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Origins of Photodamage in Pheomelanin Constituents: Photochemistry of 4-Hydroxybenzothiazole Tolga N.V. Karsili, Barbara Marchetti, and Spiridoula Matsika J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b09690 • Publication Date (Web): 02 Feb 2018 Downloaded from http://pubs.acs.org on February 14, 2018

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The Journal of Physical Chemistry

Origins of Photodamage in Pheomelanin Constituents: Photochemistry of 4-Hydroxybenzothiazole Tolga N. V. Karsili,∗,† Barbara Marchetti,‡ and Spiridoula Matsika† †Department of Chemistry, Temple University, Philadelphia, PA 19122, USA ‡Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA E-mail: [email protected]

Abstract 4-Hydroxybenzothiazole (HBT) is a molecular constituent of pheomelanin − a polymeric skin centered pigment which acts as a natural photoprotector against harmful solar-UV radiation. Its molecular structure is therefore required to sustain a degree of photostability upon electronic excitation with UV irradiation. Despite its function as a protector against UV, pheomelanin is known to be less photostable than that of its close derivative eumelanin - a dark skin centered pigment. The HBT subunit has long being attributed as a key contributor to the lack of photostability of pheomelanin - a hypothesis which we aim to test in this manuscript. Using high-level multi-reference computational methods, coupled with on-the-fly surface-hopping molecular dynamics, we find excited-state reaction paths that show potential detriment to HBT leading to phototoxic radicals and products that are distinct from the original ground-state molecule. Such radicals and photoproducts include those formed by classic πσ* photodissociations, intramolecular proton-transfer and ring-opening reactions. Such reactions shed light on the types of molecular structure that show photo-detrimental effects

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upon UV irradiation allowing judicious predictions for synthetic analogues that may offer enhanced photoprotection in commercial sunscreens.

Introduction The photochemistry and photophysics of biological chromophores has attracted vast attention since at least the turn of the 20th century. 1–6 Constituent molecules, that make up natural and synthetic sunscreens, have gained particular momentum within the past 2 years. 7–11 Recent studies on the intrinsic photophysics of sunscreen molecules have aided in the understanding of their specific structures and functions - enabling the predictive developments of more efficient alternatives in commercial products. 7 Following light irradiation, a given skin-centered natural sunscreen molecule/oligomer (e.g. eumelanin and pheomelanin) generally absorbs across the near-UV regions of the solar spectrum. The subsequent excited state generally decays via ultrafast internal conversion (IC) - reforming the ground state parent molecule and dissipating the excess excited state energy as heat. This phenomenon, in which a given molecule redistributes the excited state energy and reforms the ground state parent molecule is more commonly referred to as photostability. Photostability is however a limited property in most skin-centered sunscreens under continuous exposure to UV-light. It is therefore paramount that commercial sunscreen products are used sparingly and as a supplement. Such commercial products contain synthetic sunscreen molecules that are required to absorb across the UV-A and UV-B regions of the solar spectrum ( 280 - 400 nm), rapidly dissipate the excess excited state energy as heat and reform the parent ground state molecule with little or no detriment. In many cases, ultrafast molecular IC is driven by regions of the potential energy (PE) surface in which the excited and ground state energies become degenerate manifesting in so-called conical intersections (CIs). 12 CIs are ubiquitous in all polyatomic molecules and are now recognized as the main contributors to many of the ultrafast phenomena observed in

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molecular photochemistry. To date, many nuclear motions that lead to CIs have been identified all of which can be crudely grouped under bond-stretches or atomic isomerisations. 12 A well-known example includes CIs that govern molecular photofragmentations mediated by πσ* state PE surfaces. 13–18 Such electronic states are ubiquitous in most heteraromatic and heteroatom-containing functionalised aromatic molecules and arise via an electron promotion from a bonding π to an anti-bonding σ* orbital the latter of which is localized around the bond containing the heteroatom (e.g. O, N, S etc.) and the leaving group (e.g. H, alkyls, halogens etc.). The inevitable lowering of the bond-order of the bond along which the σ* orbital is localised leads to subsequent dissociation. Motion along the dissociation coordinate is characterised by a dissociative πσ* electronic state profile. Building-block functionalised aromatics such as pyrrole, phenol and indole are known to decay by πσ*-state mediated heteroatom-H bond fissions following near-UV excitation. Such fragmentations lead to the irreversible formation of radicals representing a lack of photostability in such systems. Continued functionalisation of a heteroatom containing aromatic building block via, for example, ring-centered nitrogenation, is known to improve photostability and quench detrimental photofragmentations (such as those mediated by πσ* states). 18 DNA/RNA nucleobases represent a class of molecules that are functionalized from simple aromatic building blocks. In such biomolecules, electronic excitation is followed by sub-picosecond IC via well-known out-of-plane ring deformation CIs that lead to the reformation of the ground state molecule. 19–23 Such properties fortunately give DNA/RNA nucleobases some protection against harmful UV radiation minimizing damaging lesions. 4-hydroxybenzothiazole (4-HBT) is a molecular sub-unit present within the repeating oligomeric motif of the skin centered natural sunscreen pheomelanin. 24 It is known to contribute to the limited photostability and hence the poor photoprotection offered by pheomelanin 8,25–28 - though the precise mechanism by which 4-HBT undergoes photodamage is, as yet, poorly understood. Recent high-profile work by Sundstr¨om and co-workers have revealed some insight into its possible degradation process. Using ultrafast pump-probe fluorescence spectroscopy the authors

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conclude a net excited-state reactivity which they propose to be dominated by excited state proton-transfer. 8 In the present manuscript we aim to pinpoint the intrinsic decay mechanism of 4-HBT using high-level multi-reference ab initio methods in order to model the energetics associated with the excited state reaction paths. Additionally, we have undertaken on-the-fly surface hopping molecular dynamics simulations in order to confirm the feasibly of the reaction paths and to discern the lifetimes associated with the excited state decay of 4-HBT. In so doing we also explore the ways in which aqueous solvation effects the intrinsic photophysics and photochemistry of 4-HBT.

Results and discussion Ground state structure and vertical excitation energies Fig. 1 depicts the CASSCF optimised minimum energy geometry of 4-HBT. The assigned atomic numberings in fig. 1 will be henceforth used in order to describe various aspects of 4-HBTs chemistry.

Figure 1: Molecular geometry associated with the minimum energy configuration of 4-HBT. The assigned atomic numberings will be henceforth used in the proceeding text

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As shown, all atoms are in a common ring plane - manifesting in a planar molecule. The pendent O-H group contains a C1-O7-H bond angle of 105◦ which is smaller than that of phenol ( 111◦ ). The relative decrease in bond angle can be understood by the presence of a basic N atom acceptor - which forms a weak hydrogen bond with the terminal H-atom of the O-H group. Table 1 lists the vertical excitation energies, state characters and oscillator strengths associated with excitation to the lowest five singlet excited states - which, as with analogous chromophores, are all predicted to absorb in the near-UV. 16 The orbitals and orbital promotions associated with the listed excited states are depicted in fig. 2. As shown, the S1 and S2 states are characterised by a ππ* transition - in which an electron is promoted from a bonding π to an anti-bonding π* orbital. The characteristically large oscillator strength associated with S1 and S2 is a manifestation of the appreciable spatial overlap between the π and π* orbitals. In contrast, the S3 state is characterised by a πσ* transition - which contains a characteristically weak oscillator strengths. The πσ* state arises from an electronic transition from a ring-centered π to the pendant O-H centered σ* orbital.The energetics reported herein compare well with the experimentally measured UV-visible absorption spectrum (in methanol solution) which shows an initial absorption band centred at ≈ 280 nm (4.3 eV) and a stronger absorption feature centred at ≈ 250 nm (4.9 eV). 8 Through our returned excitation energies and oscillator strengths, we plausibly assign these two experiental bands to the first and second 1 ππ* states.

Table 1: CASPT2 energies and oscilator strengths (in parenthesis) and state characters associated with the lowest three singlet excited states of 4-HBT. Transition Excitation energy / eV Character S1 -S0 S2 -S0 S3 -S0

4.13 (0.0491) 4.98 (0.3810) 5.63 (0.0026)

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ππ ∗ ππ ∗ πσ ∗


Figure 2: Orbitals and dominant orbital promotions associated with excitation to the lowest three excited states of 4-HBT

Excited-state reaction paths Fig. 3 depicts the linear interpolated CASPT2 potential energy (PE) profiles connecting the Franck-Condon (FC) geometry of 4-HBT with the CASSCF optimised S1 geometry. As shown, the path en route to the S1 minimum is exoergic by ≈ 0.2 eV - representing a small change in the FC geometry upon relaxation. This relaxation is a manifestation of a ring expansion which can be understood by considering the reduction of the bondorder associated with the ring-centred π-system upon π* ← π electron promotion. At the equilibrium geometry, the S1 -S0 energy separations is ≈ 4 eV - precluding the possibility of labile internal conversion of excited state population by a barrierless relaxation via a S0 /S1 CI within the local configuration space around the FC region. We therefore explore other intuitive paths, remote from the FC region, that may promote nonadiabatic coupling with other electronic states and drive the fate of the initially prepared excited states. One such intuitive decay path is dissociation along πσ* states that are repulsive along certain bond-stretching coordinates. Two such coordinates, intrinsic to 4-HBT, are displayed 6


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Figure 3: PE profiles connecting the FC geometry to the S1 minimum. in Fig. 4 which presents the unrelaxed (rigid-body) and relaxed PE profiles (see methodology for details) of the ground and various excited states along the RO7−H and RC9−S10 (henceforth simply ROH and RCS ) stretch coordinates. In analogous systems, e.g. pyrrole, pyridine and adenine, it is well-known documented that ring-opening via RCN bond fission is restrictive and is thus not a focus in the present work. We start our description with the PE profiles along ROH (fig 4(a)) - which represents dissociation along the pendant acidic OH moiety. This dissociation coordinate has been the focus of many photodissociation studies in related molecules. 16,17 The unrelaxed, rigid-body scans (open-circles in fig 4(a)) show parallels with analogous systems; 29 i.e. that the S0 and ππ* states are bound with respect to ROH and diabatically correlate with electronically excited asymptotic products (H + co-fragment) whilst the πσ* state is dissociative with respect to O-H bond elongation and diabatically correlates with ground state asymptotic products. By comparison, the relaxed PE profiles (filled data points in fig 4(a)) along ROH show many obvious differences from those of the unrelaxed PE profiles. The S0 relaxed PE profile (filled blue triangle) shows an initial rise in PE, in the range 1.0 ≤ ROH ≤ 1.4 ˚ A, 7



representing a lack of driving force for O-H bond elongation. At ROH ≥ 1.4 ˚ A, the profile of the relaxed S0 state shows a slight decline in PE. This decline in PE, with respect to ROH , can be understood by considering the minimum energy path upon O-H bond elongation i.e. that upon progressive O-H bond elongation the basic N-heteroatom is optimally aligned to accept the departing H atom - manifesting in a enol-imino tautomerisation mediated via proton-transfer (PT). This PT process contains a potential barrier of 1.45 eV, beyond which the imino-tautomer represents a small stabilisation of ≈ 0.2 eV. The corresponding energies of the S1 and S2 states (open triangles), calculated using the S0 relaxed geometries along ROH , contain an analogous topography to that of S0 but show a more pronounced stabilisation beyond the barrier top at ROH ≥ 1.4 ˚ A. The observed cusp on S1 and S2 (at ROH ≈ 1.4 ˚ A) - which separates the initial rise and subsequent decline in PE - is a manifestation of the change in electron configuration. In the range 1.0 ≤ ROH ≤ 1.4 ˚ A the S1 and S2 states contain locally excited (LE) character - i.e. the electronic configurations displayed in fig. 2. Upon progressive O-H bond elongation (at ROH ≥ 1.4 ˚ A), the S1 and the S2 states contain chargetransfer (CT) character, in which an electron is promoted from the pendent OH centred O(2PY ) lone pair to the π* orbitals of the indene ring. The decrease in PE associated with the CT portion of the S1 and S2 states can therefore be understood by the subsequent neutralisation of the pre-existing charge separation via proton transfer from the positive hole site to the net negative ring site. This inherent reactivity was investigated further by means of an S1 relaxed scan along ROH (filled red squares in fig. 4(a)). The returned S1 relaxed profile shows a reduction in the barrier (cf. S0 relaxed geometry) connecting the LE and CT configurations of S1 - which likely manifests in a high yield for excited-state PT. In contrast to related systems, the S1 and S0 states do not cross at large ROH values - driving the thesis that a PT reaction would yield an imino-tautomer with a sufficiently long lifetime. The corresponding S0 energy, calculated using the S1 relaxed geometries along ROH (open blue squares), show that relaxation via fluorescence would prepare a ground state with a total energy above that of the returned barrier along the S0 relaxed path. Favourable

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motion in the reverse PT direction will therefore lead to the reformation of the parent 4-HBT molecule, whilst prompt relaxation following flouorescence will likely lead to the formation of the keto-tautomer form of 4-HBT. In isolated gas phase conditions, a lack of proximal molecules precludes energy transfer and thus relaxation - favouring the former pathways for reforming of the parent 4-HBT. In bulk solution, however, collisional deactivation will lead to vibrational energy transfer to the surrounding solvent, favouring the latter pathway for relaxation to the keto-minimum. As well as dissociation along ROH , 4-HBT contains an additional dissociation coordinate along RCS , which involves the well-known photo-induced heteroaromatic ring-opening mechanism that has made up the basis of many photodissociation studies in the gas phase and in bulk solution. 30,31 Fig. 4(b) presents the PE profiles associated with the C-S bond extension coordinate in 4-HBT (i.e. along the C9-S10 bond). The S0 relaxed profile (filled blue circles) and corresponding 11 ππ* and 21 ππ* state energies (open red and grey circles) along RCS (see methodology for details) all show a steep increase in PE as a function of RCS - indicative of a lack of driving force for C-S ring-opening. In contrast the πσ* state PE profile (open purple circles), computed at the S0 relaxed geometries, is dissociative with respect to RCS - indicating a favourable driving force of ring-opening via C-S bond fission. The observed reactivity of this states motivated further investigation of the topography of the relaxed PE profile of the πσ* state along RCS . The returned πσ* state profile is given by the filled purple circles in fig. 4 alongside the corresponding S0 energies (open blue circles). The topography associated with the relaxed πσ* state contains a steeper gradients upon increasing RCS (cf. unrelaxed πσ* state) and shows a PE crossing with the S0 state at RCS ≈ 3.4 ˚ A. This crossing will most likely develop into a CI when motion along orthogonal coordinates are considered. The steep gradient associated with the relaxed πσ* state may mediate predissociation via initial excitation to a bright ππ* and IC make to S0 via this long-range crossing. If IC prevails at this crossing, the two most likely products are a vibrationally-hot, ring-opened biradical or reformation of the parent S0 molecule. These two limiting cases are again dependent on

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Figure 4: CASPT2 PE profiles of 4-HBT along the (a) ROH and (b) RCS coordinates. See main text for description. In both cases, the the open circles represent the unrelaxed rigid-body scans along ROH and RCS coordinates. The filled and open triangles represent, respectively, the relaxed S0 state along ROH RCS and the S1 and S2 energies at the corresponding S0 relaxed geometry. The filled and open squares represent, respectively, the relaxed S1 state and the S0 energies at the corresponding S1 relaxed geometry. In (b) the filled purple squares represent the relaxed πσ* state whilst the open blue squares represent the corresponding S0 energies computed at the corresponding πσ* state relaxed geometries.

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the phase within which the photoprocess occurs. In gas phase, an absence of a sink leads to a highly vibrationally-excited biradical that is unable to disspate the excess energy and relax. In this case, the biradical likely remains ring-opened. In contrast, in bulk solution will like favour collisional deavitation and thus vibrational energy transfer to the bulk solvent environment - mediating reformation of the ground state parent 4-HBT molecule.

Excited-state dynamics In order to garner further information on the excited state dynamics and associated timescales surface-hopping dynamics (SHD) were performed. In SHD, the atomic nuclei are treated classically by integrating Newton’s equations of motion whilst the electrons are treated quantum mechanically by numerically integrating the time-dependent Schrodinger equation. The obvious disadvantage of SHD is the inability to treat quantum effects within the nuclear coordinates that may be important in processes such as PT (e.g. tunnelling) but, by computing energies and gradients associated with the nuclear coordinates ’on-the-fly’, the dynamics can be treated in full-dimensionality (which is an obvious short-coming of quantum nuclear dynamics). Fig. 5 presents the way in which population in the S1 state of 4-HBT varies as a function of time (orange decay curve). A decay of a particular trajectory is signified by S0 ← S1 IC. Since we are using TDDFT (see methodology for details), the breakdown of the singledeterminant approximation precludes non-adiabatic coupling between S0 /S1 - manifesting in no hopping events to S0 . Therefore, in the present case, IC is approximated by terminating trajectories when the S0 /S1 energy gap ≤ 0.15 eV. The decay profile in fig. 5 is therefore a representation of trajectories that have fulled this energy gap criterion. Trajectories that do not satisfy this energy-gap requirement were propagated for a maximum time of 1.5 ps. As such the returned trajectories should be used as a qualitative guide rather than an absolute quantitative representation of the excited-state lifetime. In order to derive an S1

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Figure 5: S1 decay profiles associated with isolate 4-HBT (orange) and the 4-HBT-water complex (blue). state lifetime, the data points associated with the decay profile in fig. 5 were fit to the equation 1 - in which t0 is the time taken for the first trajectory to decay, t is the horizontal scale time evolution and τ is the decay time representing the S1 state lifetime. Subsequent fitting to equation 1 returned an S1 lifetime of ≈ 1 ps.

y = exp−

t − t0 τ

Figure 5 is a section through the total decay profile, up to the maximum propagation time of 1.5 ps. The entire profile is given in fig. S1 of the ESI. As evident in fig. S1, ≈ 70 % of all total trajectories decay from S1 . Of those that decayed ≈ 90 % did so via C-S bond fission whilst the remaining 10 % decayed via other decay paths (i.e. ring-deformation. Interestingly, no trajectories decayed via O-H bond fission or by OH to N excited-state proton transfer (ESPT) - i.e. via the paths displayed in fig. 4. This is reinforced by fig 6(a) which show that the mean value of the O-H bond distance across all trajectories remains at ≈ 1 ˚ A (i.e. at equilibrium value) throughout the entire propagation time window. In contrast the 12


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mean ring-centred C-S bond length shows a gradual elongation upon increasing propagation times, indicating the propensity for majority of trajectories to undergo ring-opening. In order to garner information of short-range environmental effects, we repeated the SHD simulations on a 4-HBT-water complex in which the water molecule is positions between the acidic OH donor and the basic N-acceptor (see inset of fig. 6(b)). The observed dynamics upon water complexation is striking. First, as the blue decay curve in fig. 5 shows, the S1 decay profile associated with the 4-HBT-water complex is significantly shallower than that of isolated 4-HBT - implying a longer S1 lifetime. Subsequent fitting of the obtained decay profile to equation 1 returns τ ≈ 3 ps. Fig 6(b) shows the way in the mean C-S and O-H bond distances (taken as an average across all trajectories) vary as a function of time. In this case, the mean C-S bond distance remains centred around the equilibrium value whilst the O-H bond distance gradually increases upon increasing time. It is therefore evident that ESPT out-competes ring-opening via C-S bond fission. That said, the longer lived S1 state implies that ESPT occurs on the S1 and prepares the imino-tautomer of 4-HBT form in the electronically excited state. This high-energy metastable intermediate is likely highly reaction and may thus contribute to the detrimental effects reported for 4-HBT. We note however that of those small number of trajectories that did decay to S0 , these were driven by C-S bond elongation. This intermolecular ESPT is analogous to related systems such as 7-azaindole in a range of water clusters. 32

General discussion and conclusions We start this section by advocating the cautious note that the present study is based solely on singlet states - precluding the possible involvement of triplet states. We have also carried out of present computations in the isolate gas/cluster phase, precluding the electrostatic effects of the bulk (bio)molecular structure that may be important in a biochemical study. Despite these two caveats, the presents findings are nonetheless very revealing. In particular, we have

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Figure 6: The variation of the average O-H and C-S bond distances across all trajectories as a function of time for (a) isolated 4-HBT and (b) the 4-HBT-water cluster. The arrows indicate the bond stretch distance a specific colour refers to.

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outlined the details of the excited-state dynamics of 4-HBT following electronic excitation to S1 - a potentially detrimental molecular constituent of pheomelanin. The returned dynamics simulations reveal C-S bond extension (implying aromatic ring-opening) as the dominant decay channel by which photoexcited 4-HBT undergoes S0 ← S1 IC. This is somewhat similar to analogous thiol-systems that have been experimentally and theoretically studied in the gasphase that also show ring-opening via C-S bond fission as a dominant relaxation path. 33,34 The static electronic structure calculations reinforce the SHD simulations by showing a dissociative πσ* state that is repulsive with respect to C-S bond fission. A lack of O-H bond extension and subsequent ESPT in isolated 4-HBT is however surprising since the relaxed S1 state profiles along ROH , computed at the CASPT2 level of theory, shows a reactive S1 profile for ESPT - which is barriered by ≈ 0.2 eV. This discrepancy may be a reflection of TDDFT’s poorer description of charge-separated states (cf. CASPT2). More likely, it may be a manifestion of the differing properties returned in SHD when compared to static scans of the PE profiles. static electronic structure calculations, free from Normal-mode analysis, give (at best) a thermodynamic account for the feasibility of a given reaction. It is only with full-dimensional MD that the entire picture of the overall dynamics emerges. The inherent inclusion of velocity, momentum and entropy in such dynamics calculations, and the lack of such properties in static electronic structure calculations, may show reaction paths that are restrictive in PE. In other words, it may be thought of as SHD simulations returning a fuller picture of the Free-energy surface (with the inclusion of vibrations and thus entropy) whilst the CASPT2 relaxed profiles offers a portion of the total energy (i.e. the PE) free from entropic factors. In contrast, complexation with a single water molecule enhances ESPT - driving greater competition of this process. Whilst water-complexation introduces enhanced competition, the ESPT process does not completely quench deactivation by C-S bond elongation. S0 ← S1 IC via C-S bond elongation is still active upon complex but merely comprises 10 % of the total quantum yield in the 4-HBT-complex when compared to the ≈ 70 % in the gas-phase.

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The excited state reactivity of 4-HBT with a aproximal water molecule studied herein is in qualitative agreement with previous experiments that have ascribed ESPT as a viable excited-state reaction path in pheomelanin consistuents. Notable studies include those undertaken by Sundstrom and co-workers 8 who advocate ESPT as a viable process dominating the fate of photoexcited 4-HBT. Analogous molecules, such as hydroxyphenylbenzothiazole and hydroxyphenylbenzoxazole are also known to decay via ESPT upon photoexcitation, although such flexible systems undergo non-radiative decay via respective ring-twisting motions. 35 In 4-HBT, the rigid aromatic ring system is conformationally locked and is thus unable to internally convert via ring-puckering after the initial ESPT process. Although we note that the single water cluster represents a vastly reduced dimensional model of the bulk reactivity, it nonetheless offers glimses into the photoreactivity of 4-HBT in bulk aqueous solution. An enhancement of ESPT upon water complexation - forming an metastable excited-states of the imino tautomer represents 1) a potential detriment to the parent 4-HBT and 2) possible reactivity with proximal molecules. If such reactivity persists in 4-HBT containing pheomelanin, reactive side-reactions may lead to detriment of the bulk polymeric structure of pheomelanin. Therefore, the far richer molecular structure comprising the Mammalian epidermis may enhance such side reactions in a skin-centred bulk environment. This may be important in explaining the well-known photo-toxicity of pheomelanin. The natural next step is to use the present computations as an important stepping stone for analogous computations in bulk pheomelanin. Such studies are not only informative but reveal the important electronic and geometric properties that give a UV-protecting sunscreen molecule its required photostability (as well as their short-comings). Such studies are clearly important in manufacturing molecular sunscreen constituents in commercial sunscreen lotions that offer enhanced protection to sun exposure.

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Computational methodology Static electronic structure calculations Using Molpro 2010.1, the ground state minimum energy geometry of 4-HBT was optimized using state-averaged complete active space self-consistent field (SA5-CASSCF) theory alongside Dunnings augmented correlation-consistent basis set of double-ζ quality (henceforth cc-pVDZ). 36,37 The active space was chosen in order to describe all important static and dynamics correlation effects in an even-handed a way as possible whilst reducing the computational expense. After careful testing, an optimal active space of 10 electrons in 10 orbitals was used in all CASSCF calculations. The active orbitals comprised three π and π*, one σ and two σ* and one 2P Y nitrogen-centered lone-pair orbitals. The active orbitals are displayed in fig. S2 of the ESI. Single-point excitation energies were calculated using the internally-contracted (single-state) complete active space second-order perturbation theory (CASPT2) based on the aforementioned SA5-CASSCF reference wavefunction. An imaginary level shift of 0.5 EH was used in all CASPT2 calculations in order to aid convergence and mitigate the effects of intruder states. An additional IPEA shift was not deemed necessary. Oscillator strengths accompanying excitations to and from the ground (E0 ) to the various excited states (Ej ) were calculated using equations 2. X 2 µ2i f = (Ej − E0 ) 3 i=x,y,z Ej and E0 represent the CASPT2 energies and are the CASSCF transition dipole moments. Relaxed PE profiles (with CS symmetry constraints) along the O-H stretch and C-S ring-opening coordinate (henceforth ROH and RCS , respectively) were calculated by keeping either ROH or RCS fixed at various values whilst allowing all other degrees of freedom to relax to the ground (or excited) state minimum energy geometry. Although the CASSCF and CASPT2 optimised geometries may return slightly differing relaxed geometries, we deem these to be negligible as well as computationally restrictive with internally17



contracted CASPT2 which lacks analytical gradients. As such, we prefer to use CASSCF for our optimisations along given reaction paths, followed by a simple and inexpensive CASPT2 energy correction. Such an approach has been shown to work well in analogous systems.

Surface-hopping molecular dynamics The ground state equilibrium geometry and normal-mode wavenumbers of isolated 4-HBT and the 4-HBT-water complex were computed using the DFT/CAM-B3LYP/6-31G(d) level of theory in Gaussian 09. In the 4-HBT-water complex, the water position was chosen such that it would form a bridging complex with the acidic O-H donor and basic N-acceptor sites of 4-HBT, so as to study the possibility of excited state intermolecular proton transfer. Using a locally developed version of Newton-X, 38,39 surface-hopping molecular dynamics simulations in order to garner further understanding on the energetics and timescales for the excited state reactivity of 4-HBT. The initial conditions were obtained by sampling 200 initial velocities and positions via a Wigner distribution, which in turn were based on the normal mode wavenumbers of the CAM-B3LYP/6-31G(d) 40,41 optimized ground state geometry of 4-HBT. The nuclear coordinates of each Wigner point were propagated by integrating Newtons classical equations of motion, using a step size of 0.5 fs up to a maximum time of 2 ps. The electronic coordinates were numerically integrated using Butchers 5thorder Runge-Kutta method using a step size of 0.01 fs. 42 The energies and gradients were obtained on-the-fly using the coulomb attenuated model Becke-3rd parameter-Lee-YangParr functional of time-dependent density functional theory (TD-DFT) obtained from the Gaussian 09 computational package. 43 The 6-31G, 6-31G(d) and 6-31+G(d) basis sets were assigned to the H/C, S/O and N atoms respectively. Ideally we would have used the diffuse 6-31+G(d) basis function on all atoms but this proved computationally restrictive, especially for the 4-HBT-water complex. We reduced the size of the basis functions on the C and H atoms, but retained larger basis sets for the heavier, O, S and N atoms, in order to describe all significant donor-acceptor affects local to the heteroatom-containing bonds. All trajectories 18


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were started on S1 and propagated up to a maximum propagation time of 1.5 ps or when the S1 /S0 energy gap fell below 0.15 eV (whichever occurred first). Computation of the CAM-B3LYP/6-31G(d) vertical excitation energy to S1 returned a value of 4.2 eV (cf. 4.13 eV using CASPT2 - vide supra) and an identical electronic state character obtained using CASSCF/CASPT2. This reinforces our choice of CAM-B3LYP/6-31G(d) for obtaining the energies and gradients used in the present SHD simulations.

Supporting Information Available Cartesian coordinates associated with the various ground state minima; Total decay profile associated with the excited state lifetime of isolated 4-HBT; pictorial illustration of the active orbitals used for CASSCF/CASPT2 computations.

Acknowledgement The authors are grateful to the National Science Foundation (grant number: CHE1465138) for funding.

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Origins of Photodamage in Pheomelanin ... - ACS Publications

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