StructureâReactivity Correlations and Mechanistic Understanding of

Article pubs.acs.org/crystal

Structure−Reactivity Correlations and Mechanistic Understanding of the Photorearrangement and Photosalient Effect of α‑Santonin and Its Derivatives in Solutions, Crystals, and Nanocrystalline Suspensions Patrick Commins,†,‡ Arunkumar Natarajan,† Chao-Kuan Tsai,† Saeed I. Khan,† Naba K. Nath,‡ Panče Naumov,*,‡ and Miguel A. Garcia-Garibay*,† †

Department of Chemistry & Biochemistry, University of California−Los Angeles, Los Angeles, California 90095-1569, United States New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates

‡

S Supporting Information *

ABSTRACT: The synthesis, crystal packing and photochemical reactions of α-santonin (1a) and its methyl, ethyl, n-propyl, and n-butyl derivatives (1b−e) are described to explore the effect that a photochemically benign yet structurally significant synthetic modification can have on the solid-state photochemical reactivity. The structures of the derivatives were determined using single crystal X-ray diffraction and compared against the packing of α-santonin. A cage dimer (12a) found exclusively upon irradiation of 1a in the solid state was not found when the other derivatives were exposed to light, because the alkylation proved to perturb the crystal packing away from an optimal dimerization alignment. Using a high-speed camera, we monitored the photosalient effect of α-santonin and found it to occur at an angle orthogonal to the b-axis of the unit cell, which we suspect is caused by the formation of the cage dimer 12. The photochemistry of 1a−e in solution and crystalline suspensions was also analyzed. The solution photochemistry was in accord with literature precedence, and the crystalline suspensions yielded a variety of photoproducts including a tertiary alcohol (7b−e), which is not commonly observed in neutral water. An exocyclic alkene photoproduct (8b) was also discovered, and its presence is hypothesized to be caused by an intermolecular deprotonation caused by a water molecule present in the crystal.

1. INTRODUCTION The photocoloration and bursting of α-santonin crystals (1a, Scheme 1) exposed to sunlight was the first photochemical reaction reported in the literature, where Trommsdorff described it in 1834.1 Soon after, Pfizer and Erhart mixed αsantonin with almond toffee to create the first commercial drug formulated in the USA, knowing that it has anthelmintic properties.2 Photochemical studies in solution performed throughout the 1960s revealed the formation of lumisantonin (4), mazdasantonin (5), and photosantonic acid (6) as primary, secondary, and tertiary photoproducts, respectively, but there were no investigations into what appeared to be exceedingly complex solid state transformations (Scheme 1).3 In 1968 Matsuura et al. analyzed the photochemical reaction of 1a in the crystalline state, identified the cage dimer 12, and suggested sequential Diels−Alder and 2π + 2π photodimerization reactions from the formally antiaromatic cyclopentadienone 10 (Scheme 1).4 However, it was not until Reish et al. confirmed the structure of the cage dimer using X-ray analysis that the topochemical nature of the dimerization was revealed.5 It was shown that santonin molecules crystallize in pairs with © 2015 American Chemical Society

double bond center-to-center distances of 4.54 Å, with an orientation that determines the formation of the observed photocyclodimerization product. Recently, some of us reported the occurrence of three consecutive reactions during the photoreaction of 1a and uncovered that the first step is a remarkably site-specific single-crystal-to-single-crystal reaction.6 Recognizing that the crystal packing of 1a must be critical for the occurrence of the three consecutive reactions (a unimolecular reaction followed by a bimolecular reaction, and then a unimolecular reaction) to obtain a cage dimer, we set out to explore the influence of simple structural perturbations that may alter the packing of the reactant. With this in mind, we synthesized the simple derivatives 1b− e shown in Scheme 2 by taking advantage of the ease of alkylation at the most acidic hydrogen on the carbon α to the carbonyl group of the lactone ring. In this paper, we report the synthesis and photochemistry of compounds 1a−e in solution Received: January 30, 2015 Revised: February 16, 2015 Published: February 23, 2015 1983

DOI: 10.1021/acs.cgd.5b00135 Cryst. Growth Des. 2015, 15, 1983−1990

Crystal Growth & Design

Article

Scheme 1

Scheme 2

unexpected photoproducts. A tertiary alcohol photoproduct (7b−e), which is normally generated by irradiation in solutions of acetic acid, was detected for all of the alkylated derivatives. Furthermore, a thermodynamically less stable exocyclic alkene (8b) was also observed during the irradiation of 1b, and its formation is rationalized. The results presented here provide a remarkable example for the potential of photochemistry in crystalline suspensions for discovering new chemical reactivity, even for compounds whose bulk photochemistry has been heavily explored.9

and crystalline state. The earlier results showing that crystals in the 50−500 nm size range allow for optimal solid-state reactions when suspended in water7 prompted us to also study the photochemistry of compounds 1a−e as aqueous nanocrystalline suspensions.8 As described in detail below, the solution photochemistry of compounds 1b−e is in good agreement with that reported for compound 1a. Reactions carried out in nanocrystalline suspensions revealed several

2. RESULTS AND DISCUSSION 2.1. Synthesis and Solid-State Characterization. Compounds 1b−1e were synthesized in one step by alkylation of 1a using lithium bis(trimethylsilyl)amide and the corresponding alkyl halide to afford one diastereomer of each compound in >85% yield (Scheme 2). The reaction is stereoselective because the corresponding alkyl halide can

Table 1. Unit Cell Parameters of the Crystal Structures of Compounds 1a−e 1a formula mpb (°C) cryst syst space group Z a (Å) b (Å) c (Å) α, β, γ (deg) Θc (°C) V (Å3)

C15H18O3 170 orthorhombic P212121 8 6.9000(6) 10.5226(10) 34.483(3) 90, 90, 90 −173 2503.7(4)

1b

1b-hydrate

C16H20O3 114−116 trigonal P3121 6 10.3886(8) 10.3886(8) 23.2837(18) 90, 90, 120 −173 2176.2(4)

C16H20O3·0.46H2O 88−90 trigonal R3 9 20.2723(18) 20.2723(18) 9.1702(9) 90, 90, 120 −173 3263.7(7)

a

1c

1d

1e (form α)

1e (form β)

C17H22O3 126−130 orthorhombic P212121 4 7.7968(9) 11.8457(13) 15.6772(17) 90, 90, 90 −173 1444.6(5)

C18H24O3 144−150 orthorhombic P212121 4 8.8879(4) 11.5833(5) 15.3566(6) 90, 90, 90 −173 1580.98(12)

C19H26O3 174−178 monoclinic P21 4 8.4151(12) 15.769(2) 12.5295(18) 90, 90.072(2), 90 −173 1662.6(4)

C19H26O3 d monoclinic P21 2 8.7870(7) 8.7757(7) 11.5690(9) 90, 108.5407(14), 90 −173 845.81(12)

a

The water content was determined crystallographically and using thermogravimetric analysis. bMelting point determined by the capillary method using a Mel-temp apparatus. cDiffraction data acquisition temperature. dNot determined. 1984



Article

have only one molecule per asymmetric unit and their reaction centers are displaced in geometries that do not favor the reaction. 2.2. Kinematic Analysis. Since 1834 single crystals of αsantonin have been known to yellow and then crack, splinter, or jump in response to light (Figure 2a,b).1 For the first time, this

only approach the santonin enolate from the less hindered concave face. Compounds 1b−e were characterized using 1H and 13C NMR spectroscopy, ATR−FTIR, and high-resolution mass spectrometry. The resulting solids were recrystallized by slow evaporation from either a solution of ethyl acetate or methanol. Their structures were determined by single crystal Xray diffraction analysis (see below). The original report by Trommsdorff in 1834 described1a three distinct crystal shapes of santonin: plattgedrückte sechsseitige säule [flattened hexagonal columns], blättchen [leaf-like crystals], and tafeln [a word that is used to describe rectangular objects]. We investigated the presence of polymorphs of 1a and its derivatives. By recrystallizing from ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide, we were able to reproduce the three distinct crystal habits of 1a, parallelepipeds, very slender platy crystals that resemble leaves, and prisms, respectively (for micrographs of the three habits, see Supporting Information, Figure S31). However, single crystal X-ray diffraction of the three crystal habits showed that their structures were identical. Additional screening for solid forms conducted by slow evaporation from solutions of common solvents (toluene, ethyl acetate, dichloromethane, acetonitrile, acetone, methanol, N,N-dimethylformamide, and dimethyl sulfoxide) did not afford additional polymorphs of compounds 1a, 1c, and 1d. However, when recrystallized from N,N-dimethylformamide or ethyl acetate 1b formed a solid hydrate, but it separated as solvent-free crystals from methanol or dichloromethane. Two polymorphs were obtained for compound 1e. The basic crystallographic parameters of 1a−e are reported in Table 1. The nature of the alkyl groups installed in the corresponding derivatives had an interesting effect on the crystal packing (Figure 1). The anhydrous methyl derivative (1b) packs in the

Figure 2. Crystals of α-santonin before (a) and during (b) irradiation. (c) Snapshots of high-speed recordings of the photosalient effect of single crystals of α-santonin recrystallized from N,N-dimethylformamide at different time points: 0 ms (I), 1.0 ms (II), 2.5 ms (III), and 5 ms (IV). The piece being ejected during the splitting is highlighted by the red circle. The plots on the top explain the splitting event at a molecular level, as the cleavage occurs normal to the b axis of the unit cell, separating the two layers of santonin molecules. A one millimeter scale bar is located in the center of the circle in images I, II, III, and IV.

photoinduced jumping of 1a, recently termed photosalient effect,10a was recorded using a high-speed camera, and its kinematics was analyzed (Figure 2). The composition of the sample after the photosalient effect was also analyzed with the intention of discovering the photochemical intermediate(s) responsible for the jumping. Single flat rectangular crystals of 1a were grown by slow evaporation of a solution in N,Ndimethylformamide. The crystals were placed flat on their largest face at a fixed position relative to the incident light and irradiated with light from a 150 W solar simulator, which was focused using a planoconvex lens onto a point at the center of the crystal. For crystals of 1a with a flat rectangular habit, the crystals were found to only split perpendicular to the long axis of the crystal, usually at very clean 90° angles. Using an X-ray diffractometer, we found that the crystals split perpendicular to the b axis of the unit cell (Figure 2c). In an attempt to understand which intermediate or product was responsible for the bursting event, several crystals of 1a were analyzed by 1H NMR spectroscopy to determine the composition of the reaction, immediately after the splitting.

Figure 1. Molecular packing in crystals of the santonins 1a−e and the shortest centroid-to-centroid distances between the rings. The alignment required for dimerization in 1a is also present in the solvent-free form of 1b, but it is absent in the higher-order alkylated derivatives.

trigonal space group P3121 with six molecules per unit cell. Although the alignment of the two molecules for dimerization is in place, it occurs in a different orientation compared with 1a. In the structure of the hydrate (1b-hydrate), the two chromophores are misaligned for dimerization, and the molecules adopt a different conformation to accommodate the water molecule. Unlike crystals of α-santonin, where two crystallographically different molecules engage in photodimerization, all of the alkyl derivatives except for form “alpha” of 1e 1985



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2.4. Photochemistry in Solution. The photochemistry of 1a in solution has been studied extensively, and the mechanisms by which it creates its primary, secondary, and in some cases tertiary photoproducts have been well established (Scheme 1).12 Upon irradiation with UV light, 1a becomes photoexcited to the singlet state and undergoes intersystem crossing to the triplet state. The triplet can be seen as an open shell oxyallyl species, which then undergoes intersystem crossing to form 2. Bond I in the zwitterionic intermediate 2 in Scheme 1 may be broken, whereby the reaction may continue down the cage dimer pathway, or bond II could be broken to follow the so-called “lumi” (lumisantonin) pathway. The intermediate 2 may also be intercepted by a molecule of water to form product 7 or deprotonated to give 8. When bond II is broken, a spiro intermediate 3 is generated, and this intermediate then undergoes the “lumi” rearrangement to form lumisantonin (4). Upon further irradiation, lumisantonin undergoes a methyl migration and becomes mazdasantonin (5), the secondary photoproduct of santonin. If the compound is further irradiated in the presence of water, photosantonic acid (6) may also be observed. When bond I is broken to form the intermediate 9, the reaction continues to afford the antiaromatic cyclopentadienone intermediate 10, which can undergo a Diels−Alder and [2 + 2] photodimerization to create the cage dimer 12. However, if the solid is dissolved before the cage dimer 12 is formed, or when the required arrangement is not present, then the intermediate 10 may quickly tautomerize to the diene 11. To study the solution photochemistry, the alkylated derivatives 1a−e were dissolved in deuterated chloroform, irradiated in a Hanovia photoreactor with 450 W medium pressure Hg lamp, and monitored with 1H NMR spectroscopy (Figure 4). Although deuterated chloroform is not an ideal reaction medium, most of the previously reported intermediates have been characterized in CDCl3. Not surprisingly, the photoproducts and rates of reactions of the alkylated derivatives are nearly identical to those of 1a. Derivatives 1a−e are alkylated in the position α to the carbonyl ester, which is not a

However, the correlations were impeded by the unpredictability of the bursting event, because some crystals were found to split after 3 min of irradiation and others required longer than 45 min. This unpredictability caused difficulty in the product analysis, because the crystals that required longer irradiation times showed product mixtures that were far more progressed than the shorter irradiation times. We believe the bursting event of α-santonin is caused by localized stress accumulation at one point in the crystal, and a bulk analytical technique such as NMR spectroscopy was not sensitive enough to determine which intermediate or product caused the photosalient effect. However, knowing that the largest amount of molecular displacement in the crystal lattice would be caused by the cage dimer 12 and that the dimer is formed along the b axis, we suspect the bursting event is caused by the accumulated stress accrued in the crystal by formation of 12. There was a 0.5% and 3.2% expansion along the a- and b-axes, respectively, accompanied by a 0.4% contraction of the c-axis after 50 h of irradiation as followed by in situ X-ray diffraction.6 This unit cell expansion may cause the strain necessary for the subsequent bursting of the crystals normal to the b-axis. 2.3. Crystalline Suspensions. To study the reactivity of solid 1a, we have chosen to use crystalline suspensions. Crystalline suspensions of 1a and its derivatives 1b−e were prepared using the reprecipitation method reported by Kasai et al.11 The suspensions are made by dissolving the desired material in a minimal amount of an organic solvent miscible with water and subsequent injection of the solution into highly agitated water. This procedure was used to obtain crystalline suspensions that have the same solid phase as the bulk powders for compounds 1a−e. A modified version of the protocol was used for 1e (for details, see the Supporting Information). For crystalline suspensions of compound 1b, only the hydrate could be obtained, and the anhydrous nanocrystalline solid phase was not observed. Therefore, all the crystalline suspension studies involving compound 1b were performed on the hydrated solid phase. The calculated powder X-ray diffraction pattern of 1a and the one from its crystalline suspensions are shown in Figure 3, and the patterns for the other derivatives were deposited as Supporting Information (Figures S25−S30). One can see from the diffractograms that the suspensions and the bulk solids are in good agreement and are of the same solid phase.

Figure 3. Calculated (green) and experimentally recorded (purple) Xray diffraction patterns of the crystalline suspension of α-santonin. The sample was not ground to prevent any possible grinding-induced phase transitions, as previously observed. There is a slight shift in the x-axis between the experimental and calculated patterns.

Figure 4. Time course of the photoreactions of 1a−e in CDCl3 solution using a Hanovia photoreactor with a 450 W Hg lamp for 8.5 h. The composition of the reaction mixtures was determined by 1H NMR spectroscopy. 1986



Article

the formation of a topochemical dimer. To test whether the dimerization would occur for 1b, a solid powder of 1b was irradiated using the same experimental setup as the suspensions for 48 h (Supporting Information, Figure S31). However, after 48 h of irradiation only lumisantonin products and the diene 11b were observed, confirming that even a subtle alteration of the packing of α-santonin can dramatically change its solid-state reactivity. The results observed upon irradiation of 1a as a crystalline suspension are in good agreement with results from irradiation as a dry powder,6 with the reactions in suspensions occurring at an increased rate. However, instead of observing mazdasantonin 5a, photosantonic acid 6a is detected. The initially observed photoproducts are photosantonic acid, the diene 11a, and the cage dimer product 12a. The presence of the cage dimer shows that the inherent reactivity of the solid was retained in the suspensions, because the dimer is known to be produced only in the crystalline state.4 During the reaction, a consistent amount of the diene 11a can also be observed. Since 11a arises from reaction of cyclopentadienone 10a, apparently when it goes into solution, one may suggest that there is a consistent amount of 10a (ca. 12%) present in the solid during the reaction. It is reasonable to assume that if the progress of the reaction had not been interrupted for analysis, cyclopentadienone 10a would have gone on to form the cage dimer. In addition to products 11a and 12a, there are trace amounts of lumisantonin 4a observed throughout the reaction, but photosantonic acid 6a is one of the initial photoproducts of the reaction. Photosantonic acid is the third and final photoproduct resulting from the initial cleavage of bond II. Its presence is reasonable since it is produced from mazdasantonin and mazdasantonin was detected as one of the photoproducts when 1a was irradiated as a dry powder.6 However, it is interesting to notice the lack of 7a from αsantonin and its presence in all the other derivatives. This observation suggests that 2a reacts in a different manner compared with analogs 2b−e since 7a would be formed by the attack of water on 2a (Scheme 1). The reason for this observation is puzzling, because 2a appears to be similar to 2b− e. Therefore, we may infer that there are other factors dictating reactivity, such as sterics near the reactive site or a distinct change in physical property, such as a potential increase in the solubility of the solid solution in water as the reaction progresses. It should be noted that we cannot remove the possibility of dissolution of the sample as a possible explanation for the observtion of 7 in compounds 1b−e. However, the lack of 7a from 1a, which one would predict to be the most soluble in water, the presence of 12a and 8b (8b discussed below), both of which are only observed in the solid state, and the difference of product distributions of our results from those previously reported in neutral water14 suggests that dissolution is an unlikely cause for the presence of 7 in compounds 1b−e. The irradiation of the α-santonin derivatives 1b−e in crystalline suspensions showed that the primary photoproducts are photosantonic acid 6 and product 7 containing a tertiary alcohol group. Both products 6b−d and 7b−d can be seen as arising from the “lumi” pathway for all of the alkylated derivatives 1b−e. Unlike 1a in suspension, the derivatives favor breaking bond II and forming lumisantonin analogs. Compound 7 is a common photoproduct of α-santonin, but it is normally obtained by irradiating samples of 1a in acidic aqueous media;15 irradiation in neutral media is reported to produce lumisantonin products.14 The mechanism for the

part of the cyclohexyldienone chromophore; thus, functionalization at this position is not expected to alter the reactivity in solution. After 2 h of irradiation, there is a very rapid generation of the first photoproduct, lumisantonin (4, Figure 4). Subsequent irradiation produced lumisantonin 4 and mazdasantonin 5 at a slower rate, which is consistent with literature reports on lumisantonin acting as a filter.13 It is clear from the results that the primary mechanism in solution is to break bond II depicted in Scheme 1 and follow the pathway mediated by lumisantonin. 2.5. Photochemistry in Nanocrystalline Suspensions. Nanocrystalline suspensions of 1a−e were freshly prepared as described above and irradiated simultaneously for 36 h. The solutions were individually agitated to ensure uniform distribution and then 1 mL aliquots were removed from the reaction at various time points. Samples were dissolved in ethyl acetate and washed with water and brine, and then the organic layer was evaporated under reduced pressure. The resulting residues were analyzed by 1H NMR spectroscopy. The data is shown in Figure 5, and additional information for other time points were deposited as Supporting Information (Tables S1 and S2).

Figure 5. Reaction progression of crystalline suspensions of 1a−d after 36 h of irradiation. The photoreaction of 1e was monitored over 25 h.

From Figure 5, one can see that all of the compounds react during the irradiation with 1a being the slowest and 1c the fastest with an order of 1a < 1b < 1e < 1d < 1c. It can also be seen that 1a and 1b tend to favor ring contraction products over “lumi” products. The opposite is true for 1c, 1d and 1e, where the “lumi” products are generally favored. Overall the reaction progression is quite complex, and the most common photoproducts were 6 and 7, both of which are derived from reaction with water. Also, it should be noted that as the reaction progressed small amounts of unidentified products were observed, and they were not taken into account toward the product distributions. The data also showed that, except for 1a, there were no dimers formed in those reactions. This is in accord with the crystal structures of compounds 1b-hydrate and 1c−e because they either lack the proper alignment or distance between molecules to form dimers in the solid. However, the solvent-free form of 1b, which could not be produced with the reprecipitation method may be able to favor 1987



Article

formation of 7 that was proposed by Kropp14b suggests that intermediate 2 is intercepted by a nucleophilic water molecule and must approach from the opposite face of the methyl group to produce the single diastereomer that is observed (Scheme 3). Since 7 is normally not observed in neutral water, to Scheme 3

Figure 6. Molecule of water present in 1b-hydrate is well positioned in the crystalline lattice to act as a Brønsted base. The resulting hydronium ion can be stabilized by both the ester and ketone groups of two adjacent molecules.

rationalize its formation, we believe two features are key. The first is that in order to generate 7 water must reach intermediate 2 to perform the nucleophilic addition. The second is that the crystalline suspensions may extend the lifetime of intermediate 2 enough such that the addition reaction is now a competitive with the lumisantonin transformations since both originate from the same intermediate. In addition to 7, to our surprise, as one of the photoproducts from 1b we also obtained a significant amount of the exocyclic alkene 8b. The exocyclic alkene 8a has been obtained by irradiation of α-santonin in a solution of anhydrous dioxane; however it has not been reported from the solid state or in neutral aqueous solution.16 The observation of this product only in the case of the methylated derivative 1b indicates that this reaction may be facilitated by the water molecules in the crystal. The exocyclic alkene is presumably formed by deprotonation of the angular methyl group in the cyclopropyl intermediate 2. Analysis of the crystal structure of the hydrate of 1b shows that the water molecule is located 2.54 Å away from the methyl group and is perfectly positioned to act as a base (Figure 1). To test whether water from the lattice or from the solution could be acting as a base to form 8, a dry powder of 1b-hydrate was irradiated for 24 h. The 1H NMR spectrum of the reaction (Supporting Information, Figure S32) shows a pair of singlets at 5.04 and 4.88 ppm and a doublet at 4.99 ppm, indicative of the exocyclic alkene product. The presence of the exocyclic alkene in irradiated dry powders strongly suggests that the lattice water facilitates the reaction. In line with this, when solid powders of the anhydrous form of 1b were irradiated under the same conditions, 8b could not be observed (Supporting Information, Figure S33). From the evidence gathered, we suggest that the formation of the exocyclic alkene 8b is unique to the hydrated form of 1b and is caused by deprotonation of the methyl group by the water present in the crystal. This hypothesis is further supported by the crystallographic data, in which the resulting hydronium atom is near the ester and ketone groups of two adjacent molecules with bond distances of 2.95 and 2.91 Å, respectively, and a bond angle of 111.6° (Figure 6). This role of a strategically placed “privileged” water molecule to activate a specific part of the molecule is very common in nature and is reminiscent of biological enzymes such as trypsin.17 To the best of our knowledge, this is one of the few cases that report the use of a molecule of water in the solid state to generate unique photoproducts.18 This use of solvent trapped in the crystals provides a unique window to the possible reactivity that can be obtained by studying compounds in the solid state.

3. CONCLUSIONS The packing and unique photochemical reactivity of α-santonin and its alkylated derivatives were studied, and it was found to have very exciting and unique photochemical properties as a crystalline suspension. We investigated the packing effects on α-santonin by varying the extent of alkylation and its effects on its photochemical dimerization and discovered that even a slight chemical addition of a methyl group can dramatically alter its solid-state photochemical reactivity. The photosalient effect of α-santonin was monitored using a high-speed camera, and we determined that the splitting occurs normal to the b axis. We tested the solid-state photochemical reactivity on αsantonin and its derivatives and found unique reactivity exclusively in crystalline suspensions. The alkylated derivatives were found to undergo a previously unreported reaction in neutral media to form tertiary alcohols 7b−e. Also, an exocyclic alkene product 8b was formed exclusively from the methylated derivative 1b−hydrate in suspension and as a powder. From this, we propose that the unique chemical reaction is promoted by a molecule of water present in the crystal and it is able to function in a way similar to biological enzymes. This use of water trapped in the crystals opens up many possibilities and showcases the unique transformations that can be found by studying compounds in the solid state. 4. EXPERIMENTAL SECTION 4.1. General. Commercial reagents of the highest purity available were used without further purification. 1H and 13C NMR spectra were obtained with 300 MHz, 500 MHz, or 600 MHz spectrometers. IR spectra were obtained with an instrument equipped with universal attenuated total reflectance (ATR) accessory. Melting points are uncorrected. 4.2. Synthesis and Characterization. Commercial α-santonin was recrystallized in methanol or ethyl acetate, and the single crystals obtained were used for further study. Compounds 1b−e were synthesized by C-alkylation of α-santonin 1a. Compound 1a (1 g) was dissolved in 200 mL of dry THF and cooled to −5 °C, 1.1 equiv of LiHDMS was added, and the solution was stirred for 1 h after which 2 equiv of the corresponding alkyl halide was added and the reaction mixture was stirred overnight. Reaction workup and separation by column chromatography (ethyl acetate/hexanes = 3:7) gave >85% yield of the products 1b−e. The compounds (1a−e) were recrystallized using ethyl acetate. Compound 1b was recrystallized from ethyl acetate to afford 1b-hydrate and recrystallized from methanol to achieve a solventless structure. The compounds were characterized by 1 H NMR, 13C NMR, and ATR FTIR spectroscopies. 1988



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4.3. Solid-State Photoreaction of 1b and 1b-hydrate. Crystals of 1b and 1b-hydrate (50 mg) were crushed between two Pyrex glass plates so as to cover a surface area of 2−3 cm2, plates were sealed with Parafilm on all sides before the irradiation process, and samples were photolyzed with a Hanovia 400-W lamp for appropriate times. After irradiation, the solid was dissolved in an appropriate solvent, and the products were analyzed using NMR and TLC. 4.4. Kinematic Analysis of the Solid-State Photoreaction of 1a. Crystals of 1a were freshly recrystallized from a solution of N,Ndimethylformamide to yield rectangular plates. The crystals were placed flat on their largest face at a fixed position relative to the incident light and irradiated with light from a full-spectrum solar simulator 2 × 2 beam with 150 W xenon lamp focused using a planoconvex lens onto a point at the center of the crystal. The photosalient effect was monitored using a high-speed camera from NAC (Germany) operating at 2000 frames per second mounted on a trinocular stereoscope. 4.5. Crystalline Photoreaction of 1a−e in Suspension. A saturated solution of santonin crystals (5 mg) in tetrahydrofuran was prepared and injected into 2 mL of vortexing water. The crystal suspension thus obtained was photolyzed with a 450 W lamp for 36 h. The suspension was extracted using ethyl acetate, washed with water and then brine, and dried using magnesium sulfate. The solution was then dried on a rotary evaporator. The reaction mixture was analyzed using IR and 1H NMR spectroscopies. 4.6. Single Crystal X-ray Diffraction Analysis. Single crystal Xray diffraction data for compounds 1a−e was collected at −173 °C with a diffractometer equipped with monochromatic Mo Kα radiation (λ = 0.71073 Å). All data were collected at −173 °C by cooling the sample in a cold nitrogen stream. The data were integrated and scaled,19 and corrected for absorption by applying the multiscan method with SADABS.20 The structures were solved by direct methods (SHELXS-97)21 and refined (on F2) by performing successive cycles of full-matrix least-squares refinement following recalculation of the difference electron density. For the crystal structures 1a, 1c, and 1e (form α) all calculations were performed with the SHELXTL program package,22 whereas the crystal structures 1b, 1b-hydrate, 1d, and 1e (form β) were refined with SHELXL2014.23 The non-hydrogen atoms were refined anisotropically, and the C−H hydrogen atoms were placed at calculated positions using the riding atom model. The crystallographic data of compounds 1b−e are deposited with the Cambridge Crystallographic Data Centre (CCDC nos. 1042051−1042056).

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ASSOCIATED CONTENT

S Supporting Information *

Spectroscopic data (1H, 13C NMR, FTIR) for compounds 1b− e, 7b, and 8b, crystallographic information files (CIF) for compounds 1b−e, powder X-ray diffraction patterns for powders and their crystalline suspensions for compounds 1a−e, and photochemical analysis of compounds 1a−e in both solution and suspensions and of 1b as a powder. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (P. N.). *E-mail: [email protected] (M.G.-G.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Support by NSF Grant CHE1266405 and NYUAD is gratefully acknowledged. We thank Dr. Susanne Quadflieg (NYUAD) for the translation of Trommsdorff’s original paper. 1989



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(18) (a) Kirk, A. D.; Warren, P. A. Inorg. Chem. 1985, 24, 720. (b) Mondal, B.; Zhang, T.; Prabhakar, R.; Captain, B.; Ramamurthy, V. Photochem. Photobiol. Sci. 2014, 13, 1509. (19) Bruker Saint; Bruker AXS Inc., Madison, Wisconsin, USA, 2007. (20) Sheldrick, G. M. SADABS, University of Göttingen, Göttingen, Germany, 1996. (21) Sheldrick, G. M. A Short history of SHELX. Acta Crystallogr. 2008, A64, 112−122. (22) SHELXTL, ver. 6.14, Bruker AXS Inc., Madison, WI, USA, 2003. (23) Sheldrick, G. M. SHELXL2014. University of Göttingen, Göttingen, Germany, 2014.

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