chemical reactions that produce stereospecific molecules. The photoreaction of thymine is interesting because the dimeric photoproduct can form four types of stereoisomers and when the dimer is formed in DNA helices it can cause skin cancers. We investigated the photoreaction of five multisubstituted thymine derivatives in the solid-state, which were designed with crystal engineering concepts to promote π−π stacking of benzene rings in the crystal. Powder X-ray diffraction analysis revealed that a para-substituted bis-thymine derivative was aligned along the c axis in the crystal and was susceptible to topochemical reaction to form a polymer, as previously reported. Ortho- and meta-substituted bis-thymine derivatives and a tetrakis-substituted derivative were found to be topochemically unreactive using both gel permeation chromatography (GPC) and X-ray crystal structural analysis. The tris-substituted thymine derivative was found to be topochemically reactive due to favorable crystal packing, which included ethanol molecules to form hydrogen bonding with one of the thymine moieties and stabilize the crystal packing. GPC and crystal structural analysis revealed that it could form tetramer at most via topochemical [2+2]-cycloaddition upon UV irradiation. Based on the crystal structure of the tris-substituted thymine derivative, the structure of the tetrameric photoproduct is expected to link via cis−syn, trans−anti and cis−syn cyclobutane isomers. KEYWORDS: Solid-state reaction, Photochemical reaction, Thymine, Organic crystals, Green chemistry
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INTRODUCTION One of the principles of green chemistry is “Safer Solvents and Auxiliaries” and the use of auxiliary substances such as solvents should be avoided wherever possible.1 Topochemical reactions, which are solid-state reactions triggered by thermal or photo irradiation in crystals, are known to be useful reactions in the solvent-free and green chemical synthesis of complex molecules with controlled structures.2−5 For example, the topochemical asymmetric photocyclization reaction of achiral oxo amide to produce enantiomeric β-lactum in its chiral crystal with high enantioselectivity was reported by Toda et al.6 Macgillivray et al. reported the topochemical dimerization of cinnamic acid derivatives and other derivatives upon UV irradiation in the cocrystals with template molecules and metal−organic framework to align the photoreactive molecules expectedly.7 Recently, Yang et al. reported the topochemical reaction of 1,4-bis[2-(4pyridyl)ethenyl]-benzene in the cavity of coordination polymer as a guest molecule to form its polymer.8 Among all the solid© XXXX American Chemical Society
state reactions, photochemical [2+2]-cycloaddition of olefins to generate a cyclobutane has been extensively investigated. In the 1960s, Schmidt postulated that for a [2+2]-cycloaddition to occur in the crystal-phase, the distance between the reactive olefins of adjacent molecules should be 3.5−4.2 Å.9,10 Since this concept was proposed, there have been attempts to conduct topochemical reactions, including [2+2]-cycloaddition, based on strategies to align reactants in the crystal lattice through the control of intermolecular interactions.9−21 Thymine, one of the components of DNA, can be reversibly dimerized via [2+2]-cycloaddition upon UV irradiation.22,23 It is Special Issue: Building on 25 Years of Green Chemistry and Engineering for a Sustainable Future Received: July 4, 2016 Revised: August 23, 2016
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DOI: 10.1021/acssuschemeng.6b01529 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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ACS Sustainable Chemistry & Engineering
apparatus. Electrospray ionization high-resolution mass spectra (ESI HRMS) were recorded on a JEOL AccuTOF CS Electrospray mass spectrometer. Synthesis of Thyminyl Derivatives. Methyl 3-(5-Methyl-2,4dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)propanoate (Thyminyl Methyl Propanoate). The titled compound was synthesized according to the literature procedures.31 Its NMR spectroscopic characterization matched the previously reported one. Methyl 3-{3-[(4-{[3-(3-Methoxy-3-oxopropyl)-5-methyl-2,6-dioxo1,3-diazinan-1-yl]methyl}phenyl)methyl]-5-methyl-2,4-dioxo1,2,3,4-tetrahydropyrimidin-1-yl}propanoate (2Tp). Compound 2Tp was synthesized according to the literature procedures.32 Its NMR spectroscopic characterization matched the previously reported one.32 Polycrystalline sample of 2Tp was obtained by the slow evaporation of the solvents from the CH2Cl2 solution of 2Tp. Methyl 3-{3-[(2-{[3-(3-Methoxy-3-oxopropyl)-5-methyl-2,6-dioxo1,2,3,6-tetrahydropyrimidin-1-yl]methyl}phenyl)methyl]-5-methyl2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}propanoate (2To). Thyminyl methyl propanoate (2.99 g, 14.8 mmol), K2CO3 (2.45 g, 17.8 mmol) and 1,2-bis(bromomethyl) benzene (1.56 g, 5.92 mmol) were combined in 50 mL MeCN. The mixture was refluxed for 20 h, cooled to ambient temperature and decanted into CH2Cl2 (150 mL). The salts were removed by the filtration, and the solvent was evaporated from the filtrate to yield a solid. The crude solid was purified by column chromatography on silica gel using EtOAc/hexane mixture (2:1) as the eluent. It was attempted that crystalline sample of 2To was obtained by the slow evaporation of the solvents from the EtOH solution of 2To. Yield: 2.91 g, 90%. M.P.: 140.7−142.2 °C. 1H NMR (500 MHz, CDCl3), δ/ppm: 1.93 (s, 6H), 2.77 (t, 6.0 Hz 4H), 3.69 (s, 6H), 3.98 (t, 6.5 Hz, 4H), 5.43 (s, 4H), 7.14−7.18 (m, 4H), 7.27−7.30 (m, 4H). 13C NMR (125 MHz, CDCl3), δ/ppm: 13.1, 33.0, 41.8, 45.9, 52.0, 109.6, 127.5, 128.6, 135.3, 139.6, 151.5, 163.9, 171.9. ESI HRMS: calcd, 549.1956 (C26H30N4O8, + Na+); found, m/z = 549.1957. Methyl 3-{3-[(3-{[3-(3-Methoxy-3-oxopropyl)-5-methyl-2,6-dioxo1,3-diazinan-1-yl]methyl}phenyl)methyl]-5-methyl-2,4-dioxo1,2,3,4-tetrahydropyrimidin-1-yl}propanoate (2Tm). Thyminyl methyl propanoate (1.06 g, 5.00 mmol), K2CO3 (0.829 g, 6.00 mmol) and 1,3-bis(bromomethyl)benzene (0.541 g, 2.05 mmol) were combined in 15 mL of MeCN. The mixture was refluxed for 20 h, cooled to ambient temperature and decanted into CH2Cl2 (50 mL). The salts were removed by the filtration, and the solvent was evaporated from the filtrate to yield a solid. The crude solid was purified by column chromatography on silica gel using EtOAc/hexane mixture (2:1) as the eluent. Single crystal of 2Tm was obtained by the slow evaporation of the solvents from the EtOAc solution of 2Tm. Yield: 0.512 g, 47%. M.P.: 183.2−183.9 °C. 1H NMR (500 MHz, CDCl3), δ/ppm: 1.92 (s, 6H), 2.78 (t, 6.0 Hz 4H), 3.68 (s, 6H), 3.97 (t, 6.3 Hz, 4H), 5.09 (s, 4H), 7.17 (s, 2H), 7.19−7.23 (m, 1H), 7.27−7.30 (m, 2H), 7.54 (s, 1H). 13C NMR (125 MHz, CDCl3), δ/ppm: 13.1, 33.0, 44.4, 45.9, 52.1, 109.7, 127.9, 128.5, 129.5, 137.0, 139.6, 151.5, 163.8, 172.0. ESI HRMS: calcd, 549.1956 (C26H30N4O8, + Na+); found, m/z = 549.1956. Methyl 3-(3-{[3,5-Bis({[3-(3-methoxy-3-oxopropyl)-5-methyl-2,6dioxo-1,3-diazinan-1-yl]methyl})phenyl]methyl}-5-methyl-2,4dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)propanoate (3T). Thyminyl methyl propanoate (1.06 g, 5.0 mmol), K2CO3 (0.829 g, 6.00 mmol) and tetrakis(bromomethyl)benzene (0.397 g, 1.11 mmol) were combined in 15 mL MeCN. The mixture was stirred at 180 °C for 2 h upon microwave irradiation (300 W, 300 psi), cooled to ambient temperature and decanted into CH2Cl2 (100 mL). The salts were removed by the filtration, and the solvent was evaporated from the filtrate to yield a solid. The crude solid was purified by column chromatography on silica gel using EtOAc as the eluent. A single crystal of 3T was obtained by the slow evaporation of the solvents from the EtOH solution of 3T. Yield: 141.3 mg, 17%. M.P.: 301.4−322.9 °C. 1H NMR (500 MHz, d6-DMSO), δ/ppm: 1.80 (s, 9H), 2.71 (t, 6.0 Hz, 6H), 3.58 (s, 9H), 3.92 (t, 6.5 Hz, 6H), 4.90 (s, 6H), 7.00 (s, 3H), 7.62 (s, 3H). 13C NMR (125 MHz, d6-DMSO): 11.6, 32.4, 43.7, 45.5, 51.0, 108.8, 126.4, 137.3, 140.7, 152.2, 162.2, 171.9. ESI HRMS: calcd, 773.2758 (C36H42N6O12, + Na+); found, m/z = 773.2749. Methyl 3-(5-Methyl-2,4-dioxo-3-{[2,4,5-tris({[3-(3-methoxy-3-oxopropyl)-5-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-yl]-
known that photodimerization of thymine causes disruption of the helical structure of DNA, leading to the formation of DNA lesions.24 The lesions cause loss of genetic information giving rise to skin cancers.25 In addition, the topochemical reaction of thymine has been investigated because the photoreversible property is useful in various materials for applications such as photoresists and drug delivery.23,26−28 Due to the stereospecificity of the topochemical reaction, it was reported that the stereochemistry of the thyminyl dimer was controlled by the alignment of thymine moieties prior to photoirradiation.29,30 It is therefore important to investigate the topochemical photoreactivity of thymine derivatives in order to understand how the photoreaction of thymine in confined spaces such as DNA double helices and crystal lattices can be applied to develop novel reusable molecules via green chemical reactions. We have previously reported the reversible topochemical reaction of bis-thymine derivatives upon UV irradiation and discuss their reactivity based on the monomer crystal structure prior to UV irradiation.31,32 It is difficult to proceed the thymine dimerization reaction in solution and the topochemical reaction of bis-thymine derivatives is the powerful method to synthesize the molecules with thymine dimer structure. We also proposed the potential of those bis-thymine derivatives for application in various fields such as photoresists, drug delivery materials and self-healing materials.31,32 To achieve the topochemical reaction, several studies concluded that intermolecular interactions, like π−π interaction, were important to align molecules in the crystals to be expected.11−21 Furthermore, it was recently reported that a benzyl derivative baring four trans-cinnamic acid substituent underwent topochemical reaction to form plane-like macromolecular structure.33 Therefore, the crystal structure of benzyllinked thymine derivatives may also undergo topochemical reaction to form interesting structures due to the expected π−π interactions between benzene rings causing the preferential alignment of the molecules for photoreaction (Figure 1).
Figure 1. Possible topochemical photoproducts of multisubstituted benzyl-linked thymine derivatives.
In this study, we synthesized multisubstituted benzyl-linked thyminyl derivatives that were anticipated to undergo topochemical reaction in the crystals through the expected π−π interaction between benzene rings based on the concepts of crystal engineering, and we investigated the relationship between crystal packing and photoreactivity upon UV irradiation.
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EXPERIMENTAL SECTION
Materials. All chemicals were purchased from Tokyo Chemical Industry Co. and Sigma-Aldrich Japan and were used without further purification. General Characterization. 1H NMR and 13C NMR spectra were recorded on a JEOL ECZ500 spectrometer with chemical shifts downfield from tetramethylsilane as the internal standard. Melting points were determined using Mettler Toledo MP90 melting point apparatus with a digital thermometer and Rigaku TG8120 TG-DTA B
DOI: 10.1021/acssuschemeng.6b01529 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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ACS Sustainable Chemistry & Engineering Scheme 1. Synthesis of Multisubstituted Thymine Derivatives
methyl})phenyl]methyl}-1,2,3,4-tetrahydropyrimidin-1-yl)propanoate (4T). Thyminyl methyl propanoate (2.12 g, 10.0 mmol), K2CO3 (1.66 g, 12.0 mmol) and tetrakis(bromomethyl)benzene (0.865 g, 1.92 mmol) were combined in 30 mL of toluene. The mixture was stirred at 70 °C for 48 h, cooled to ambient temperature and decanted into CH2Cl2 (150 mL). The salts were removed by the filtration, and the solvent was evaporated from the filtrate to yield a solid. The crude solid was purified by column chromatography on silica gel using EtOAc as the eluent. A single crystal of 4T was obtained by the slow evaporation of the solvents from the CHCl3/MeOH mixture solution of 4T. Yield: 0.619 g, 33%. M.P.: 223.7−226.6 °C. 1H NMR (500 MHz, CDCl3), δ/ppm: 1.88 (s, 12H), 2.81 (t, 6.3 Hz, 8H), 3.69 (s, 12H), 3.97 (t, 6.3 Hz, 8H), 5.31 (s, 8H), 7.16 (s, 4H), 7.23 (s, 2H). 13C NMR (125 MHz, CDCl3), δ/ ppm: 13.1, 33.0, 41.1, 45.8, 52.0, 109.4, 128.8, 134.3, 139.4, 151.5, 163.8, 172.1. ESI HRMS: calcd, 997.3550 (C46H54N8O16, + Na+); found, m/z = 997.3549. Crystal Structure Determination from Single Crystals. Singlecrystal X-ray diffraction (XRD) data of the compounds 2Tm, 3T and 4T were collected by using a Rigaku R-AXIS RAPID diffractometer equipped with monochromatic Cu Kα radiation (λ = 1.541 87 Å). The crystal structures were solved by using a direct method within SHELXL201334 and refined on F2 by the full-matrix least-squares method. Calculations were performed using Rigaku crystal structure software packages. Crystal Structure Determination from Powdered Crystals. A high quality Powder XRD pattern of 2Tp was recorded at 293 K using a Rigaku SmartLab diffractometer with CuKα radiation (1.5418 Å) at 45 kV and 200 mA operating in transmission mode with a foil type sample holder (2θ range 1°−70°; step size 0.01°; data collection time 12 h).
The powder XRD pattern of 2Tp was indexed with the program DICVOL0435 to give a triclinic unit cell (a = 9.6432 Å, b = 7.6422 Å, c = 9.1029 Å, α = 84.635°, β = 99.821°, γ = 108.422°) with excellent figures of merit (M(20) = 34.8 and F(20) = 81.3). The space group was assigned as P1. Structure determination was performed by the simulated annealing method with the program DASH.36 The following procedures were conducted referring a previous report by Kawano et al.37 The rigid group of 2Tp in the asymmetric unit and Z = 1 for space group P1 were input by using a constrained Z-matrix description and the molecular geometry were taken from the optimized structure from DFT calculation (B3LYP/6-31G). Twenty runs of 1 × 107 Monte Carlo moves each were conducted and the same excellent fits to the data for 17 out of the 20 attempts were obtained with a χ2 value of 27.74. The best structure solution was taken as the starting structural model for Rietveld refinement. The final Rietveld refinement of the crystal structure was performed with the program RIETAN-FP.37,38 Restraints but no constraints for all bond lengths, several bond angles and several torsion angles were employed to maintain the molecular geometry. Thermal temperature factors were refined isotropically and uniform values were applied to the molecule. a = 9.650(2) Å, b = 7.6431(9) Å, c = 9.101(1) Å, α = 84.613(5)°, β = 99.889(7)°, γ = 108.411(7)°, Rwp = 6.19% (Re = 0.94%), Rp = 4.93%, RB = 5.012%, RF = 1.731%; 6701 profile points; 253 refined variables (see Supporting Information, Figure S1). Temperature Dependent Powder X-ray Diffraction Measurement. The temperature dependent powder X-ray diffraction (XRD) data for investigating the stability of the crystallinity of 3T was collected using Rigaku SmartLab diffractometer with Cu Kα radiation (1.5418 Å) at 40 kV and 40 mA operating in the reflection mode with samples on C
DOI: 10.1021/acssuschemeng.6b01529 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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ACS Sustainable Chemistry & Engineering Table 1. Crystal Structures and Photoreactivity of Multisubstituted Thymine Derivatives 2Tp sample chemical formula crystal system T (K) space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z density (g cm−3) photoproduct
powdered crystal C26H30N4O8 triclinic 293 P1 9.650(2) 7.6431(9) 9.101(1) 84.613(5) 99.889(7) 108.411(7) 626.8(1) 1 1.395 polymer32
2To
2Tm
3T
4T
unreactive
single crystal C26H30N4O8·H2O monoclinic 173 P21/c 10.9430(7) 12.7063(8) 19.0931(12) 90 95.517(3) 90 2642.5(3) 4 1.323 unreactive
single crystal C36H42N6O12·C2H5OH monoclinic 173 C2/c 41.6712(9) 9.02761(18) 26.1878(5) 90 128.2466(9) 90 7737.0(3) 8 1.289 tetramer
single crystal C46H54N8O16 monoclinic 173 P21/c 11.0679(5) 13.2125(5) 16.1614(7) 90 106.704(3) 90 2263.63(17) 2 1.430 unreactive
the flat platinum stage with temperature controller (2θ range 4°−60°; step size 0.01°; data collection time 5.6 min for each pattern). The temperature was elevated with the increment speed of 10 °C min−1 from 25 to 160 °C. XRD data were collected at 25 °C and every 10 °C from 30 °C. The powder XRD data for confirming the crystallinity of 2To was collected using Rigaku RINT Ultima III diffractometer with Cu Kα radiation (1.5418 Å) at 40 kV and 40 mA operating in the reflection mode with samples on the glass substrates (2θ range 5°−60°; step size 0.01°; data collection time 5.5 min). Photoreaction of Thymine Derivative Crystals. Single crystals of thymine derivatives were milled with a mortar and pestle. The resulting powder was spread into a thin layer on a Pyrex Petri dish, and irradiated for 16, 32 or 48 h with an Ultraviolet Products CL1000 M UVcross-linker lamp that produced midrange UV-wavelengths centered at 302 nm. The photoreaction was traced by gel permeation chromatography (GPC) performed on TOSOH Ecosec HLC-8320GPC equipped with both refractive index (RI) and ultraviolet (UV) detectors (UVdetection, λ = 280 nm) using Tosoh alpha 4000 and 2000 columns. DMF containing 10 mM LiBr or CHCl3 were used as the eluent.
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RESULTS AND DISCUSSIONS Synthesis. Five multisubstituted benzyl thymine derivatives were synthesized using a substitution reaction between a multibromomethylbenzene and thyminyl propanoate in acetonitrile or toluene (Scheme 1). Three bis-thymines were formed by substitution at the para-, ortho- and meta- positions (2Tp,32 2To and 2Tm, respectively), as well as the trifunctional (3T) and tetra-functional (4T) derivatives. The products were obtained as solids after purification by column chromatography, except for 2Tp that was purified by trituration with a mixture of ethanol and ethyl acetate.29 Crystal Structures of Multisubstituted Thymine Derivatives. Single crystals of 2Tm, 3T and 4T were obtained by the slow evaporation of ethyl acetate, ethanol and methanol/ chloroform mixture solutions of the compounds at ambient temperature, respectively. For 2Tp and 2To, polycrystalline samples were obtained by the slow evaporation of dichloromethane and ethanol solutions, respectively. The results of the crystal structural analysis are summarized in Table 1. The crystal structure of 2To was not determined because of the difficulty to obtain either polycrystals with high crystallinity or single crystals of sufficient size for X-ray structural analysis despite many attempts to crystallize this compound from various solvents (see Supporting Information, Figure S2). The crystal structure of 2Tp was elucidated from the powder diffraction data shown in Figure 2. Schmidt’s topochemical
Figure 2. Crystal structure of 2Tp; (a) single molecular structure (b) three adjacent molecules: each molecule with different colors (yellow, green and blue) has reactive olefin sites (red) (c) sets of the 2Tp molecules expected to form covalent bonds (each set with colored red, yellow and blue).
postulates state that [2+2]-cycloaddition can only occur when the reactive double bonds are separated by a distance less than 4.2 Å. The crystal structure of 2Tp reveals that the olefin bonds of thyminyl pairs formed between adjacent molecules were separated by 3.964 and 4.720 Å, respectively. This geometry was similar to the crystal structure reported for a photoreactive butyl-linked bis-thymine derivative, where the reactive olefins between adjacent molecules were separated by 4.213 and 4.597 Å (i.e., almost same as and larger than 4.2 Å, respectively).31 Sets of D
DOI: 10.1021/acssuschemeng.6b01529 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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Photoreactivity and Crystal Structure of 3T. The single crystals of 3T were spread onto a Petri dish and irradiated with UV light (302 nm). The change in molecular weight of 3T upon UV irradiation was examined by GPC using CHCl3 as the eluent detected by UV absorption intensity (Figure 4). Without UV
2Tp molecules with the separation distance of 3.964 Å were aligned along the c axis (illustrated for clarity with the same colors in Figure 2c). Accordingly, this molecular alignment should make it possible for 2Tp to form a high molecular weight polymer from the topochemical reaction via [2+2]-cycloaddition upon UV irradiation. This result is reasonably consistent with our previous report.32 Photoreactivity and Crystal Structure of Thymine Derivatives of 2To, 2Tm and 4T. Crystalline samples of 2To, 2Tm and 4T were spread on Petri dishes and were then irradiated with 302 nm UV light for 48 h. The photoreactivity of the samples was investigated by monitoring the molecular weight by GPC using DMF as the eluent. The GPC chromatograms of 2To, 2Tm and 4T were the same before and after UV irradiation, which indicated that no photoreaction occurred (see Supporting Information, Figure S3). We also confirmed that the structure remained unchanged after UV irradiation by NMRs. Therefore, 2To, 2Tm and 4T were found to be topochemically unreactive via [2+2]-cycloaddition reaction. The crystal structures of 2Tm and 4T determined from single crystal are shown in Figure 3. For the crystal structure of 2Tm,
Figure 4. GPC chromatogram of 3T; (a) before and (b) after UV irradiation in the crystalline state.
irradiation, a single sharp peak assigned to the monomeric 3T appeared. After irradiation, a broad peak at a lower retention time appears in addition to the sharp peak of monomer, which means 3T reacted with adjacent molecules via [2+2]-cycloaddition to produce macromolecules. However, the reaction did not complete even after 48 h of irradiation. The average molecular weight (Mn) of the broad peak was calculated to be 3300 (relative to the polystyrene standards), which is nearly equal to the tetramer of 3T. The crystal structure of 3T determined from a single crystal is shown in Figure 5. In the crystal structure, benzene rings were stacked along the b axis with a separation distance of 9.028 Å, and ethanol molecules were included between the molecules. It means that there is little π−π interaction to affect the molecular alignment contrary to the expectation from the concept of crystal engineering. From the attempts to obtain single crystal by evaporation of other various solvents, we only obtained transparent amorphous solid. It is suggesting that ethanol helped the crystal formation of 3T molecules by forming hydrogen bonding with 3T and filling in the cavity space. As shown in the crystal packing of 3T along the b axis (Figure 5b), ethanol molecules filled the space between 3T molecules to stabilize the crystal packing. The orientation of one out of the three thymine moieties was stabilized by hydrogen bonding between a thyminyl carbonyl oxygen and an included ethanol molecule, whereas the reactive olefins of the other two thyminyl moieties in adjacent molecules were separated by 3.848 and 3.661 Å (Figure 5c). Therefore, it appeared that adjacent 3T molecules could be topochemically reacted upon UV irradiation. This finding was consistent with the molecular weight measurements made by GPC before and after irradiation. It is expected that trans−anti isomer is produced from the thymine rings separated with 3.848 Å where thymine rings were stacked parallel, while cis−syn isomer is produced from the thymine rings separated with 3.661 Å where thymine rings were faced with tilting angle of 19.74°. As shown in Figure 5d, 3T can form the covalent bonds with adjacent molecules to produce molecules with several units of 3T due to the molecular geometry. Based on the crystal structure of 3T, the highest molecular weight photoproduct that could yield from the reaction would be a tetramer, the molecule with 4 units of 3T, and further polymerization reactions would be difficult due to the row of ethanol molecules blocking further [2+2]cycloadditions. Nevertheless, it was expected that topochemical reaction of 3T would generate a maximum tetrameric photo-
Figure 3. Crystal structures of (a,b) 2Tm and (c,d) 4T; (a, c) single molecules, (b, d) adjacent molecules: each molecule has reactive olefin sites (red) and shown in different colors ((b) yellow, green and blue).
the main driving force of crystal packing was hydrogen bonding between carbonyl oxygen and included water molecules. Benzene rings were stacked along the a axis of the crystallographic lattice, though the distance of 10.943 Å was not effective to direct the molecular geometry in the crystal through π−π interactions. Moreover, the reactive olefins of adjacent molecules were separated by a distance significantly larger than 4.2 Å. In the crystal structure of 4T, the benzene rings were stacked along the b axis of the crystallographic lattice, though the distance of 13.213 Å was even larger than 2Tm and it was not effective to direct the molecular alignment in the crystal by π−π interactions. One of the four thyminyl moieties was stacked parallel to the adjacent molecule. However, the stacked thymine moieties were separated by 4.779 Å, which was not suitable for topochemical [2+2]-cycloaddition. Therefore, crystals of 2Tm and 4T were not expected to react via [2+2]-cycloaddition upon UV irradiation, which is consistent with the GPC and NMR analyses. E
DOI: 10.1021/acssuschemeng.6b01529 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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Figure 5. Crystal structure of 3T; (a) single molecule; (b) crystal packing of 3T viewed along the b axis; (c) adjacent moleculeseach molecule with different colors (yellow, blue, violet) has reactive olefin sites (red), methyl group in thymine group were shown in ball-shape for clarity; (d) expected topochemical reaction of 3T (red dashed lines mean the expected covalent bonds formed via [2+2]-cycloaddition), and three-dimensional structure of the expected tetrameric photoproduct simulated from the crystal structure of 3T by molecular mechanics calculationmethyl group in thymine group were shown in ball-shape for clarity to understand the stereochemistry (left), the stereospecific photoproduct of 3T (right).
product linked with cyclobutanes in the isomeric sequence: cis− syntrans−anticis−syn (see Supporting Information, Figure S4 and Figure S5). Because of the possibility that photoreactions can occur simultaneously anywhere in the crystal upon UV irradiation, it can form the dimer and trimer as well as the tetramer, resulting in the isolation of several unreacted monomers. This could be the reason for having the peaks assigned to monomer and other photoproducts in addition to the tetramer in the GPC chromatogram. We confirmed the stereochemistry of photoproduct by 1H NMR study, where several peaks appeared around 4.0 ppm indicating that the photoproduct contains at least two isomers. Furthermore, to investigate the structural effect of the included ethanol on the crystal packing, temperature dependent XRD of 3T was examined. Intriguingly, diffraction peaks attributed to the crystal broadened and decreased in intensity from 80 °C and almost vanished at 110 °C (Figure 6). The result indicates that ethanol played an important role in the crystal packing of the 3T molecules since the crystal packing of 3T disrupted to be amorphous when the included ethanol molecules were removed by evaporation. TG-DTA measurements further supported the existence of the ethanol molecules with the same number of 3T molecules in the crystal packing. This is because the weight loss of 6.16% around 114.1 °C was nearly equal to the weight ratio of the ethanol with the molecular weight of 46.1 g mol−1 from the sum of ethanol and 3T with that of 750.8 g mol−1 (see Supporting Information, Figure S6).
Figure 6. Temperature dependent powder XRD patterns of 3T crystals.
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CONCLUSION We investigated the crystal structure and photoreactivity of five multisubstituted benzyl-thymine derivatives, anticipating that π−π stacking of the benzene rings would direct stacking of the photoreactive thyminyl units. The crystal structure of 2Tp was successfully determined from powder diffraction data, and the relationship between the crystal structure and the previously reported photoreactivity to form a polymer with high molecular weight was revealed. 2To, 2Tm and 4T were found to be unreactive from both GPC and X-ray crystal structural analysis. 3T underwent partial photoreaction but only formed tetramers due to the crystal structure with the inclusion of ethanol molecules. From all the crystal structures determined in this study, it was concluded that benzene rings did not form strong π−π interactions, although they aligned parallel along crystallographic cell axes. F
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.6b01529. Powder X-ray diffraction pattern of 2To, GPC chromatogram of 2To, 2Tm and 4T, 1H NMR charts of 3T before and after UV irradiation, and TG-DTA chart of crystalline 3T (PDF) Crystallographic data for 2Tm (CIF) Crystallographic data for 2Tp (CIF) Crystallographic data for 3T (CIF) Crystallographic data for 4T (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*Dr. Kei Saito. Tel: +61-3-9905-4600. Fax: +61-3-9905-8501. Email:
[email protected]. *Prof. Toru Asahi. Tel: +81-3-5369-7327. Fax: +81-3-53697327. E-mail:
[email protected]. Author Contributions
Collection and assembly of data were conducted by A.U. The draft of the paper was written by A.U., P.J. and K.S. H.U. supported the high quality XRD measurement for powder X-ray structural analysis. Analysis and interpretation of data were conducted by A.U., K.S., H.K. and T.A. All authors have given approval to the final version of the paper. Funding
The Leading Graduate Program in Science and Engineering, Waseda University. The cooperation of organization between Waseda University and JX Nippon Oil & Energy Corporation. PRESTO, JST. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by the Leading Graduate Program in Science and Engineering, Waseda University and the cooperation of organization between Waseda University and JX Nippon Oil & Energy Corporation. This work was also supported by PRESTO, JST. A.U. deeply appreciates the practical support for crystal structure determination from powder X-ray diffraction data of 2Tp from Dr. Fujio Izumi at National Institute of Materials Sciences (NIMS), Japan. (CCDC reference numbers: 1489677−1489680.)
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DOI: 10.1021/acssuschemeng.6b01529 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acssuschemeng.6b01529 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
