Environment-sensitive behavior of fluorescent molecular rotors
© Haidekker and Theodorakis; licensee BioMed Central Ltd. 2010
Received: 24 June 2010
Accepted: 15 September 2010
Published: 15 September 2010
Molecular rotors are a group of fluorescent molecules that form twisted intramolecular charge transfer (TICT) states upon photoexcitation. When intramolecular twisting occurs, the molecular rotor returns to the ground state either by emission of a red-shifted emission band or by nonradiative relaxation. The emission properties are strongly solvent-dependent, and the solvent viscosity is the primary determinant of the fluorescent quantum yield from the planar (non-twisted) conformation. This viscosity-sensitive behavior gives rise to applications in, for example, fluid mechanics, polymer chemistry, cell physiology, and the food sciences. However, the relationship between bulk viscosity and the molecular-scale interaction of a molecular rotor with its environment are not fully understood. This review presents the pertinent theories of the rotor-solvent interaction on the molecular level and how this interaction leads to the viscosity-sensitive behavior. Furthermore, current applications of molecular rotors as microviscosity sensors are reviewed, and engineering aspects are presented on how measurement accuracy and precision can be improved.
Overview of the most important groups of molecular rotors with the key spectral properties of one representative example.
Relaxation from the TICT state occurs in one of two ways (see Table 1): In the case of DMABN, the S1 - S0 energy gap in the twisted state is large enough to allow photon emission when the molecule returns to the ground state in a twisted conformation. Such a molecule exhibits a distinct second emission band that is red-shifted from the LE fluorescence. DMABN, for example, has a twisted-state energy gap that is approximately 30% lower than the LE energy gap, and relaxation from both LE and twisted conformation leads to photon emission. Conversely, when the TICT energy gap is much smaller than the LE energy gap, nonradiative relaxation occurs from the TICT conformation. In the example of DCVJ, the twisted-state S1 - S0 energy gap is three times smaller than the LE energy gap . Fluorophores of this class exhibit only a single emission band.
The most notable feature of molecular rotors is the dependency of the twisted state formation rate on the local microenvironment, predominantly the microviscosity of the solvent. In the case of molecular rotors that emit from the twisted state with a red-shifted emission band, steric hindrance of the twisted-state formation in higher-viscosity solvents changes the emission in favor of the shorter-wavelength emission from the planar state . In the case of molecular rotors that exhibit nonradiative relaxation from the twisted state, the fluorescent quantum yield increases in higher-viscosity solvents . The molecular and photophysical phenomena that govern this behavior are explained after the next section.
Biological and Chemical Applications of Molecular Rotors
Bulk viscosity measurement of fluids advertises itself as a possible application. Viscosity changes of protein-containing biofluids, i.e., blood plasma and interstitial fluid, have been linked to various diseases  that are mostly associated with altered protein levels. Examples include infections and infarction , hypertension , diabetes , atherosclerosis , and normal aging . Furthermore, one of the adverse effects of smoking is elevated plasma viscosity , which may be the link between cigarette consumption and cardiovascular disease. The viscosity of lymphatic fluid is directly linked to blood plasma viscosity, because the lymphatic system captures fluid and protein that diffused into the tissue and returns it to the vascular system. Lymphatic fluid viscosity is increased, for example, in conjunction with breast cancer treatment , and viscosity changes alter lymphatic fluid circulation during acute shock .
Some progress has been made in providing proof-of-principle for this application  and in demonstrating that measurement precision of an optical method based on fluorescent molecular rotors is comparable to that of conventional mechanical rheometers . However, few studies exist where bulk viscosity of fluids has been measured with fluorescent molecular rotors. A likely reason is the wide availability of established mechanical rheometers . Moreover, fluorescence-based methods are confounded by the optical properties of the liquid, and correction methods are still under investigation . On the other hand, mechanical rheometers are time-consuming due to single measurements requiring measurement times in the range of minutes, they require scrupulous cleaning and are limited to bulk volumes. These disadvantages make fluorescence-based viscsoity measurements an attractive proposition, most notably due to their considerable speed advantage over mechanical methods .
A popular application of molecular rotors is real-time monitoring of aggregation and polymerization processes. Loutfy and Teegarden  demonstrated that the emission intensity of DCVJ, but not its peak emission wavelength, strongly depend on the tacticity of PMMA macromolecules: When DCVJ was embedded in PMMA films, it exhibited a quantum yield of 0.015 - 0.020 in syndiotactic PMMA and a slightly higher quantum yield of 0.018 - 0.025 in atactic PMMA. Quantum yield was markedly increased to 0.036 - 0.049 in isotactic PMMA, leading to the conclusion that the flexibility of isotactic chains is lower than that of atactic and syndiotactic chains. Loutfy  also demonstrated that the quantum yield of a molecular rotor related to DCVJ increased in polystyrene samples with increasing molecular weight. Similarly, Zhu et al.  found that emission of the molecular rotor FCVJ (a hydrophobic ester of (2-carboxy-2-cyanovinyl)-julolidine ) is strongly dependent on the chain entanglement in macromolecules - FCVJ fluorescence intensity accurately reported whether polypropylene oxide melts were in the Rouse or the reptation regime.
Molecular rotors have been used to report protein aggregation and protein conformational changes. Hawe et al.  showed that heat stressing of immunoglobulin-polysorbate 4 preparations changed the balance of DCVJ and (2-carboxy-2-cyanovinyl)-julolidine towards preferentially binding to polysorbate and thus decreasing their quantum yields. Similar observations were not possible with Nile Red . Not only protein aggregation within the rotor's solvent causes the fluorescence to shift towards emission from the planar state, but also binding of the molecular rotor to a protein. In this context, molecular rotors become fluorescent probes for protein conformational changes and protein assembly. Kung and Reed  have shown that DCVJ binds to tubulin, thereby increasing DCVJ quantum yield. DCVJ further increased its fluorescence emission intensity when tubulin aggregated as tubules over tubulin aggregating as sheets . In this study, the peak emission wavelength of DCVJ remained widely constant, indicating that viscosity and polarity do not cause a significant solvatochromic shift, an observation that was later confirmed by our group . Sawada et al.  used a molecular rotor related to DCVJ to noncovalently bind to actin, and observed that the transition from G-actin to F-actin was accompanied by a strong intensity increase form the molecular rotor reporter. Lindgren et al.  examined the folding kinetics of transthyretin, a protein known to misfold and form amyloid deposits in peripheral nerves. The authors found that the molecular rotors DCVJ and thioflavin T preferentially bind to misfolded transthyretin and allow to specifically monitor the formation dynamics of pathogenic transthyretin aggregates.
The characterization of cyclodextrins is another representative area where the ability of molecular rotors to report the properties of the microenvironment plays a key role [37, 38]. Cyclodextrins have a hydrophobic core that can be used to deliver hydrophobic compounds to aqueous environments (e.g., drug delivery) . To optimize cyclodextrins for a particular purpose, the nature of the core region needs to be explored. Dual-emission molecular rotors, such as DMABN, are ideally suited for this task, because emission from the twisted state reports hydrophobicity, whereas emission from the planar state reports on the restricted environment of the core.
Another area where molecular rotors found widespread application is the examination 5 of phospholipid bilayers and cell membranes [40–43]. Lukac , for example, examined several phospholipids that were stained with molecular rotor reporters under varying temperature conditions and found a change in the temperature-dependent behavior: When the phospholipid transitioned from the gel- to the liquid-crystal phase, a blue-shift of the emission was observed when the rotor molecules moved towards the more hydrophobic center of the bilayer as the bilayer "melted" at higher temperature. Moreover, Lukac was able to deduce an apparent bilayer microviscosity for the individual phospholipids. Following the same line of investigation, Nipper et al.  demonstrated that microviscosity, determined through molecular rotor fluorescence, correlates highly with the viscosity determined through fluorescence recovery after photobleaching (FRAP). FRAP is a microscopy method where fluorophore diffusivity in a phospholipid membrane can be determined, thus allowing to estimate microviscosity.
Whereas many fluorescent probes in biology predominantly offer qualitative information, the promise of molecular rotor fluorescence is the quantitative nature of the fluorescent response. In fact, fluorescence emission of molecular rotors can be used to determine the microviscosity of the environment with the same level of rigor as two established methods, FRAP  and fluorescence anisotropy . All three methods are based on diffusion. FRAP is governed by lateral diffusion of a fluorophore into a region where the dye has been destroyed by intense light. Fluorescence anisotropy is governed by the rotational diffusion of a dye that has been excited by polarized light, where rotational diffusion leads to depolarization of the emission light. Rotational diffusion governs the propensity of a molecular rotor to form twisted states and therefore relates diffusivity to fluorescence quantum yield. In this respect, molecular rotors report diffusivity similar to anisotropy probes. However, the dominating factor in molecular rotor emission is the rotation of one segment relative to the other. The segment (such as the dimethylamino group or the dicyanovinyl segment) is generally very small and enjoys greater freedom of rotation than a typical anisotropy probe, such as 1,6-diphenyl-1,3,5-hexatriene (DPH). The relationship between viscosity, rotational diffusivity, and intramolecular rotation makes molecular rotors attractive reporters for the microenvironment, because the sensing of the diffusivity - and with it, microviscosity - can be reduced to simple and rapid spectroscopic intensity measurements .
Photophysical Principles of Molecular Rotors
Interactions of Molecular Rotors with the Environment
where C and x are solvent- and dye-dependent constants. This relationship has been experimentally shown to be valid in a wide range of viscosities and in both polar and nonpolar fluids [15, 34, 40, 54, 55], although deviations exist particularly in the low-viscosity regime that need additional interpretation. Equation 1 has become so popular that in some instances the existence of this power-law relationship has been used to purport TICT behavior of specific molecules [56–59].
where τ0 is the natural lifetime of the fluorophore. To understand the relationship in Equation 1 and the significance of the constants C and x, it is necessary to closely examine the relationship between bulk viscosity, molecular-scale interaction of the molecular rotor with the solvent, and the fluorescence quantum yield.
Quantitative Influence of Diffusion on Tict Behavior
By combining the dye- and solvent-dependent constants k R , kN R,0, and A x into one constant C, Equation 1 readily emerges. It is noteworthy that the rigorous derivation by Förster and Hoffmann - under the assumption of rotational friction according to the DSE model - and the more empirical derivation by Loutfy and Arnold - under the assumption of a power-law microfriction behavior - lead to the same relationship between quantum yield and bulk viscosity. Contrary to the Förster- Hoffmann derivation, however, the exponent x in Equation 23 can vary with the solvent and the molecular rotor molecule.
Deviations from the model can be seen in several instances. Water with its very high polarity reduces the barrier to the TICT state  and causes an anomalous low fluorescence. Polar aprotic solvents, such as dimethylsulfoxide, dimethylformamide, and acetone show a higher DCVJ intensity than predicted by the models, and nonpolar solvents (methylene chloride, benzene and toluene) have an even higher intensity, because nonpolar solvents stabilize the LE state. It can be seen that at low viscosities, other effects than microfriction dominate. Law  has reported that the chain length of short-chain 1-alkanols has a very small effect on the quantum yield, which would corroborate the low viscosity case presented by Förster and Hoffmann (Equation 7). According to Law , long-chain 1-alkanols also deviate from the models (light blue dotted line in Figure 3), because the alkane chain becomes the main determinant of intramolecular rotation, and the viscosity of alkanes is known to be much lower than that of the corresponding 1-alkanols.
In summary, rotational diffusivity is the most important determinant of intramolecular rotation rate and therefore a molecular rotor's quantum yield. However, when the intramolecular rotation rate becomes very high in solvents of low viscosity, additional effects, such as hydrogen bond formation, excimer formation, and polar-polar interaction are no longer negligible and cause significant deviations from established models that describe the relationship between quantum yield and viscosity.
Engineering Aspects of Molecular Viscometers
There is a growing need for viscosity reporters with microscopic resolution and ultrafast response. Due to the nature of the twisted-state formation, which takes place within tens of picoseconds , a molecular rotor reports changes in the local microviscosity almost instantaneously. Since molecular rotors are affected only by their immediate microenvironment, they can be used to report spatially resolved microviscosity with resolution limited only by the optical equipment. These two features explain the popularity of molecular rotors in cell and vesicle research [40, 43–45, 69–73]. Furthermore, molecular rotors enjoy high popularity as real-time probes of polymerization processes [62, 74, 75], where one reason is the poor suitability of conventional methods due to their invasive nature and associated destructiveness, and their poor accuracy . Conversely, molecular rotors allow in situ probing. Other potential areas of application are food science, for example, the crystallization behavior of lactose  or the behavior of soy flour according to the Williams-Landel-Ferry model , and the measurement of bulk viscosity of biofluids, where short measurement and turnaround times may accelerate serial viscosity measurement by orders of magnitude . The key to these applications is the potential of a quantitatively accurate measurement.
Steady-State Spectroscopy and Intensity Measurements
Correction for fluid optical properties becomes even more complex when the dye concentration is high and when the solvent absorption is strongly wavelength-dependent. The presence of scatterers further complicates the correction. In two relatively simple cases of forward-scattering microspheres and of starch solutions, the average excitation path length was found to be increased, and the presence of the scatterer increased fluorescence intensity. By measuring the scattering intensity, a corrected fluorescence emission was found that almost completely eliminated the influence of the scattering agent . Higher scatterer content, however, would again reduce the measured intensity, and additional studies need to be performed to obtain correction formulas or algorithms for different types and concentrations of scatterers, and for combinations of scatterers and absorbers.
Natural lifetimes for some molecular rotors have been found to be between 3 ns and 4 ns [15, 64], and actual lifetimes can be in the low picosecond range for low-viscosity solvents . To accurately measure such short lifetimes, relatively sophisticated instruments are required, which can be very expensive compared to simple steady-state instruments.
Moreover, lifetime measurements may reveal multiexponential decay behavior. Vogel and Rettig  found double-exponential decays in triphenylmethane dyes and attributed the two decay components to DSE and free-volume diffusion, respectively. Law  reported that solvent diffusional rotation causes shorter measured lifetimes. Multiexponential relaxation dynamics that were dominated by solvent relaxation constants were also found by Dutta and Bhattacharyya , who reported lifetime constants in the low picosecond range and in the low nanosecond range, whereby the nanosecond range carried significant information about the type of solvent. Hara et al.  found triple-exponential decay functions when they applied pressure to the solvents to cause a pressure-induced viscosity increase. The analysis of lifetime experiments is complex, because many levels of solvent-rotor interaction, such as diffusion, electrostatic and polar interaction, and hydrogen bonding influence the lifetime dynamics and lead to complex decay patterns. This level of complexity cannot be seen in steady-state experiments. Whereas steady-state measurements can be confounded by solvent- and instrument-related factors, lifetime experiments are affected by the complex rotor-solvent interaction. More research is needed to separate and interpret the lifetime components and find an accurate relationship to the solvent's microviscosity.
On the other hand, spatially-resolved lifetime measurement, for example, fluorescence lifetime imaging microscopy (FLIM)  is a promising method, and in many cases a simplified lifetime-viscosity relationship (Equation 27) is sufficiently accurate for physiological studies. The major advantage of FLIM over steady-state fluorescence microscopy is its in-dependence from local dye concentration gradients, which makes FLIM an ideal method for studies in living cells [56, 57]. With the exception of very expensive and advanced devices, FLIM is limited to single-exponential decays , and the complexity of the decay dynamics described in the previous section is difficult to reproduce.
Ratiometric Measurements and Self-Calibrating Dyes
Molecular rotors are a twisted-state-forming subgroup of intramolecular charge transfer fluorophores. The twisted-state formation rate is strongly dependent on the environment, most dominantly on the local diffusion coefficient. Two overarching groups of these fluorophores are those where relaxation from both LE and twisted states are associated with photon emission, and those where relaxation from the twisted state occurs radiationless. The former show a dual- band emission with a strong polarity-dependent solvatochromic shift and very strong dependency of the twisted-state emission band (the red-shifted band) on both polarity and viscosity of the medium. The latter show single-band emission from the LE state with a highly viscosity-dependent quantum yield. The viscosity-dependent emission is hypothesized to be related to rotational diffusion, although different theoretical treatments of the viscosity-dependence exist. Apart from viscosity, solvent polarity, hydrogen bond formation and excimer formation also play a role in the spectroscopic properties of molecular rotors. These complex interactions with the environment provide one impediment to using molecular rotors as fluorescent microrheometers. However, at viscosities above 2 mPa s, steric hindrance dominates twisted-state formation, and viscosity becomes the singularly most dominant factor to influence the molecular rotor's quantum yield. A power- law relationship between quantum yield and viscosity is most widely used, and this relationship is confirmed by experimental observation over more than three orders of magnitude of solvent viscosity. With molecular rotors, viscosity measurement can be reduced to either intensity measurements or fluorescent lifetime measurements. A particular strength of the fluorescent method lies in the ability to spatially resolve the emission (fluorescent imaging) with applications in biology, cell physiology and polymer chemistry. However, there are confounding factors that deserve further research. First, the optical properties of the microenvironment can influence the emission signal, and the emission needs to be corrected for absorption and scattering to obtain accurate microviscosity information. Second, the constants in the power-law relationship between quantum yield and viscosity require calibration for each fluid type. Most notably, the exponent × was found to be a constant of x = 2/3 by Förster and Hoffmann, but can be variable according to the free-volume theory by Loutfy et al. Further research into the rotor-solvent interaction will likely illuminate the constants used in the relationship between quantum yield and viscosity and therefore increase the accuracy with which the microvisocsity can be measured with molecular rotors.
The authors gratefully acknowledge research support from the National Institutes of Health through NIH grant 1R21 RR 025358.
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