Unravelling Supramolecular Photocycloaddition: Cavitand-Mediated Reactivity of 3-(Aryl)Acrylic Acids

Abstract

The supramolecular photocycloaddition (PCA) of 3-(phenyl)acrylic acid has been extensively pursued by chemists to study weak interactions and synthesize substituted cyclobutanes. The stereo- and regioselectivity of the products in a supramolecularly affected reaction are often used as a probe for assessing the nature of weak interactions and/or molecular ambience of the reactants. However, some crucial aspects of this chemistry have often remained underexplored in the past, especially within the context of interpreting strength and directionality of interactions based on reaction outcomes. We present a detailed study of the cavitand-mediated PCA of a new and suitable reactant (3-(naphthyl)acrylic acids) that exhibits labile photo-reversible chemistry, which is suitable for exploring previously un-explored aspects of the supramolecular PCA chemistry. Our studies afford important insights about this chemistry that should be considered while using product selectivity as a proxy for deducing intermolecular interactions.

Introduction

The 2+2 photocycloaddition (PCA) is a symmetry-allowed excited state reaction of significance in chemistry,^1–3 biological sciences^{4, 5} and medicine.^{6, 7} Supramolecularly-controlled PCA is pursued for two reasons: as a synthetic tool for producing substituted cyclobutanes,^7–9 and as a probe to manifest weak supramolecular interactions.^{10, 11} With numerous supramolecularly directed PCA reported till-date, this approach has emerged into a convenient and efficient method for observing molecular assemblies resulting from the interplay of weak interactions (Figure 1) such as π−π^{,12, 13} hydrogen bonding,¹⁴ cation-π,¹⁵ charge transfer,¹⁶ and halogen-bonding.^{17, 18} Since the molecular insights gained from Schmidt’s topographical PCA of cinnamic acids (CAs) in the solid state,^{19, 20} chemists have used substituted CAs to gauge supramolecular characteristics of organized media²¹ such as engineered crystals,²² nanocages,²³ cavitands,²⁴ and micelles.²⁵ In this approach, the extent of dimerization is used as an indicator of the supramolecular environment’s (or host’s) ability to enforce molecular proximity, because a photoexcited CA preferentially undergoes unimolecular isomerization. Stereo/regioselectivity outcomes in supramolecular PCA is indicative of environment’s (or host’s) spatial and directional influences on CAs. Thus, the dimer structure is used as a powerful probe of molecular environment within an assembled system (such as crystals, MOFs, micelles, etc.) which is otherwise difficult to characterize. However, the typical approach of treating the dimer structure as a ‘snapshot’ of pre-reaction orientation without considering the supramolecular, photochemical, and mechanistic aspects of the system is an incomplete application of this approach. This is often due to the lack of focus on pro/non-reactive orientations, photochemical/thermal equilibria, self-directing influences, reaction multiplicity, etc. Herein we report the cavitand-mediated PCA of 3-(naphthyl)acrylic acids (Figure 2), a suitable supramolecular system that affords opportunity for studying the diverse and some previously unexplored aspects of this chemistry. Our experimental design and comprehensive analyses provide insights into the aforementioned aspects of the supramolecular PCA approach, which should be considered while inferring the molecular interactions exerted by the encapsulating system.

Figure 1.

Depiction of supramolecular photochemistry to manifest weak interaction between host-host and host-guest.

Figure 2.

3-(aryl)acrylic acids studied in the presented work to explore the supramolecular control of photocycloaddition (PCA) chemistry.

Photoexcitation of trans-(aryl)acrylic acids in solution and gas phase result in photoisomerization until a photostationary state is reached, and bimolecular PCA is typically not viable. However, PCA pathway becomes efficient when two reactants are in proximity, as established by Schmidt’s topochemical postulate, which requires less than 4.2 Å separation of the alkene bonds.²⁰ When PCA is viable, four stereochemical (Scheme 1) dimers are possible and the product geometry is often indicative of the reactants’ relative spatial orientation. The quantum yield and stereoselectivity of PCA is increased supramolecularly by engineering weak interactions that proximate and pre-orient two reactants. Two predominant approaches exist in this regard – crystal engineering^{1, 22, 26} and cavitand-mediation^{1, 27} – wherein the former relies only on self-directing influence of reactant interactions to stack them in the solid state, while the latter uses cavitands as the primary molecular agent for achieving it. The higher degree of molecular freedom of cavitand-mediated PCA, compared to crystal engineering, provides the broader framework within which to gain an overview of the dynamic aspects of supramolecular PCA, which is the aim of this work.

Scheme 1.

Photocycloaddition (PCA) of 3-naphthyl acrylic acid yielding photodimers and isomerized product.

Cyclodextrin- and cucurbituril-mediated PCA of phenyl acrylic acids (cinnamic acids, CAs) and their esters were used to direct the reactants towards specific stereoisomeric dimer to study supramolecular interactions.^{27, 28} The attractive influence of phenyl rings, halogen interactions, hydrogen bonding, etc. pre-orient guests in a head-to-head (HH) arrangement, while the steric deflection orients it into the head-to-tail (HT) arrangement. ²⁷

Results and Discussion

PCA of three previously unstudied 3-(naphthyl)acrylic acids (NpAs), two 3-(phenyl)acrylic acids (CAs) and their esters complexed to two macrocyclic hosts (Figure 3: γ-cyclodextrin, γ-CD; cucurbit[8]uril, CB8) were explored in this work. All guests were complexed efficiently by stirring a solution of the neat guests in water along with half equivalent of the respective hosts for prolonged duration. Supramolecular reactions were performed in the mg scales where complex formation was indicated by formation of homogeneous white precipitate that persisted after washing with cold organic solvents (SI-1).

Figure 3.

Structures of guests used for mediating photocycloaddition (PCA) of aryl acrylic acids

Complexation was conclusively evidenced through ¹H NMR titration, wherein the aromatic proton signals underwent clear change in chemical shifts in presence of half equivalent of γ-CD host (SI-2, SI-3, and SI-4). The neutral CA guest (4a) was soluble-enough in D₂O for observing complexation-induced chemical shift. Guest 1a was neutralized with NaOD to render it soluble in D₂O, and despite it’s anionic form there was a clear evidence for its inclusion within γ-CD cavity.

Photocycloaddition of a series of the acrylic acids and their esters were performed (Table 1). Photoexcitation of complexes of the CAs (3 and 4) with γ-CD yielded syn HH dimer as the predominant product indicating exclusive stereo- and regiochemical direction. On the other hand, photoexcitation of esters of CAs resulted in formation of more anti HT dimers with a direct correlation between size of the alkoxy group and dimer proportion. The regiochemistry is interpreted in terms of the attractive and deflective influences of two main interactive nodes in the guest: namely the aromatic ring and the alkoxy group. When no steric conflict (in CAs) was present in the tail-end of the molecule, attractive p-p interactions directed the complex self-assembly; as the size of alkoxy group increases, steric interaction overcomes the π−π attraction, resulting in HT products. ¹H NMR analysis of product mixture from these reactions are an excellent way to deduce distribution based on their distinctly characteristic chemical shifts and coupling constants (Figure 4, and SI-14 to SI-20). A juxtaposed analysis of the CA dimers is not available in literature to our knowledge and our analysis presented in the SI will serve as a valuable reference for researchers in this field.

Table 1.

Product distribution of PCA of naphthyl acrylates within γ-CD

Reactant	Host	% dimers			% cis	% conv
		syn HH	anti HT	Dimer 3
1a*	γ-CD	96	-	-	4	95
1a*	MeOH	-	-	-	100	70
1b	γ-CD	85	8	5	2	91
1c	γ-CD	78	12	7	3	72
1d	γ-CD	63	20	11	6	53
1e	γ-CD	45	-	52	3	-
2a	γ-CD	94	-	-	6	>85
3a	γ-CD	89	-	-	11	-
4d	γ-CD	-	88	-	12	-
4e	γ-CD	3	4	-	93	-
1a	CB8	93	-	-	7	100
1e	CB8	40	-	51	9	-
3a	CB8	95	-	-	5	-

^*The reaction was performed in three different conditions (N₂-purged, O₂-purged, and unpurged. Conversions are higher than 50%.

Twenty-four hrs of irradiation.

Figure 4.

Cavitand-mediated PCA of phenyl acrylates switching dimer selectivity and characteristic NMR signal.²⁷

Similar to CAs, NpAs also yielded syn HH dimer as the only product when irradiated as a slurry up to near quantitative conversions, which is predictable from the known reactivity of CAs (Table 1). However, complexes of NpA esters yielded product distributions with unabated selectivity in favour of the syn HH dimer despite increase in the steric bulk of alkyl group. Whereas the methyl ester of CA 3b resulted in equal extent of HH and HT orientations within the cavitand, in 1b appears to have assumed a predominantly HH orientation. Despite the bulkiness of an isopropyl group, the self-orienting proclivity of the π-interaction was manifested in the product distribution as noticed in more than 50% formation of syn HH dimer for 1d (Figure 5). The high favourability for HH arrangement is attributed to the strong attractive p-electronic interaction between the dinuclear aromatic rings. Computationally generated structure of 1d₂@γ-CD in pro-syn HH geometry shows feasibility of its formation (Figure 6a).

Figure 5.

¹H NMR spectra of reaction mixtures (in CDCl₃) obtained from cavitand-mediated PCA of 1a and 1d complexed to 0.5 eq. of -CD and irradiated as an aqueous slurry.

Figure 6.

(a) Geometry-optimized (HF STO-3G) structure of 1d inclusion complexes with -CD (left) and CB8 (right). Depiction of reactive and non-reactive orientations in HH arrangements within the cavity of -CD.

Non-reactive orientation – While the selectivity remained the same, reaction conversion was lower as the alkyl group size increased. This is attributed to the possibility of complex assembly in the non-reacting orientation, (Figure 6b, right) wherein the alkene bonds are criss-crossed. While this arrangement satisfies the energetic favourability of the π−π interaction and minimizes the steric conflict between the alkyl group, it renders the complex non-reactive.

Cis geometric isomer of 1a (2a) also followed suit in terms of the observed regioselectivity for the HH dimer, though the product observed did not retain the cis geometry of the reactant (Table 1); the NMR of product mixture matched that of 1a-syn HH almost entirely with one minor unidentified product. Instead of the expected all-cis syn geometry, the resulting product was the same as product from trans reactant 1a. This is due to the formation of a metastable diradical state (Figure 7) wherein the sigma bonds of diradical intermediate undergo rotation to yield the trans-geometry. While knowledge of the metastable state leading to the unexpected trans dimer is known,^{20, 29, 30} it is regarded that MS2 is the predominant intermediate owing to the radical electron conjugating with the naphthyl ring. However, our results suggest that in supramolecularly controlled reaction MS1 is a probable intermediate since the rotation of the C1-C2 bond involving aromatic group flip, included within the cavity, is not probable.

Figure 7.

Photocycloaddition of 3-naphthyl acrylic acid yielding photodimers and isomerized product.

Supramolecular catalysis of γ-CD in this reaction was assessed by using sub-stoichiometric proportion of the host with 1a^- Na⁺ guest. When the anionic guest was complexed with only 0.2 equivalents of the γ-CD host, we still observed near complete reaction conversion to syn HH (Figure 8). This was rather revealing, as it is now clear that the cavitand mediates PCA efficiently because both 1a and 2a towards 1a-syn HH, while both trans and cis isomers are in photochemical equilibrium – this characterizes supramolecular PCA as a self-directing reaction that only requires minimal intervention. This is akin to the supramolecular dimerization demonstrated by Sivaguru et al,²⁸ yet more insightful in its effect as coumarins could undergo only PCA while aryl acrylic acids could undergo both unimolecular and bimolecular chemistry.

Figure 8.

Photocycloaddition of conjugate ions of guests.

The self-directing effect of the naphthyl group and supramolecular effect of PCA was evidenced from the exclusive formation of syn HH dimer when even the sodium salts of 1a yielded exclusively syn HH with only 0.2 eq of γ-CD; no dimer was observed at all when no γ-CD was present (SI-24). Whereas, complex solution of anions of phenyl acrylic acids 3 and 4 did not yield any dimer and the only product observed was the result of unimolecular photoisomerization. Another point of comparison is the product distribution between t-butyl esters of 1 and 4 where the former yielded syn HH still as the major product while 4 was unable to form a ternary complex and yielded cis-4 predominantly (Table 1).

Multiplicity of NpAs were studied wherein the reaction was performed in the presence of benzophenone³¹ triplet sensitizer and heavy atom perturber KBr.^{32, 33} The product mixture analysis showed lower conversions in both cases (SI-21) compared to the control, suggesting a predominantly, if not exclusively, singlet excited state chemistry. This was consistent with the N₂ vs. O₂-purged experiments we performed for 1a which yielded identical product distribution, indicating that oxygen (a triplet quencher) did not affect the photochemistry of the substrate. Syn HH was the only product in all cases, which ensures that observed selectivity was only due to supramolecular control, unlike coumarins,³⁴ which is influenced by multiplicity.

Photostability, especially photo-reverse dimerization,³⁵ is an important consideration in the supramolecular mechanism of this process. We isolated the syn HH dimer of 1a, dissolved it in CDCl₃, recorded the 1H NMR spectrum, and subject the same solution to photo-irradiation for 24 hours. The NMR spectrum of the resulting solution showed more than 50% reversion to the monomers, predominantly towards to the cis isomer (SI-20). The continuous conversion of dimer’s photoactivity (∼10⁻⁴ M, Figure 9) was also followed using UV-Vis spectroscopy wherein the short-wavelength absorbance corresponding to naphthyl unit decreased while the long-wavelength absorbance (due to extended conjugation) increased with time. This suggests that the dimer underwent a photochemical ring opening reaction. Within the same timeframe the 4a-syn HH did not undergo any noticeable photochemical reversal, though future long-term experiments are needed for clarity. This is highly significant as numerous studies have been performed on the supramolecular PCA of CAs and careful consideration of its reversibility is important for proper interpretation of results. This is also significant as numerous phytochemicals with this framework exist in nature.^{36, 37} This raises questions about how NpA dimers form in γ-CD-mediated reaction without undergoing disintegration. We predict that this is potentially due to aggregation-induced deactivation in the slurry state. In addition, cavitand-conferred photostability is also potentially involved.

Figure 9.

(Left) Spectra of pure monomer and syn HH dimer to highlight the difference in electronic absorption profiles (∼2.5 × 10⁻⁴ M). (Right) UV-Vis spectra monitoring of photostability of 1-syn HH in dichloromethane (10⁻⁴ M) irradiated in pyrex test tube. Spectra were recorded after 5, 10, 20, 35, 50, 100, 220, and 360 mins in quartz cuvette.

Based on the various dynamic aspects of the supramolecular photocycloaddition reaction, the chemical flow-chart in Figure 10 is proposed. Such a comprehensive study has not been available for the supramolecular photochemistry of PCA in the past. Our work represents an exemplary case of supramolecular PCA system which highlights the features of the chemical process involved in supramolecular PCA. These chemical dynamics need to be considered while interpreting the reaction selectivity to ascertain influence of weak interactions and local environment that affects these reactions. Our research has provided leads for future detailed investigations that will shed further light on this important chemistry.

Figure 10.

Chemical flow chart for the processes involved in supramolecular PCA of aryl acrylic acids.

Table 2.

Product distribution from PCA – varying proportion of host

Time (hr)	React.	H:G	% syn HH †	% conv.
24	1a	1:2	96	95
48	1a	1:5	92	84
48	1a- Na+	1:5	95	88
48	4a-Na+	1:2	0	68

^†Remaining amounts are cis products.

Highlights.

• Supramolecular photocycloaddition (PCA) of a previously-unstudied reactant

• Broad and detailed study of multitudinal aspects of the PCA chemistry

• Photoreactant undergoing facile reverse reaction provides unique insights into the approach

• Detailed analysis of spectroscopic signature of photodimers and their characterization