Isomerization and Properties of Isomers of Carbocyanine Dyes

Review Isomerization and Properties of Isomers of Carbocyanine Dyes

Pavel Pronkin * and Alexander Tatikolov

N.M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Kosygin Str. 4, 119334 Moscow, Russia; [email protected] * Correspondence: [email protected]; Tel.: +7-495-939-7171

Received: 20 November 2018; Accepted: 26 November 2018; First Version Published: 29 November 2018 (doi:10.3390/sci1010005.v1) Second Version Published: 20 March 2019 (doi:10.3390/sci1010019)

Abstract: One of the important features of polymethine (cyanine) dyes is isomerization about one of C–C bonds of the polymethine chain. In this review, spectral properties of the isomers, photoisomerization and thermal back isomerization of carbocyanine dyes, mostly meso-substituted carbocyanine dyes, are considered. meso-Alkyl-substituted thiacarbocyanine dyes are present in polar solvents mainly as cis isomers and, hence, exhibit no photoisomerization, whereas in nonpolar solvents, in which the dyes are in the trans form, photoisomerization takes place. In contrast, the meso-substituted dyes 3,30-dimethyl-9-phenylthiacarbocyanine and 3,30-diethyl-9-(2-hydroxy-4-methoxyphenyl)thiacarbocyanine occur as trans isomers and exhibit photoisomerization in both polar and nonpolar solvents. The behavior of these dyes may be explained by the fact that the phenyl ring of the substituent in their molecules can be twisted at some angle, removing the substituent from the plane of the molecule and reducing its steric eﬀect on the conformation of the trans isomer. In some cases, photoisomerization of cis isomers of meso-substituted carbocyanine dyes is also observed (for some meso-alkyl-substituted dyes complexed with DNA and chondroitin-4-sulfate; for 3,30-diethyl-9-methoxythiacarbocyanine in moderate polarity solvents). The cycle photoisomerization–thermal back isomerization of cyanine dyes can be used in various systems of information storage and deserves further investigation using modern research methods.

Keywords: carbocyanine dyes; isomerization; trans and cis isomers; meso-substituted cyanines

1. Introduction Isomerization reactions, which involve rotation of a bulky molecular group around a body-fixed axis, often play a fundamental role in chemical and biological processes both in solution and in organized assemblies. In nature, the most important and known isomerization process is photoisomerization of 11-cis retinal, the chromophore of rhodopsin, which is a photoreceptive pigment for twilight vision [1,2]. Rotational isomerization is inherent in polyenic compounds, in particular, carotenoids and diphenylpolyenes [3]. Azo and azomethine dyes can also undergo cis-trans (or syn-anti) isomerization, while with more complex mechanisms [4,5]. The most abundant class of dyes that exhibit rotational isomerization is polymethine (cyanine) dyes. At present, cyanine dyes attract great attention of researches in different fields of science, technology engineering, pharmacology and medicine [6]. In particular, these dyes are widely used in laser technology (for creating tunable laser media in the near IR spectral range, passive Q-switches of lasers and other devices of quantum electronics and optoelectronics) [7,8]. Cyanine dyes also attract interest due to the prospects of their use as spectral-fluorescent probes and labels in the study of various biological systems [9–12], and in biomedicine for the purposes of visualization of tissues and photodynamic therapy [6,13–16]. This is due to the unique properties of cyanine dyes, which are

Sci 2019, 1, 19; doi:10.3390/sci1010019 www.mdpi.com/journal/sci Sci 2019, 1, 19 2 of 17 SciSci2019 2019, 1, ,1 19, 19 22 ofof 17 17 determined by the key features of their molecular structure. Various fields of applications of cyanine determined by the key features of their molecular structure. Various fields of applications of cyanine dyes determine the need for studying their photophysical and photochemical properties in solutions determineddyes determine by the the key need features for studying of their their molecular photop structure.hysical and Various photochemical ﬁelds of applications properties in of solutions cyanine and molecularly organized media. dyesand determinemolecularly the organized need for studyingmedia. their photophysical and photochemical properties in solutions and molecularly organized media. 2. Structure and Spectral-Fluorescent Properties of Cyanine Dyes 2. Structure and Spectral-Fluorescent Properties of Cyanine Dyes 2. Structure and Spectral-Fluorescent Properties of Cyanine Dyes Polymethine dyes contain conjugated polymethine chains (with an odd number of CH groups) Polymethine dyes contain conjugated polymethine chains (with an odd number of CH groups) withPolymethine the general dyesformula contain X(CH=CH) conjugatednCH=Y, polymethine where X and chains Y are (with terminal an odd groups number with of CHheteroatoms groups) with the general formula X(CH=CH)nCH=Y, where X and Y are terminal groups with heteroatoms with(N, theO, S, general Se) or even formula C atoms X(CH (in=CH) case ofCH carbocyclic=Y, where azulene X and Y cyanines). are terminal The groups cationic with type heteroatoms polymethine (N, O, S, Se) or even C atoms (in case nof carbocyclic azulene cyanines). The cationic type polymethine (N,dyes O, S,are Se) primarily or even Ccyanines, atoms (in streptocyanines, case of carbocyclic rhodacyanines, azulene cyanines). hemicyanines, The cationic azacyanines, type polymethine and styryl dyes are primarily cyanines, streptocyanines, rhodacyanines, hemicyanines, azacyanines, and styryl dyesdyes, are anionic primarily polymethine cyanines, dyes streptocyanines, — oxonols. rhodacyanines,Neutral cyanines hemicyanines, (merocyanines azacyanines, and ketocyanines) and styryl are dyes, anionic polymethine dyes — oxonols. Neutral cyanines (merocyanines and ketocyanines) are dyes,subtypes anionic of uncharged polymethine polymethine dyes — oxonols. dyes. Neutral cyanines (merocyanines and ketocyanines) are subtypes of uncharged polymethine dyes. subtypesIn this of uncharged article, we polymethine confine ourselves dyes. to the most common subclass of polymethine dyes—carbo- In this article, we confine ourselves to the most common subclass of polymethine dyes—carbo- cyaninesIn this with article, a positively we conﬁne charged ourselveschromophore to wi theth mostterminal common nitrogen subclass atoms. The of nitrogen polymethine atoms cyanines with a positively charged chromophore with terminal nitrogen atoms. The nitrogen atoms dyes—carbocyaninescan be a part of amino with groups a positively or terminal charged heterocycles chromophore B1 and B2 with(quinolinyl, terminal indolenyl, nitrogen benzimid- atoms. can be a part of amino groups or terminal heterocycles B1 and B2 (quinolinyl, indolenyl, benzimid- Theazolyl, nitrogen benzothiazolyl, atoms can benzoxazolyl, be a part and of other amino heterocyclic groups or residues, terminal see heterocycles Figure 1) [17,18]. B1 andNote B2that azolyl, benzothiazolyl, benzoxazolyl, and other heterocyclic residues, see Figure 1) [17,18]. Note that (quinolinyl,the total charge indolenyl, of such benzimidazolyl, dyes can be not benzothiazolyl, only positive, benzoxazolyl, but also negative and other(or neutral) heterocyclic due to residues, the pres- the total charge of such dyes can be not only positive, but also negative (or neutral) due to the pres- seeence Figure of anionic1)[ 17, 18substituents]. Note that in the heterocyclic total charge residues. of such dyes can be not only positive, but also negative ence of anionic substituents in heterocyclic residues. (or neutral) due to the presence of anionic substituents in heterocyclic residues.

R R6 R 5 R6 5

R N n N R R 3 N N R 4 3 n 4 R R R 1 n= 1, 2, 3 R 2 1 n= 1, 2, 3 2 R R X S X S

N NNN N N N NNN N N R R R R R R R R R R X= S, O, Se X= S, O, Se

FigureFigure 1. 1.Generalized Generalized molecular molecular structure structure of of cyanine cyanine dyes dyes and and examples examples of of terminal terminal heterocycles heterocycles B1 B1 Figure 1. Generalized molecular structure of cyanine dyes and examples of terminal heterocycles B1 andand B2. B2. and B2. TheThe dye dye molecule molecule usually usually carries carries a positive a positive charge char distributedge distributed over over the the polymethine polymethine chain. chain. Due Due to The dye molecule usually carries a positive charge distributed over the polymethine chain. Due completeto completeπ-electronic π-electronic conjugation conjugation in the in polymethine the polymethine chain, chain, these dyes these have dyes narrow have narrow absorption absorption bands to complete π-electronic conjugation in the polymethine5 chain,1 these1 dyes have narrow absorption withbands high with extinction high extinction coeﬃcients coefficients (of the order(of the of order 10 L of mol 10−5 Lcm mol− −)1 incm the−1) in spectral the spectral range range from 340from bands with high extinction coefficients (of the order of 105 L mol−1 cm−1) in the spectral range from to340 1400 to nm1400 [6 nm,9,17 [6,9,17,18].,18]. Note Note that symmetricthat symmetric polymethine polymethine dyes dyes are characterized are characterized by equalization by equalization of 340 to 1400 nm [6,9,17,18]. Note that symmetric polymethine dyes are characterized by equalization C–Cof C–C bonds bonds in the in chromophore the chromophore and approaching and approaching of their of orders their orders to one-and-a-half to one-and-a-half (polymethine (polymethine state). of C–C bonds in the chromophore and approaching of their orders to one-and-a-half (polymethine Fromstate). symmetry From symmetry considerations, considerations, it follows it thatfollows for symmetricthat for symmetric cyanines cyanines (B1 = B2) (B1 this = shouldB2) this lead should to state). From symmetry considerations, it follows that for symmetric cyanines (B1 = B2) this should alead uniform to a distributionuniform distribution of the electronic of the electronic density along density the along polymethine the polymethine chain and chain identical and chargesidentical lead to a uniform distribution of the electronic density along the polymethine chain and identical oncharges the terminal on the groupsterminal (Figure groups2). (Figure Hence, 2). the Hence, electronic the electronic structure structure of symmetric of symmetric cationic dyes cationic can dyes be charges on the terminal groups (Figure 2). Hence, the electronic structure of symmetric cationic dyes representedcan be represented by a superposition by a superpositio of twon resonance of two resonance structures structures [17]. [17]. can be represented by a superposition of two resonance structures [17].

B B B B B B B B N n N N n N N n N N n N R R R R R 1 R 2 R 1 R 2 1 2 1 2

Figure 2. Resonance structures of polymethine (cyanine) dyes. Figure 2. Resonance structures of polymethine (cyanine) dyes. Figure 2. Resonance structures of polymethine (cyanine) dyes.

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Elongation of the polymethine chain in the symmetric dyes by one vinylene group results in a bathochromicElongation shift of the of polymethinethe absorption chain maximum in the symmetricby about 100–130 dyes by nm one [17–19]. vinylene At group present, results there in is a a bathochromicwide variety shiftof cationic of the absorptioncarbocyanines: maximum monomethine by about cyanines, 100–130 nmcarbocyanines [17–19]. At (or present, trimethine there iscya- a widenines), variety dicarbocyanines of cationic carbocyanines: (pentamethine monomethine cyanines), tricarbocyanines cyanines, carbocyanines (heptamethine (or trimethine cyanines), cyanines), etc. dicarbocyaninesAs a rule, in (pentamethine their absorption cyanines), spectra tricarbocyanines there is only one (heptamethine short-wavelength cyanines), vibronic etc. maximum as a characteristicAs a rule, in shoulder their absorption at the edge spectra of the there main is ba onlynd. oneThe short-wavelengthpresence of a system vibronic of alternating maximum charges as a characteristicdetermines the shoulder high sensitivity at the edge of ofpolymethine the main band. dyes Theto intermolecular presence of a systeminteractions of alternating with the medium. charges determinesDue to the the high lack sensitivity of rigidity of of polymethine the molecule, dyes which to intermolecularis characteristic interactions of cyanine withdyes thewith medium. an open polymethineDue to the chain, lack ofvarious rigidity vibrations of the molecule, and rotations which of is individual characteristic fragments of cyanine are possible dyes with in their an open mol- polymethineecules, first of chain, all, torsions various and vibrations rotations and around rotations various of individualbonds of the fragments polymethine are chain possible of cyanines. in their molecules,This also ﬁrstdetermines of all, torsions the possibility and rotations of isomerization around various due bonds to rotation of the polymethinearound the C–C chain bonds of cyanines. of the Thispolymethine also determines chain. Photoisomerization the possibility of isomerization (trans → cis or due cis to→ rotation trans) is arounda potent the nonradiative C–C bonds channel of the polymethine chain. Photoisomerization (trans cis or cis trans) is a potent nonradiative channel for for deactivation of the excited state of the molecules→ of polymethine→ dyes. This determines short life- deactivationtimes (from oftens the to excited hundreds state of of picoseconds) the molecules of of their polymethine excited singlet dyes. Thisstate determines (S1), as well short as low lifetimes values (fromof the tens quantum to hundreds yields of picoseconds)fluorescence and of their intersystem excited singlet crossing state to the (S1 ),triplet as well state as low(S1 → values T) [9,17,18]. of the quantumHence, the yields study of ﬂuorescenceof photoisomerization and intersystem of polyme crossingthine to dyes the tripletis a key state to (understandingS1 T)[9,17,18 the]. Hence, photo- → thephysical study ofand photoisomerization photochemical processes of polymethine occurring dyes in their is a key molecules to understanding after photoexcitation. the photophysical and photochemical processes occurring in their molecules after photoexcitation. 3. Isomerization of Carbocyanine Dyes 3. Isomerization of Carbocyanine Dyes As noted above, one of the main paths of degradation of the energy of the S1 state of cyanines in low-viscosityAs noted above,media oneis usually of the maintrans paths→ cis of(or degradation cis → trans) of isomerization, the energy of performed the S1 state by of cyaninesrotating a in low-viscosity media is usually trans cis (or cis trans) isomerization, performed by rotating a fragment of the dye molecule around one→ of the bonds→ of the polymethine chain by ~180° (also pos- fragment of the dye molecule around one of the bonds of the polymethine chain by ~180 (also possible sible is internal conversion—the nonradiative transition S1 → S0 induced by vibrations◦ and torsions). is internal conversion—the nonradiative transition S S induced by vibrations and torsions). Figure 3 shows general molecular structures of the trans1 → and0 cis isomers of the dyes. Figure 3 shows general molecular structures of the trans and cis isomers of the dyes. R 1 N B1 2 9 B2 B1 9 B2 8 8 N N 2 N

R trans R cis R - 1 2 - 2

S S C H N N C H 2 5 2 5 N N 4 R R

1 R = CH ; 2 R = C H 3 2 5 N N C H C H 2 5 2 5 5 O O

N N N N C H C H C H C H 2 5 2 5 2 5 2 5 3 6

FigureFigure 3. 3.Generalized Generalized molecular molecular structures structures of transof transand andcis isomers cis isomers of unsubstituted of unsubstituted carbocyanine carbocyanine dyes anddyes structural and structural formulas formulas of cyanines of cyanines1–6. 1 - 6.

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The existence of photoisomers of polymethine dyes was first proven in 1965 by flash photolysis of dye solutions [20]. For example, for the unsubstituted cationic dye 3,30-dimethylthiacarbocyanine perchlorate (1), the photoisomerization quantum yield (ϕi) is 0.24 in dichloromethane [21]. Upon photoexcitation of its analogue, 3,30-diethylthiacarbocyanine iodide (2) in polar solvents (ethanol, dimethyl sulfoxide, acetonitrile), ϕi has a similar value (0.25 in methanol [22]); the contributions of fluorescence and intersystem crossing to the triplet state upon deactivation of excited singlet molecules are low. Direct photoexcitation of carbocyanine dyes with no substituents in the polymethine chain (they are mainly present in solution in the form of trans isomers) leads to the formation of a short-lived cis photoisomer (see Equation (1)), which then undergoes back dark (thermal) isomerization to form 1 the initial trans isomer (with a rate constant for 2 ki = 250 s− in ethanol [21]):

k trans-S + hν trans-S cis-S i trans-S (1) 0 → 1 → 0 → 0 Upon flash photoexcitation of aerated solutions of the unsubstituted oxacarbocyanine dye 3,30-diethyloxacarbocyanine iodide (3) in isopropanol and aqueous phosphate buffer solution (pH 7, 1 20 mmol L− ), the absorption and bleaching signals caused by photoisomerization and thermal back isomerization of the photoisomer formed was observed [22]. The criterion determining the assignment of the signals to the photoisomer was the absence of the effect of oxygen on the observed signals, since the photoisomers of cyanine dyes are formed, as a rule, from the S1 state of the dyes having a too short lifetime (hundreds of picoseconds) to be quenched with atmospheric oxygen [23]. The bleaching maximum (λmax = 480 nm) of the difference spectra of 3 approximately coincides with the absorption band of the dye (trans isomer), and the absorption maxima (λmax = 505 nm) are in the long-wavelength region. The assignment of the spectrum to the cis isomer is based on [24]. The value of ki for 3 does not depend on the excitation and registration 1 wavelengths and is 9.0 s− (in aqueous phosphate buffer solution) [25]. For the dyes that do not have substituents in the polymethine chain, as a rule, the all-trans isomer is thermodynamically more stable. These dyes are mainly present in solution in the form of this isomer [26]. Their photoisomers correspond to a cis conformation [27].

4. Potential Surfaces of Isomerization of Cyanine Dyes Historically, several models of potential surfaces of cyanine isomerization (surfaces corresponding to isomerization rotation around one of the C–C bonds of the polymethine chain) were considered in the literature. One of the first models was the Rulliere model [28], in which the potential surfaces calculated by Orlandi and Siebrand for isomerization of stilbene [29] were mechanically transferred to the case of isomerization of cyanines. However, it was later shown [30] that the potential wave functions for polyenes and cyanines are of different nature, despite some similarity of the shapes of the potential surfaces for the S1 state, so the results of Orlandi–Siebrand’s calculations are not applicable for cyanines. On the basis of quantum-chemical calculations carried out for simple open-chain cyanine dyes (streptocyanines), two models of photoisomerization of cyanine dyes were proposed, taking into account the influence of solvent polarity in different ways [22]. According to these models, photoisomerization of cyanines occurs with activation energy barrier in the excited singlet state (S1) through the formation of an intermediate perpendicular (perp) form. The models also suggest an energy barrier for the reaction of thermal back isomerization of the dyes in the ground state (S0). According to model 1, photoisomers of thiacarbocyanine dyes are characterized by twisted, distorted configuration. This model assumes stabilization of intermediate perpendicular forms of dye photoisomers in polar solvents due to dipole-dipole interactions with the solvent [31]. Solvation of the perpendicular form should lead to a significant decrease in the corresponding energy barriers (minima on the S1 and S0 energy curves) [32]. In the absence of solvation of the perpendicular form, such effects are not expected [22,31]. In nonpolar Sci 2019, 1, 19 5 of 17

Scisolvents, 2019, 1, 19 a high energy barrier will prevent isomerization in the S1 state. In accordance with model5 of 17 1, the rate of the back isomerization reaction of photoisomers of cyanine dyes in the ground state should stronglyModel depend 2 proposed on the by solvent Momicchioli polarity et [31 al.,32 [30]]. assumes the formation of planar cis-isomers; dipole- dipoleModel interactions 2 proposed with a bysolvent Momicchioli were not etexplicit al. [30ly] included assumes in the the formation calculations. of The planar model cis-isomers; assumes relativelydipole-dipole small interactions solvation effects witha on solvent isomerization were not of explicitly cyanine includeddyes in polar in the media. calculations. In [22], the The data model on theassumes photophysical relatively properties small solvation and photoisomerization effects on isomerization of dyes of 2 cyanine and 3 in dyes various in polar solvents media. were In ana- [22], lyzed.the data on the photophysical properties and photoisomerization of dyes 2 and 3 in various solvents wereThe analyzed. results obtained contradict the theoretical model of photoisomerization, in which the key role isThe played results by obtainedthe influence contradict of solvent the theoretical polarity (model model 1) of [22,31,32]. photoisomerization, It was shown in whichthat, upon the key chang- role ingis played the dielectric by the influence constant of of solvent the solvent polarity (ε = (model 2.2 to 32.7), 1) [22 no,31 ,predicted32]. It was effect shown of that,polarity upon on changing the S1 state the potentialdielectric barrier constant in of the the photoisomerization solvent (ε = 2.2 to 32.7),reaction no predictedwas observed. effect The of polarity absorption on the spectraS1 state of potentialthe pho- toisomersbarrier in theof dyes photoisomerization 2 and 3 correspond reaction to the was planar observed. structures The absorption of the molecules, spectra which of the photoisomersdoes not cor- respondof dyes 2 toand model3 correspond 1 [22]. Model to the 2 [29] planar is in structures better agreement of the molecules, with experimental which does data not and correspond allows one to tomodel take 1into [22 ].account Model the 2 [29 weak] is in effects better of agreement solvent polarity with experimental on the Arrhenius data and parameters allows one of todye take 2 back into isomerization.account the weak Fore theffects trans of solvent-to-perp polarity transition, on thethe Arrheniusactivation parametersenergy was offound dye 2toback be ~17–19 isomerization. kJ/mol, theFor transition the trans-to-perp of the cis transition, isomer to the the activation perpendicular energy state was found(cis-to-perp) to be ~17–19 is apparently kJ/mol, barrier-free the transition and of dependsthe cis isomer on the to energy the perpendicular of the viscous state flow ( cisof -to-perp)the solvent. is apparentlyFor dark processes barrier-free of back and isomerization depends on the of theenergy photoisomers, of the viscous an flow energy of the barrier solvent. of ~54–75 For dark kJ/mol processes is characteristic, of back isomerization depending of the on photoisomers, cyanine and solventan energy [22]. barrier of ~54–75 kJ/mol is characteristic, depending on cyanine and solvent [22]. Now in the the literature, literature, a a model model of of potential potential surfaces surfaces for for cyanine cyanine dyes dyes is is used, used, starting starting from from which, which, 1 irrespectiveirrespective of the solvent, only the surface of S1 has a third minimum (turn by ~90°), ~90◦), which which roughly roughly 0 corresponds to the top of the potential barrier barrier of of the the surface surface of of SS0 havinghaving two two minima minima (Figure (Figure 4)4)[ [30].30]. Upon photoexcitation, photoexcitation, a a molecule molecule in in the the form form of of a trans a trans isomerisomer passes passes to tothe the central central minimum minimum of S of1, 0 0 fromS1, from which, which, when when it reaches it reaches the surface the surface of S of, itS slips0, it slipsdown down to a minimum to a minimum of cis of-S cis (trans–cis-S0 (trans–cis pho- 0 toisomerization)photoisomerization) or trans or trans-S (nonradiative-S0 (nonradiative degradation degradation of the of exci thetation excitation energy). energy). If the excited If the excited mole- 1 culemolecule is in the is in form the formof a cis of isomer, a cis isomer, then it then also it passes also passes to the tocentral the central minimum minimum of S , from of S1 ,which, from which, when 0 0 itwhen reaches it reaches the surface the surface of S of, itS 0slips, it slips down down to a to minimum a minimum of ofciscis-S-S (nonradiative0 (nonradiative degradation degradation of of the the 0 excitation energy) orortrans trans-S-S0 ( cis-trans(cis-transphotoisomerization). photoisomerization). The The quantum quantum yields yields of of photoisomerization photoisomeriza- 1 tionand and nonradiative nonradiative degradation degradation depend depend on on the the position position of of the the minimum minimum of ofS S1 with with respectrespect to the 0 maximum of S0.. Theoretical Theoretical calculations calculations by by the the CS CS INDO INDO method method [30] [30] and and experi experimentalmental verification verification of the consistency of this model with the isomer isomerizationization process [22] [22] showed its correspondence to cyanine isomerization.

Figure 4. General scheme ofof thethe potentialpotential surfaces surfaces of of isomerization isomerization of of cyanine cyanine dyes dyes (only (onlyS0 ,SS01, ,S and1, andT1

Tsurfaces1 surfaces are are shown). shown).

For cyanines with no substituents in the polymethine chain, nonradiative relaxation of the excited singlet state (both trans- and cis-S1), occurring by movement along the potential surface of

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Sci 2019, 1, 19 6 of 17 For cyanines with no substituents in the polymethine chain, nonradiative relaxation of the excited singletisomerization, state (both leadstrans to- both and cis cis-S and1), occurring trans isomers by movement of the dye. along Thus, the for potential these dyes, surface photoisomerization of isomerization, leadsoccurs to upon both photoexcitationcis and trans isomers of both of trans the dye. and Thus,cis isomers. for these dyes, photoisomerization occurs upon photoexcitationIn the case ofof bothmosttrans mesoand-substitutedcis isomers. thiacarbocyanines (first of all, alkyl-substituted), the mini- mumIn potential the case ofenergy most mesoof the-substituted dye in the thiacarbocyaninesS1 state corresponding (ﬁrstof to all, the alkyl-substituted), perpendicular conformation the minimum is potentialshifted with energy respect of the to the dye maximum in the S1 state of the corresponding energy barrier to of the the perpendicular S0 state toward conformation the cis isomer is (Figure shifted with5) [22,30]. respect to the maximum of the energy barrier of the S0 state toward the cis isomer (Figure5)[ 22,30].

FigureFigure 5.5. Scheme of the potential surfaces of isomerization ofof meso-substituted-substituted cyaninecyanine dyesdyes (only(only SS00,

SS11, and T1 surfacessurfaces are are shown).

For this reason, upon nonradiative relaxation of the S state of such dyes by moving along the For this reason, upon nonradiative relaxation of the S1 1state of such dyes by moving along the S1 Spotential1 potential surface, surface, the the transtrans conformationconformation of the ofthe dyes dyes is not is not atta attainedined and and photoexcitation photoexcitation into into the theab- absorptionsorption band band of of the the ciscis isomerisomer does does not not lead lead to to the the formation formation of of the the transtrans form,form, that that is, the cis isomers ofof mostmost mesomeso-substituted-substituted thiacarbocyaninesthiacarbocyanines areare notnot photoisomerizedphotoisomerized [[21].21]. 5. Effect of Solvent Viscosity on the Kinetics of Photoisomerization and Back (Thermal) Isomerization 4. Effect of Solvent Viscosity on the Kinetics of Photoisomerization and Back (Thermal) Isomeri- zationThe kinetics of isomerization of cyanines in solution is determined, first of all, by a potential barrier of rotation around the isomerizing bond. In solutions, the character of molecular environment is The kinetics of isomerization of cyanines in solution is determined, first of all, by a potential also an important factor, which can have an effect on isomerization of cyanine dyes. For isomerization barrier of rotation around the isomerizing bond. In solutions, the character of molecular environment processes with relatively low activation energies close to the activation energy of the viscous flow of is also an important factor, which can have an effect on isomerization of cyanine dyes. For isomeri- the solvent (this is usually isomerization from the S state, that is, photoisomerization), it strongly zation processes with relatively low activation energies1 close to the activation energy of the viscous depends on the viscosity of the medium (slows down sharply with increasing viscosity). Due to flow of the solvent (this is usually isomerization from the S1 state, that is, photoisomerization), it the very efficient photoisomerization process, the lifetime of the S state of cyanines in low-viscosity strongly depends on the viscosity of the medium (slows down sharply1 with increasing viscosity). solvents is much shorter than the radiative lifetime and is usually hundreds of picoseconds or less. Due to the very efficient photoisomerization process, the lifetime of the S1 state of cyanines in low- In high viscosity media, internal rotations in the cyanine molecule are hindered, which leads to a drop viscosity solvents is much shorter than the radiative lifetime and is usually hundreds of picoseconds in the quantum yield of photoisomerization and an increase in the quantum yield of fluorescence, or less. In high viscosity media, internal rotations in the cyanine molecule are hindered, which leads the fluorescence lifetime, and the quantum yield of the triplet state, since fluorescence and intersystem to a drop in the quantum yield of photoisomerization and an increase in the quantum yield of fluo- crossing to the triplet state compete with photoisomerization [30]. rescence, the fluorescence lifetime, and the quantum yield of the triplet state, since fluorescence and The influence of viscosity on ultrafast processes of cyanine dye photoisomerization was intersystem crossing to the triplet state compete with photoisomerization [30]. studied in a number of works. In particular, in [33] the formation of short-lived photoisomers of The influence of viscosity on ultrafast processes of cyanine dye photoisomerization was studied 1,1 -diethyl-4,4 -cyanine (4), 2,2 -trimethinequinocyanine (5, Pinacyanol) was studied after excitation in 0a number of0 works. In particular,0 in [33] the formation of short-lived photoisomers of 1,1′-diethyl- with picosecond laser pulses. It was shown that the yield of photoisomers of the dyes strongly depends 4,4′-cyanine (4), 2,2′-trimethinequinocyanine (5, Pinacyanol) was studied after excitation with pico- on viscosity: the relative concentration of the photoisomer decreases with an increase in the viscosity second laser pulses. It was shown that the yield of photoisomers of the dyes strongly depends on of the solvent (a mixture of glycerol and methanol). Studies using ultrafast femtosecond spectroscopy viscosity: the relative concentration of the photoisomer decreases with an increase in the viscosity of of the process of photoisomerization of the cationic monometinecyanine dye 1,1’-diethyl-2,2’-cyanine the solvent (a mixture of glycerol and methanol). Studies using ultrafast femtosecond spectroscopy (6) in alcohols are reported in [34]. A lower quantum yield for the photoisomer was observed in more of the process of photoisomerization of the cationic monometinecyanine dye 1,1’-diethyl-2,2’-cyanine (6) in alcohols are reported in [34]. A lower quantum yield for the photoisomer was observed in more viscous solvents. The increase in viscosity results in slowing down intramolecular vibrations and

Sci 2019, 1, 19 7 of 17 viscous solvents. The increase in viscosity results in slowing down intramolecular vibrations and torsions in the photoexcited cyanine molecule, including rotations of fragments of the dye molecule around C–C bonds of the polymethine chain leading to photoisomerization. In [35], the kinetics of isomerization of molecules of indocarbocyanine dyes with substituents in positions 3 and 3’ of various length in solutions of alcohols (methanol–decanol series) was studied. The results indicate, in particular, that the nature of the reaction coordinate plays an important role in determining the dependence of photoisomerization on viscosity. To take into account the effect of viscosity on the rate of the photoisomerization reaction, a number of theoretical approaches have been proposed. First of all, this is the approach based on the Kramers theory [36]:  s  !2 ωrγ  2 2ω m   b  Ea/RT k =  1 + 1e− (2) 4πωbm γ −  where k is the rate constant, ωr and ωb are the frequency factors of the barrier on the potential energy surface in the vicinity of the reactants (ωr) and the top of the reaction barrier (ωb), respectively, γ—friction coefficient, m—effective mass, Ea is the activation energy of the reaction, and R is the universal gas constant. It is common to assume that γ η (η is viscosity), and in the hydrodynamic framework at high ∝ viscosity, Equation (2) turns into:

1 Ea/RT k e− (3) ∼ η Under these conditions, the reaction rate constant should be inversely proportional to the viscosity (η) of the solvent. However, for the isomerization reactions, this proportionality is usually not observed; it has been shown that the reaction rate constant with increasing solvent viscosity decreases much slower than Equation (3) predicts [37,38]. An explanation of the dependence of the isomerization rate constant on viscosity was also proposed in the theory of Grote and Hynes [39], which introduces the concept of frequency-dependent friction aﬀecting the rate of chemical processes in the solvent phase. Due to the inclusion of frequency-dependent friction instead of constant friction, the theory of Grote and Hynes successfully predicts the rate constant of chemical reactions in viscous liquids. A more detailed consideration of theoretical approaches describing the dependence of the isomerization kinetics on viscosity is beyond the scope of this review. For isomerization processes, the following semi-empirical equation is also used [40–42]:

Ea = E0 + αEη, (4) where Ea is the apparent activation energy of isomerization, E0 is the internal energy barrier of isomerization, Eη is the activation energy of a viscous flow, and α is a coefficient depending on the slope of the potential barrier in the transient state of the process (0 α 1). For photoisomerization, ≤ ≤ the coefficient α is larger than for the thermal back isomerization (in the latter case, a weak dependence of Ea on the viscosity is observed, which is manifested only in highly viscous solvents). In [42], for photoisomerization of dye 3 in different alcohols the values of α were found to be in the range of 0.54 to 0.76, and for thermal back isomerization α ~ 0.27–0.41.

6. Effects of Ion Pair Formation on the Isomerization Processes of Cyanine Dyes In polar solvents, cyanine dyes are present in the form of free ions (cations); in this case, the influence of polarity of the medium on the isomerization of polymethine dyes is small (see above) [22,42]. However, in weakly polar and nonpolar solvents, the dyes form ion pairs with a counterion, which can affect their photochemistry, in particular, the processes of photoisomerization and back isomerization of the resulting photoisomer. Sci 2019, 1, 19 8 of 17

In [43], photophysical and photochemical processes occurring upon flash photoexcitation in molecules of dyes 1 (iodide) and 2 (chloride) in a mixture of dimethyl sulfoxide (DMSO)–toluene of various compositions were studied. With a decrease in the DMSO content in the solution down to 3 vol %, the relative quantum yield of intersystem crossing of dye 1 to the triplet state increases by two orders of magnitude, which is accompanied by a decrease in the quantum yield of trans–cis photoisomerization. This effect is not observed for dye 2. The authors explain these results by the heavy atom effect upon the formation of ion pairs of the dye cation 1 with the iodide counterion under nonpolar conditions. In [44], the effect of counterions (ClO4−, Cl−,I−) on photochemical processes (including isomerization) in molecules of cationic benzimidacyanine dyes was studied in acetonitrile–toluene mixtures. In low polarity media, in which the dyes formed ion pairs with counterions, an increase in the rate constant and a decrease in the activation energy of back isomerization of benzimidacyanines were observed. The effect was explained by the electrostatic influence of the counterion in ion pairs on the electronic density distribution in the dye cation, leading to a decrease in the activation barrier of the process [44]. The influence of the counterion on the transient (“twisted”) state of isomerization, which lowers its energy, is also possible.

7. Isomerization of Meso-Substituted Carbocyanine Dyes While carbocyanine dyes, which do not have meso substituents in the polymethine chain, are present in solutions as trans isomers, meso-substituted thiacarbocyanine dyes in the crystalline state are usually present as cis isomers [45]. Bulky substituents in the meso (9) position of the polymethine chain create signiﬁcant steric hindrances to the formation of the trans isomer (Figure6). At low temperatures in solutions, the absorption bands of meso-substituted thiacarbocyanines are split into two closely spaced bands [46]. Simultaneous presence (in comparable concentrations) of all-trans and cis isomers can be observed [45, 46]. In particular, it has been shown that 3,30,9-trimethylthiacarbocyanine iodide (7; Cyan 2), having a meso-methyl substituent in the polymethine chain, is mainly in the cis form in polar solvents [47]. The equilibrium position depends strongly on the solvent polarity: the trans isomer predominates in low polarity media, while in highly polar solvents the trans isomer presents only as a small impurity to the cis isomer [26,45–48]. As an example, it was shown that 3,30-diethyl-9-methoxythiacarbocyanine 8 in solvents of moderate polarity (ethyl acetate, isopropanol) is in the form of an equilibrium mixture of cis and trans isomers (Figure7). The meso-substituted carbocyanine dye 3,30,9-triethylthiacarbocyanine iodide (9) in isopropanol is in the form of a cis isomer, and in dioxane in the form of a trans isomer [49]. It was shown that 3,30-diethyl-9-chlorothiacarbocyanine perchlorate (dye 10) is in the form of a cis isomer in water, and in the form of a trans isomer in a less polar solvent, isopropanol [50]. Sci 2019, 1, 19 8 of 17

vol %, the relative quantum yield of intersystem crossing of dye 1 to the triplet state increases by two orders of magnitude, which is accompanied by a decrease in the quantum yield of trans–cis photoisomerization. This effect is not observed for dye 2. The authors explain these results by the heavy atom effect upon the formation of ion pairs of the dye cation 1 with the iodide counterion under nonpolar conditions. In [44], the effect of counterions (ClO4−, Cl−, I−) on photochemical processes (including isomerization) in molecules of cationic benzimidacyanine dyes was studied in acetonitrile–toluene mixtures. In low polarity media, in which the dyes formed ion pairs with counterions, an increase in the rate constant and a decrease in the activation energy of back isomerization of benzimidacyanines were observed. The effect was explained by the electrostatic influence of the counterion in ion pairs on the electronic density distribution in the dye cation, leading to a decrease in the activation barrier of the process [44]. The influence of the counterion on the transient (“twisted”) state of isomerization, which lowers its energy, is also possible.

6. Isomerization of Meso-Substituted Carbocyanine Dyes While carbocyanine dyes, which do not have meso substituents in the polymethine chain, are present in solutions as trans isomers, meso-substituted thiacarbocyanine dyes in the crystalline state Sciare2019 usually, 1, 19 present as cis isomers [45]. 9 of 17

R 8 9 R R 1 2 B1 2 9 B2 N B2 8 N N B1 N trans cis R

R - R 2 1 2 - R O 1 O

R N N R 2 2 R S 1 S R R 12 R = CH R = C H R = H R 3 1 2 5 2 2 N N R 13 R = R = C H R = CH 2 1 2 5 2 3 R R R R C H 6 3 S 2 5 S 7 R = R = CH R = H 1 3 2 Sci 2019, 18, 19 R = C H R = OCH R = H R 9 of 17 2 5 1 3 2 R N N 5 9 R = R = C H R = H 2 1 2 5 2 R polarity1 media,0 R = C whileH R =in C lhighly R = H polar solvents the trans isomerR presents only as a small 4impurity to 2 5 1 2 1 (CHS O2)3- (CHS O2)3- 11 R = C H R = tert-butyl R = H 3 3 the cis isomer [26,45–48].2 5 1 As an example,2 it was shown that 3,3′-diethyl-9-methoxythiacarbocyanine 14 R = CH R = phenyl R = H 16 R = CH R = R = benzo R = R = R = 3 1 2 2 3 4 5 1 3 5 8 in solvents15 R of= C moderateH R = 2- hpolarityydroxy- (ethyl acetate, isopropanol)= R = H isO in the form of an equilibrium mixture 2 5 1 6 4- methoxyphenyl R = H 17 R = R = CH R = R = R = R = H of cis and trans isomers 2(Figure 7). The meso-substituted carbocyanine3 6 3 dye1 3,32′,9-triethylthiacarbocy-4 5 20 R = C H R = CH R = H 18 R = CH R = phenyl R = R = R = R = H anine iodide (9)2 in5 isopropanol1 3 2 is in the form of a cis isomer,2 and3 in5 dioxane 1in the3 form4 of6 a trans 21 R = R = C H R = OC H R = Cl 19 R = R = R = R = benzo R = R = H isomer [49]. It was1 2shown5 1 that 33,32′-diethyl-9-chlorothiacarbocyanine1 2 4 perchlorate5 (dye3 610) is in the form of a cis isomer in water, and in the form of a trans isomer in a less polar solvent, isopropanol Figure 6. Generalized molecular structures of trans and cis isomers of of meso-substituted carbocyanine [50]. Figure 6. Generalized molecular structures of trans and cis isomers of of meso-substituted carbocya- dyes and structural formulas of cyanines 7–21. nine dyes and structural formulas of cyanines 7 - 21. A Bulky substituents in the meso (9) position of the polymethine chain create significant steric hin- 4 drances to the formation of the trans isomer (Figure1 6). At low temperatures in solutions, the absorption bands of meso-substituted0.06 thiacarbocyanines2 are split into two closely spaced bands [46]. Simul- taneous presence (in comparable concentrations) of all-trans and cis isomers can be observed [45,46]. In particular, it has been shown that 3,3′,9-trimethylthiacarbocyanine iodide (7; Cyan 2), having a meso-methyl substituent in the polymethine chain, is mainly in the cis form in polar solvents [47]. The 0.04 equilibrium position depends strongly on the solvent polarity:3 the trans isomer predominates in low

0.02

0.00 400 450 500 550 600 λ, nm

Figure 7. Absorption spectra of dye 8 (3,3 -diethyl-9-methoxythiacarbocyanine iodide; c = 1.1 0 dye −6 Figure6 7. Absorption1 spectra of dye 8 (3,3′-diethyl-9-methoxythiacarbocyanine iodide; cdye = 1.1 × 10 10− mol L− ) in (1) acetonitrile, (2) isopropanol, (3) mixture of isopropanol and dioxane (1:1), ×mol L−1) in (1) acetonitrile, (2) isopropanol, (3) mixture of isopropanol and dioxane (1:1), and (4) diox- and (4) dioxane. ane. An increase in the eﬀective volume of the substituent in the meso position of the polymethine chainAn of increase the molecule in the promoteseffective vo anlume increase of the in substituent the cis isomer in the content. meso position It was of the established polymethine that chain of the molecule promotes an increase in the cis isomer content. It was established that 9-tert- 9-tert-butyl-3,30-diethylthiacarbocyanine cation (11) exists both in solution and in the solid phase exclusivelybutyl-3,3′-diethylthiacarbocyanine as a nonplanar di-cis form cation [26, 47(11].) exists both in solution and in the solid phase exclu- sivelyThe as simultaneousa nonplanar di- presencecis form of [26,47].trans and cis isomers in dye solutions is explained by distortion of the planarThe simultaneous structure of thepresence dye made of trans by substituentsand cis isomers in the in dyemeso solutionsposition is of explained the polymethine by distortion chain of the planar structure of the dye made by substituents in the meso position of the polymethine chain of the dyes. This leads to a significant increase in the energy of the trans isomer, which becomes close to that of the cis isomer [45,46,51]. The observed dynamic equilibrium depending on the solvent polarity is due to the electrostatic interaction of the dye cation with a counterion in ion pairs formed in low polarity media. The formation of ion pairs in low polarity media leads to a decrease in the energy of the trans isomer and its preferential formation, whereas in polar media the cis isomer is formed, which has a lower energy. The different isomers present in the solution cause a difference in the photochemical properties of meso-substituted carbocyanine dyes in solvents of different polarity. In polar solvents, where the dyes are predominantly in the form of cis isomers, photoisomerization is generally not observed, while in low polarity solvents, in which the dyes are present as trans isomers, photoisomerization to form cis isomers occurs upon photoexcitation. This empirical rule is fulfilled by a series of thia- and oxacarbocyanines with bulky meso-substituents. Upon flash photoexcitation of the carbocyanine dye 9, the signals corresponding to photoisomerization processes were not detected in the polar media (isopropanol), i.e., the cis isomer of 9 was not photoisomerized. In nonpolar dioxane solution, the signals corresponding to trans–cis photoisomerization and subsequent decay of the cis photoisomer of dye 9 were detected [50]. The

Sci 2019, 1, 19 10 of 17 the dyes. This leads to a significant increase in the energy of the trans isomer, which becomes close to that of the cis isomer [45,46,51]. The observed dynamic equilibrium depending on the solvent polarity is due to the electrostatic interaction of the dye cation with a counterion in ion pairs formed in low polarity media. The formation of ion pairs in low polarity media leads to a decrease in the energy of the trans isomer and its preferential formation, whereas in polar media the cis isomer is formed, which has a lower energy. The different isomers present in the solution cause a difference in the photochemical properties of meso-substituted carbocyanine dyes in solvents of different polarity. In polar solvents, where the dyes are predominantly in the form of cis isomers, photoisomerization is generally not observed, while in low polarity solvents, in which the dyes are present as trans isomers, photoisomerization to form cis isomers occurs upon photoexcitation. This empirical rule is fulfilled by a series of thia- and oxacarbocyanines with bulky meso-substituents. Upon flash photoexcitation of the carbocyanine dye 9, the signals corresponding to photoisomerization processes were not detected in the polar media (isopropanol), i.e., the cis isomer of 9 was not photoisomerized. In nonpolar dioxane solution, the signals corresponding to trans–cis photoisomerization and subsequent decay of the cis photoisomer of dye 9 were detected [50]. The thiacarbocyanine dye 10, which has Cl as a substituent in the meso-position of the polymethine chain, forms cis isomer by trans–cis photosomerization upon flash photolysis in isopropanol solution [50]. For meso-substituted oxacarbocyanine dyes 3,30-dimethyl-9-ethyloxacarbocyanine (12) and 3,30,9-triethyl-5,50-dimethyloxacarbocyanine (13), the formation of cis photoisomers from their trans forms in aqueous solutions is also detected upon flash photoexcitation. The intensity of the signals of photoisomers of 12 and 13 is much lower than that for their unsubstituted analogue 3, being in the trans form, which can be explained by the presence of a significant admixture of cis isomers of the dyes (in equilibrium with trans isomers), whose photoisomerization does not occur [45,46]. It should be noted that the empirical rule under consideration also found exceptions. First of all, these include the case of two meso-substituted thiacarbocyanine dyes, 3,30-dimethyl- 9-phenylthiacarbocyanine iodide (14) and its analogue, 3,30-diethyl-9-(2-hydroxy-4-methoxyphenyl) thiacarbocyanine iodide (15). For these dyes, the simple empirical rule that we are considering here is not satisfied. The analysis of the absorption, fluorescence, and fluorescence excitation spectra has shown that dyes 14 and 15 in solutions, regardless of the polarity of the solvent, are in the form of trans isomers [52]. Photoisomerization is observed for these dyes even in polar solvents. In particular, upon flash photoexcitation of 14 and 15 in ethanol, the difference spectra of cis photoisomers are observed, the bleaching maxima of which (λ = 560 and 568 nm, respectively) approximately coincide with the positions of the trans isomers in the stationary absorption spectra of the dyes. As in the case of meso-unsubstituted dye 2, which forms cis photoisomer upon photoexcitation [21,24], the stationary absorption spectra of the photoisomers of dyes 14 and 15 are shifted to the short-wavelength side (λmax ~ 550 and 558 nm, respectively). Apparently, for dyes 14 and 15, the substituents in the meso position of the polymethine chain introduce less steric distortion into the structures of the trans isomers than alkyl substituents in the meso-alkyl-substituted dyes [52]. This is probably explained by twisting of the phenyl meso substituents in 14 and 15 relative to the dye chromophore plane, which sharply reduces their distorting effect on the planar structure of the dye chromophore and, hence, on the relative energy of the isomers. Furthermore, for some meso-substituted thiacarbocyanines, photoisomerization of both trans and cis isomers is observed. As an example, dye 8 may be considered, for which both trans cis → and cis trans photoisomerization processes were detected. In solvents of moderate polarity (ethyl → acetate, isopropanol), depending on the photoexcitation wavelength, photoisomerization of either cis or trans isomer of 8 was observed, leading to the formation of trans or cis photoisomer, respectively [50]. The rate constants of thermal cis–trans transitions for ethyl acetate and isopropanol solution of 8 are given in Table1. Since the cis and trans isomers in the solution of dye 8 are in equilibrium, the observed Sci 2019, 1, 19 11 of 17 rate constant of the signal decay corresponds to the sum of the rate constants of cis trans and trans → cis isomerization. → The rate constants of thermal cis–trans transitions for most meso-substituted thiacarbocyanine dyes were found to be much higher than for their unsubstituted analogs (see Table1)[ 21,24]. Such an increase in the rate constants of the thermal back isomerization is due to steric hindrances, which create bulky groups of substituents in the meso position of the polymethine chain. The steric influence of the meso substituents leads to removing terminal heterocyclic groups of dye molecules from the plane, which results in distortion of the valence angles, an increase in the energy of the cis and trans isomers, and a corresponding decrease in the potential barrier of thermal isomerization in the ground state [21]. The observed rate constants for the decay of cis photoisomers of 14 and 15 were rather close to ki for the unsubstituted dye 2 (see Table1), indicating a weak steric e ffect of meso substituents in 14 and 15 on the configuration of the cis photoisomer [52]. This also can be explained by the possibility of turning the phenyl ring of the substituent, which removes the substituent from the chromophore’s plane of the molecule and reduces its steric effect on the configuration of the isomers.

1 Table 1. Thermal back isomerization rate constants (ki, s− ) for photoisomers of carbocyanine dyes.

1 Dye R Solvent ki, s− Ref. Thiacarbocyanine dyes 2 – ethanol 250 [21] 8 OCH isopropanol 1.7 106 3 × 9 C H dioxane ~5 103 [50] 2 5 × 10 Cl isopropanol 1.6 103 × 14 C H 340 6 5 ethanol [52] 15 C7H6OH 865 20 SCH isopropanol 5 105 [53] 3 × Oxacarbocyanine dyes 3 – 9.0 11 C H aqueous solutions 1.5 104 [25] 2 5 × 12 C H 1 104 2 5 ×

8. Isomerization of Cyanine Dyes in Structurally Organized Media It is known that polymethine dyes can form noncovalent complexes with surfactants, polyelectrolytes, biomacromolecules [6,9,10,14,15,18,54–57]. The formation of such complexes, as a rule, hinders the intramolecular degrees of freedom of dye molecules leading to nonradiative dissipation of excitation energy, which results in a drop in the quantum yield of photoisomerization and an increase in the quantum yield of fluorescence [6,9,10,54]. In the case of meso-substituted polymethine dyes, which are characterized by dynamic cis–trans equilibrium depending on the medium, the formation of such complexes can significantly affect the cis–trans equilibrium. In [55], photophysical and photochemical processes occurring in molecules of meso-substituted thiacarbocyanine dyes 3,30-bis(γ-sulfopropyl)-5-methoxy-40,50-benzo-9-ethylthiacarbocyanine (16), 3,30-bis(γ-sulfopropyl)-6,60-dimethyl-9-ethylthiacarbocyanine (17), and 3,30-bis(γ- sulfopropyl)-5- methyl-50-phenyl-9-ethylthiacarbocyanine (18) in aqueous solutions in the presence of cationic (cetyltrimethylammonium bromide), anionic (sodium dodecyl sulfate, SDS) and neutral (Triton X-100) surfactants were studied. In an aqueous solution in the absence of surfactants, dyes 16–18 are in the form of dimers in equilibrium with cis monomers and are not capable of photoisomerization. At surfactant concentrations above critical micelle concentration (CMC), the dimers decompose into monomers, and cis monomers are converted into the trans form upon solubilization of the dye molecules in the surfactant micelles. The resulting trans isomers of the dyes are capable of photoisomerization to form cis photoisomers. Sci 2019, 1, 19 12 of 17

The behavior of meso-substituted polymethine dyes 3,30-di-(γ-sulfopropyl)-4,5,40,50-dibenzo-9- ethylthiacarbocyanine betaine (19, DEC) and 7 was studied in micellar systems of biological surfactants—bile salts sodium cholate, sodium deoxycholate, and sodium taurocholate [56]. Upon binding to micelles of bile salts, as in the case of synthetic surfactants, these dyes are converted into a trans form. Upon flash photolysis of aerated aqueous solutions of the dyes in the presence of micelles of bile salts and SDS, signals caused by photoisomerization of the trans isomers of the dyes and thermal back isomerization of the cis photoisomers formed were observed. The lifetimes of photoisomers of 7 and 19 in the presence of bile salt micelles were in the range of 60–190 µs. In deoxygenated solutions, the appearance of the triplet state of the dyes was also observed. In [57], photophysical and photochemical properties of thiacarbocyanine dyes 2, 3,30-diethyl- 9-methylthiacarbocyanine iodide (20) and 3,30,9-triethyl-5,50-dichlorothiacarbocyanine iodide (21) were studied in the presence of water-soluble polyelectrolytes: polystyrene sulfonate (PSS), polyacrylic acid (PAA), and polymethacrylic acid (PMA). For 2 in the presence of PSS, a significant (tenfold) decrease in the quantum yield of trans–cis photoisomerization (accompanied by an increase in fluorescence and a moderate increase in the intersystem crossing to the triplet state) was observed. Besides surfactants and synthetic polyanions, cationic cyanine dyes are capable of forming noncovalent complexes with DNA. The interaction with DNA hampers the formation of photoisomers of meso-unsubstituted polymethine dyes. In [58], a drop in the yield of the photoisomer of dye 2 was Sciobserved 2019, 1, 19 upon the formation of its noncovalent complex with ds-DNA in a buffer solution. Upon12 flashof 17 photolysis of aerated solutions of meso-substituted thiacarbocyanine dyes 4, 9, 10, 14, 15 in the presence presenceof DNA (withof DNA DNA (with concentration DNA concentration in the range in the of (2.3–5.0) range of (2.3–5.0)10 4 mol × L101−),4 mol signals L−1), of signals photoisomers of pho- × − − weretoisomers not observed were not [50observed,52,53]. [50, Photoisomerization52,58]. Photoisomerization was also hampered was also hampered by noncovalent by noncovalent interaction in- of teractionoxacarbocyanine of oxacarbocyanine dyes 3, 12, 13 dyeswith 3, DNA 12, 13 [ 25with]. Upon DNA flash [25]. photolysisUpon flash of ph aeratedotolysis solutions of aerated of 12solutionsand 13 5 1 −5 −1 withof 12 DNAand 13 at withcDNA DNA= 4.4 at c10DNA− =mol 4.4 L× −10and mol higher, L and the higher, signals the of signals photoisomers of photoisomers were not observed.were not × 4 1 observed.For dye 3 Forwith dyec 3 with= 2.39 cDNA 10= 2.39mol × 10 L−4 mol, the L absorption−1, the absorption intensity intensity of the photoisomerof the photoisomer decreases de- DNA × − − creases2.5 times, 2.5 and times, its lifetimeand its lifetime increases increases 5 times (Figure5 times8 (Figure). 8).

A, ΔA 1 3 0.10

0.05

0.00 400 425 450 475 500 525 550 -1 λ, nm ki, s -0.05 10.0 7.5 2 -0.10 5.0 2.5 -0.15 200 400 600 800 c /c DNA Dye

Figure 8. (1) Absorption spectrum of oxacarbocyanine dye 3 (c = 1.17 10 6 mol L 1) in a phosphate Figure 8. (1) Absorption spectrum of oxacarbocyanine dye 3 (dyecdye = 1.17× × 10−−6 mol L−1) in a phosphate buffer solution in the presence of DNA (c = 7.5 10 5 mol L 1), (2) difference absorption spectrum buffer solution in the presence of DNA (DNAcDNA = 7.5 ×× 10−5 mol L−−1), (2) difference absorption spectrum of the dye photoisomer (c = 6.2 10 7 mol L 1) obtained by flash photolysis in the presence of DNA, of the dye photoisomer (cdyedye = 6.2 ×× 10−−7 mol L−1−) obtained by flash photolysis in the presence of DNA, and (3) reconstruction ofof thethe photoisomerphotoisomer absorption absorption spectrum. spectrum. Inset: Inset: dependence dependence of of the the decay decay kinetics kinet- icsof theof the photoisomer photoisomer of of dye dye 3 corresponding3 corresponding to to back back dark dark isomerization isomerizationon on thethe relativerelative concentration of DNA. of DNA.

Thus, the interaction with DNA and synthetic polyanions hampers the formation of photoisomers in the case of a large number of cationic polymethine dyes, which is explained by the steric factor of complexation, which slows down the nonradiative processes of dissipation of excitation energy. Nevertheless, for some meso-substituted thiacarbocyanine dyes, the formation of photoisomers was enhanced upon the complexation. In particular, in [59], the photophysical and photochemical properties of the meso-methyl-substituted dye 20 were studied in aqueous solutions in the presence of PSS, PAA and PMA. Flash photolysis of 20 in the presence of PAA and PMA revealed a weak signal due to cis → trans photoisomerization of the dye bound to the polyelectrolyte in the cis form and subsequent dark decay of the resulting trans photoisomer (τ = 700 μs at 560 nm). This contradicts the rule that cis isomers of meso-alkyl-substituted carbocyanines are not photoisomerized (dye 20 is not photoisomerized in an aqueous solution without polyelectrolytes). Similarly, in [47], an enhancement of cis → trans photoisomerization of meso-methyl-substituted dyes 7 and 20 by noncovalent binding to DNA and chondroitin-4-sulfate in a buffer solution was shown. Upon flash photolysis of 7 and 20 in the presence of DNA and chondroitin-4-sulfate, signals due to the formation of trans photoisomers and their subsequent dark decay (τ = 3.9 and 2.2 ms for 7 in the presence of DNA and chondroitin-4-sulfate, respectively; τ = 0.7 ms for 20 in the presence of biopolymers, λreg = 560 nm) were observed. To explain the effect of stimulation of photoisomerization of meso-substituted cis isomers by complexation with polyelectrolytes, an assumption was made that the biopolymer matrix of polyelectrolyte affects the potential surfaces of photoisomerization of the dyes: deformation of the potential surface of S1 occurs with a shift of its minimum toward the trans isomer [47,59].

8. Conclusions

Sci 2019, 1, 19 13 of 17

Thus, the interaction with DNA and synthetic polyanions hampers the formation of photoisomers in the case of a large number of cationic polymethine dyes, which is explained by the steric factor of complexation, which slows down the nonradiative processes of dissipation of excitation energy. Nevertheless, for some meso-substituted thiacarbocyanine dyes, the formation of photoisomers was enhanced upon the complexation. In particular, in [59], the photophysical and photochemical properties of the meso-methyl-substituted dye 20 were studied in aqueous solutions in the presence of PSS, PAA and PMA. Flash photolysis of 20 in the presence of PAA and PMA revealed a weak signal due to cis trans → photoisomerization of the dye bound to the polyelectrolyte in the cis form and subsequent dark decay of the resulting trans photoisomer (τ = 700 µs at 560 nm). This contradicts the rule that cis isomers of meso-alkyl-substituted carbocyanines are not photoisomerized (dye 20 is not photoisomerized in an aqueous solution without polyelectrolytes). Similarly, in [47], an enhancement of cis trans → photoisomerization of meso-methyl-substituted dyes 7 and 20 by noncovalent binding to DNA and chondroitin-4-sulfate in a buffer solution was shown. Upon flash photolysis of 7 and 20 in the presence of DNA and chondroitin-4-sulfate, signals due to the formation of trans photoisomers and their subsequent dark decay (τ = 3.9 and 2.2 ms for 7 in the presence of DNA and chondroitin-4-sulfate, respectively; τ = 0.7 ms for 20 in the presence of biopolymers, λreg = 560 nm) were observed. To explain the effect of stimulation of photoisomerization of meso-substituted cis isomers by complexation with polyelectrolytes, an assumption was made that the biopolymer matrix of polyelectrolyte affects the potential surfaces of photoisomerization of the dyes: deformation of the potential surface of S1 occurs with a shift of its minimum toward the trans isomer [47,59].

9. Conclusions The use of polymethine dyes in various fields of science and technology requires a detailed study of their photophysical and photochemical properties. Recently, a lot of works have been published on photophysics and photochemistry of polymethine dyes (see, for example, [11,12,14–16,60–62]). Photoisomerization (followed by back isomerization of a photoisomer) is one of the main properties of polymethine dyes; at present, it is being studied in detail with the use of modern micro-, nano-, pico- and femtosecond techniques. While trans–cis (photo)isomerization of various compounds is widely used in molecular photoswitches, over the past decades, most works have been focused mainly on azobenzene derivatives [63], spiropyrans [64], diarylethenes [65], and stilbenes [66], and, until recently, this property of cyanine dyes has not been applied in practice. The use of cyanine photoisomerization in research is mainly for probing microviscosity of microheterogeneous media [67,68]. On the contrary, rigidization of the polymethine chain of dyes is often carried out by introducing “bridges” that suppress internal conversion and photoisomerization processes to increase the stability of the dyes and the fluorescence quantum yield [17,18,69,70]. It should be noted that the cycle photoisomerization–reverse dark isomerization of the photoisomer is completely reversible and, ideally, does not lead to decomposition of the dye molecule. Since the lifetime of the photoisomer, depending on the structure of the dye and the medium, can vary in very wide range (from seconds to picoseconds), this cycle can be used for transient recording and storage of information within different time ranges in modern information recording systems and devices. So we may expect in future widespread use of polymethine dyes as information storage media in various fields of science and technology. Of great importance is also the dynamic cis–trans isomeric equilibrium, which strongly depends on the molecular microenvironment, observed for meso-substituted polymethine dyes. Since the photophysical and photochemical properties of the cis and trans isomers of such dyes are very different, these dyes can be widely used as probes for studying various molecularly organized and nanostructured systems. Indeed, a number of meso-substituted cyanine dyes have already been used as spectral-fluorescent probes for biomacromolecules (DNA, albumins, etc.) [71–77]. Next in turn is the use of polymethine dyes as kinetic probes, as it has been found recently that the lifetime of the photoisomers of meso-substituted oxonols (anionic polymethine dyes) [78] and squarylium cyanines [79] depend strongly on the polarity of the molecular microenvironment. Sci 2019, 1, 19 14 of 17

In summary, it can be noted that the study of (photo)isomerization and the properties of isomers of cyanine dyes using modern research methods is still relevant both for theory and for the practical application of cyanine dyes.

Author Contributions: P.P. and A.T. collected the data from the literature, analyzed the data, and wrote the manuscript. Both P.P. and A.T. contributed equally to the final version of the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the Russian Foundation for Basic Research (RFBR), grant number 16-03-00735. This work was performed under the Russian Federation State Assignment no. 001201253314. Acknowledgments: The authors are grateful to B.I. Shapiro (Research Center Niikhimfotoproekt) for the supply of the polymethine dyes. Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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