Efficient Light-Induced pKa Modulation Coupled to Base-Catalyzed Photochromism

Photoswitchable acid–base pairs, whose pKa values can be reversibly altered, are attractive molecular tools to control chemical and biological processes with light. A significant, light-induced pKa change of three units in aqueous medium has been realized for two thermally stable states, which can be interconverted using UV and green light. The lightinduced pKa modulation is based on incorporating a 3-Hthiazol-2-one moiety into the framework of a diarylethene photoswitch, which loses the heteroaromatic stabilization of the negatively charged conjugate base upon photochemical ring closure, and hence becomes significantly less acidic. In addition, the efficiency of the photoreactions is drastically increased in the deprotonated state, giving rise to catalytically enhanced photochromism. It appears that protonation has a significant influence on the shape of the groundand excitedstate potential energy surfaces, as indicated by quantumchemical calculations. Coupling orthogonal thermal and photochemical equilibria allows for light-gated ground-state reactivity as well as chemically gated photochromism, which can be combined in multistate reaction cycles to construct functional molecular systems that are controlled and driven by light. We have targeted the remote modulation of acid–base equilibria as one of the most fundamental chemical reactions highly relevant for the materials and life sciences. Beyond changing chemical reactivity and related catalytic activity, reversible control over the pKa value of a compound should have profound influence on key properties, such as solubility, intermolecular interactions, as well as bioavailability, that are critical for drug design. To induce a sufficient light-induced acidity change, defined here by interconverting 95% of a protonated species (acid) into 95% of a deprotonated species (conjugate base), would require a (reversible) pKa modulation of at least 2.5 units. A variety of reversible photoacids have been developed over the past 50 years, in particular by exploiting the acidity difference between ground and excited states to realize large pKa shifts, which, however, were associated with very short lifetimes only. Much longer lifetimes have been achieved by photoisomerization between two metastable ground-state species. For this purpose, various spiropyran, azobenzene, and diarylethene (DAE) derivatives have been investigated (Figure 1a), but these either exhibited thermal instability 9] or insufficient pKa modulation. Hence, the development of photoswitchable acids that can efficiently be interconverted between thermally stable states with sufficiently large acidity modulation (DpKa+ 2.5) remains an important objective in this field. We focused here on the use of DAE photoswitches in analogy to work by Lehn and co-workers, who pioneered their use to modulate acid–base properties. In contrast to other classes of photochromic molecules, optimized DAE derivatives display efficient, (nearly) quantitative, and robust Figure 1. a) Selected pKa photoswitches in water or [a] in methanol/ water (5:2) or [b] in acetonitrile. b) The pKa–structure relationship of linear and cyclic carbamates. [*] J. Gurke, Dr. B. M. Schmidt, Prof. S. Hecht Department of Chemistry & IRIS Adlershof Humboldt-Universit-t zu Berlin Brook-Taylor-Straße 2, 12489 Berlin (Germany) E-mail: sh@chemie.hu-berlin.de Dr. Š. Budz#k, Prof. D. Jacquemin Laboratoire CEISAM, UMR CNRS 6230 Universit8 de Nantes 2 Rue de la HoussiniHre, BP 92208, 44322 Nantes Cedex 3 (France)

Coupling orthogonal thermal and photochemical equilibria allows for light-gated ground-state reactivity as well as chemically gated photochromism, which can be combined in multistate reaction cycles to construct functional molecular systems that are controlled and driven by light. [1] We have targeted the remote modulation of acid-base equilibria as one of the most fundamental chemical reactions highly relevant for the materials and life sciences.Beyond changing chemical reactivity and related catalytic activity, [2] reversible control over the pK a value of ac ompound should have profound influence on key properties,such as solubility,intermolecular interactions, [3] as well as bioavailability, [4] that are critical for drug design. To induce as ufficient light-induced acidity change,defined here by interconverting 95 %ofaprotonated species (acid) into 95 %ofadeprotonated species (conjugate base), would require a(reversible) pK a modulation of at least 2.5 units. [5] Av ariety of reversible [6] photoacids have been developed over the past 50 years,i np articular by exploiting the acidity difference between ground and excited states to realize large pK a shifts,which, however,were associated with very short lifetimes only. [7] Much longer lifetimes have been achieved by photoisomerization between two metastable ground-state species. [8] Fort his purpose,v arious spiropyran, [8a-d] azobenzene, [8e-i] and diarylethene (DAE) [8j-m] derivatives have been investigated (Figure 1a), but these either exhibited thermal instability [8a-i, 9] or insufficient pK a modulation. [8j-m] Hence,the development of photoswitchable acids that can efficiently be interconverted between thermally stable states with sufficiently large acidity modulation (DpK a ! 2.5) remains an important objective in this field.
We focused here on the use of DAEp hotoswitches in analogy to work by Lehn and co-workers,who pioneered their use to modulate acid-base properties. [8j] In contrast to other classes of photochromic molecules,o ptimized DAEd erivatives display efficient, (nearly) quantitative,a nd robust photoconversion in both photoisomerization directions. [10] In view of this advantageous photochemical behavior and the absence of thermal interconversion (P-type photochromism), [11] for DAEs,t he system can be precisely adjusted between two distinct and temporally independent forms.This property has been successfully used to modulate chemical reactivity, [12] most frequently taking advantage of relocating double bonds during al ight-induced 6p electrocyclicr ing opening/closure. [13] Inspired by the pK a dependence observed for 2-oxazolidinones and oxazolones (Figure 1b), [14] we herein explore this powerful concept to control the acidity of an integrated 3H-thiazol-2-one moiety by photochemically removing and reinstalling an internal carbon-carbon double bond, thus tuning the aromatic stabilization of its conjugate base ( Figure 2).
Target molecule 1oH (Figure 2a;s ee the Supporting Information for its synthesis) is composed of a4-(4'-methoxyphenyl)-2-methylthien-3-yl residue connected to the commonly used hexafluorocyclopentene bridge, [15] which also carries a4 -trifluoromethyl-3H-thiazol-2-on-5-yl substituent serving as the acidic site.D eprotonation leads to negatively charged 1o,w hich is primarily stabilized because of its aromatic character.T he strongly electron-accepting hexafluorocyclopentene bridge [16] and the adjacent trifluoromethyl group also help stabilize anion 1o.T his is supported by the fact that the HOMO of 1o is located on the thiazole moiety whereas it is centered on the thiophene ring in 1oH (see Figure S16 in the Supporting Information). Upon UV-lightinduced ring closure and the resulting double bond migration, the acidity and hence the stability of 1cshould be significantly lower than that of 1o for several reasons:1)loss of aromatic stabilization, 2) cross-conjugation with the electron-withdrawing bridge,a nd 3) decoupling from the inductively electron-withdrawing effect ("ÀIe ffect") of the trifluoromethyl group (Figure 2a). In addition, the electron-donating methoxy group attached to the opposite terminus of the DAE becomes p-conjugated and thus further reduces the acidity of the closed isomer 1cH.I rradiation with visible light should induce ring opening and therefore reverse these effects.
Titration of 1o ( Figure 3a)i na na queous 0.15 m KCl solution containing 30 vol %a cetonitrile with 0.7 m HCl (in the same solvent composition) gave as olvent-mixture-specific [17] s s pK a value of 4.0 AE 0.1 (DG a = 5.0 kcal mol À1 )w hereas titration of isomer 1c gave a s s pK a value of 6.8 AE 0.1 (DG a = 8.5 kcal mol À1 ). This corresponds to ap K a shift of 2.8 units, consistent with DFT calculations that had predicted achange of 2.6 units (see Section S5 in the Supporting Information). Therefore,c omplete protonation and deprotonation of both isomers can be achieved by using 0.1m HCl and KOH solutions,r espectively.B oth open compounds (1oH and 1o) strongly absorb in the UV region up to l = 330 nm (Figure 3b), which was attributed to ac ombination of high-lying states according to time-dependent (TD) DFT calculations.
In 1oH,t he lower-energy S 0 !S 1 transition is much less intense,which is aconsequence of the small overlap between the HOMO and the LUMO,w hereas it has significant intensity in 1o (band at l % 360 nm) as aresult of the stronger overlap (see Figure S16). Irradiation with UV light (313 nm) leads to an intense absorption band at l = 500 nm in both cases owing to the formation of the protonated and deprotonated closed isomers (1cH and 1c), which present similar orbital topologies.I rradiation with green light (l = 546 nm) induces quantitative ring opening and thus leads to complete reversion. Spectral analysis of both cyclization and cycloreversion showed clean photoreactions for the protonated as well as the deprotonated forms ( Figure S7). Photokinetic analysis of the ring closure and ring opening revealed astrong dependence of the rate and conversion of the photoreaction on the protonation state (Figure 3c).
Whereas the conversion of the protonated form 1oH is low and the rate of the reaction is also low,the conversion and rate of deprotonated 1o are much higher. In both cases, cycloreversion is complete (owing to selective excitation of the closed isomers), yet again the photoinduced ring opening Figure 2. Light-inducedpK a modulation.a )Four-state reaction cycle involving photoisomerization (1oH!1cH, 1o!1c)a nd thermal acidbase (1oHÐ1o, 1cHÐ1c)equilibria of athiazolone-based diarylethene (EDG = electron-donating group, here:4 -methoxyphenyl) at pH 5. Deprotonation of the open isomer 1oH leads to aromatic and thus stable negatively charged 1o,w hich undergoesr ing closure upon UV irradiation with ahigh quantum yield. The negative charge in the closed form 1c is isolated, leading to protonation and thus formation of 1cH,w hich undergoes cycloreversion to 1oH upon irradiation with visible light to close the catalytic cycle. Inductive (I) and mesomeric (M) effects of the substituents attached are indicated with arrows visualizingt heir directionality.b)Schematic potentiale nergy diagram for an ideal pK a switch.
is faster for deprotonated 1c than for protonated 1cH. Evaluation of these photokinetic data (Table 1) showed that the quantum yields for cyclization differ by more than one order of magnitude between the deprotonated and protonated forms (F 1o!1c = 47 AE 5% vs. F 1oH!1cH = 2.1 AE 0.2 %; Table 1). Note that the quantum yields of the ring opening depend not only on the protonation state but also on the irradiation wavelength, as reported for DAEs in the liter-ature. [18] Thei nterplay of the differences in quantum yields and extinction coefficients is consequently reflected in the composition of the photostationary states (PSSs) after UV irradiation, which show much higher conversions in the deprotonated state (amount of closed isomer c c (PSS) = 85 AE 5%)t han in the protonated state (c c (PSS) = 35 AE 5%). It is important to point out that no thermal ring opening was observed, neither in the protonated nor in the deprotonated form. At this point, we underline that according to DFT calculations, 1o should show astrong preference for adopting the antiparallel conformation (98 %e stimated population), which is very favorable for DAEs as the photochemical ring closure proceeds solely from this conformation. In addition to the thermal stability,t he photochemical fatigue was investigated as well;p hotodegradation was observed upon l = 313 nm irradiation under strongly basic conditions whereas only marginal fatigue occurred in an acidic milieu (Figures S10). Furthermore,arather slow thermal side reaction of the closed, deprotonated form 1c with water was noticed. [8j,m, 19] Our system describes af our-state reaction cycle,w hich allows for unidirectional operation (counterclockwise in Figure 2a)o wing to the wavelength selectivity of the photochemical ring-closure and ring-opening steps and the thus altered acid-base equilibrium. If the pH is adjusted to avalue in between the two different pK a values of the open and closed isomers,acatalytic cooperative interconnection can be achieved in which the efficiencyofthe photoisomerization is significantly enhanced by coupling it to the thermal acid-base equilibrium. Indeed, irradiation of the solution with UV light (l = 313 nm) at pH 5l eads to complete conversion and ar eaction rate comparable with that for the ring closure of the deprotonated form, that is, 1o!1c (see Figure 3c as well as the PSS compositions and effective quantum yields given at the bottom of Table 1). At pH 5, cycloreversion occurs with the rate of reaction of the protonated species, 1cH!1oH,as confirmed by calculations of the corresponding effective quantum yield (see Table 1). Thus our four-state system can be described in terms of ac atalytic cycle where the photoisomerization of compound 1 (at 10 À5 m concentration) is catalyzed by the presence of base,t hat is,s mall amounts of hydroxide (ca. 10 À9 m), in aqueous medium at pH 5i nt his case.
To obtain an in-depth understanding of the energetics of this process (Figure 4), calculations to map critical points on the ground-and excited-state energy surfaces in acetonitrile solution were carried out (note that the photochromism shows the same trends in pure acetonitrile as in acetonitrile containing 30 vol %water, investigated above;see Figure S6). In agreement with at hermally forbidden conrotatory ring opening/closure,t he computational results indicate that the conversion between the closed and open isomers is prevented in the ground state by large barriers for the neutral molecules (DG°= 52.5 kcal mol À1 for 1cH!1oH)aswell as the deprotonated switch (DG°= 51.1 kcal mol À1 for 1c!1o). In both cases,t he open isomer is thermodynamically more stable,i n the neutral form by DG r = À7.6 kcal mol À1 (1cHÐ1oH)a nd in the deprotonated form by DG r = À4.0 kcal mol À1 (1cÐ1o). Both protonated forms (1oH and 1cH)aswell as the closed, deprotonated form (1c)exhibit excited-state energy diagrams (see Sections S5) similar to those of already characterized DAEs. [20] Theirradiation of 1oH results in excitation to the S 2 state.Direct excitation to S 1 is less likely owing to its very low oscillator strength (TD-DFT: f = 0.02), and thus it is mostly populated indirectly by internal conversion. TheS 1 state relaxes in abarrier-free fashion towards aconical intersection. In agreement with previous reports on DAEs, [11a,18a, 21] small barriers were found along the cycloreversion path in the excited state for both acidic as well as basic milieus.I n contrast, the calculations suggest that the excited-state energy surface for photocyclization of the deprotonated form (1o! 1c)d iffers from those of other DAEs as an additional local minimum was found between the Franck-Condon point and the conical intersection, separated by as mall barrier. This might seem counterintuitive considering the observed quantum yield, but the reaction dynamics of DAEs are known to be complex, and al ocal minimum might indeed be able to "focus" the reaction as as maller portion of the potential energy surface is explored. Excitation of 1o results in direct population of its S 1 state,w hich exhibits am uch higher oscillator strength than that of 1oH.
Theh erein presented four-state system (Figure 2a)e nabled us to realize two important and interwoven functions:Onthe one hand, we were able to establish al ightinduced pK a modulation of D s s pK a = 2.8 AE 0.2 units between two thermally stable isomers.O n the other hand, we described the base-catalyzed photochemical ring closure of DAE 1,t hereby expanding the area of pH-gated photochromism [8l, 22] towards acid/base catalysis.O ur design is based on the coupling of multiple thermal and photochemical equilibria, [1] which, in the present cyclic system, allows for the light-driven and wavelength-selective modulation of acidity as well as ac atalytic enhancement of photoisomerization by the resulting charge state at the operating pH value.Based on our experimental and computational data, it appears that deprotonation indeed seems to affect the excited-state energy surface and thus the dynamics of the system. Currently,w ea re trying to decipher the underlying reasons for the accelerated photocyclization of the deprotonated species (1o). Future work will be devoted to further maximizing the extent of light-induced pK a modulation and to shift the operating pH value to physiological conditions to be able to harness these systems for the control of biological processes.F urthermore,t he use of 1o as aphotoactive buffer to modulate the pH value of an aqueous solution will be investigated.  a) The deprotonated isomers 1o and 1c with DG°= 51.1 kcal mol À1 and DG r = 4.0 kcal mol À1 .b)The protonated isomers 1oH and 1cH with DG°= 52.5 kcal mol À1 and DG r = 7.6 kcal mol À1 .