Optimized synthesis and detailed NMR spectroscopic characterization of the 1,8a-dihydroazulene-1,1-dicarbonitrile photoswitch

An economical and effective protocol for large scale synthesis of the 2-phenyl-1,8a-dihydroazulene-1,1-dicarbonitrile (DHA) photoswitch has been developed. This compound is ring-opened by light to a vinylheptafulvene (VHF), which is thermally closed back to DHA. This compound serves as an important starting material for dihydroazulene photoswitches incorporating a substituent in the seven-membered ring and as a reference compound for comparison of properties. A detailed NMR spectroscopic characterization has allowed the assignment of all proton and carbon signals. In addition, the compound was characterized by X-ray crystallography. A correlation between the rate constant for thermal ring-closure of VHF to DHA and empirical parameters of solvent polarity ( E T 30) was established.


Introduction
Molecular switches possess at least two reversible interconvertible states. 1 A photochromic switch is a system where at least one of the conversions is light-induced. 2 These systems are particularly interesting within the fields of molecular electronics, materials science, supramolecular chemistry, and biotechnology. 3Systems such as the azobenzene 4 and the dithienylethene 5 show great potential as future building blocks within molecular electronics.We have become interested in the dihydroazulene/vinylheptafulvene system (Scheme 1). 6DHA undergoes a light-induced ring-opening reaction to VHF that in turn undergoes a thermal ringclosure back to DHA.A wide variety of derivatives has been synthesized, incorporating both electron-withdrawing and -donating groups in the five-membered ring 7 and very recently also in the seven-membered ring. 8To exploit the DHA/VHF system in molecular electronics a handle in both the sevenmembered and the five-membered ring is needed.We reported in 2009 a procedure for incorporating a bromine atom selectively at C-7 (Figure 1) of the seven-membered ring of the DHA.8a This functionality was next employed for incorporation of an arylethynyl group at C-7 by a Sonogashira cross-coupling reaction.8b Studies on electron-donating and -withdrawing aryl substituents have shed light on the mechanism for the ring-closure reaction.8b Thus, the first step of ring-closure involves a change of conformation from an unreactive s-trans to a reactive s-cis conformation (Scheme 1) and the ring-closure goes through a zwitterionic transition state or intermediate. 8The kinetics of the ring-closure was shown to follow a Hammett correlation when plotting ln(k) against σp + (Hammett constant including through-conjugation). 8b The most advanced systems actually provide the possibility to control the switching abilities by the redoxstate of the substituent, 9 or by the pH of the solution.8b CN NC 8 8a 7 The DHA photoswitch has been much less studied than the two aforementioned systems.This is most likely due to the lack, until recently, of a protocol for functionalizing the system in both the five-and seven-membered rings.Moreover, access to DHA in large scale is a prerequisite for its wider applicability in advanced systems.2-Phenyl-1,8a-dihydroazulene-1,1dicarbonitrile 1 was one of the first photochromic DHAs to be reported by Daub and coworkers. 10Different synthetic protocols for obtaining DHAs were developed.One protocol involves a [8+2] cycloaddition between 8-methoxyheptafulvene and a derivative of 1,1dicyanoethylene, followed by elimination of methanol (Scheme 2). 10 In this route the DHA is formed directly in the final elimination step.In another route, the VHF precursor was first prepared. 11The first step was here an acid-catalyzed nucleophilic addition of an acetophenone derivative to tropylium tetrafluoroborate.A Knoevenagel condensation with malononitrile, followed by hydride and proton abstractions, or by oxidation with DDQ or chloroanil, 11 provided the corresponding VHF that was then thermally converted to DHA.This protocol however had some limitations, for synthesis of multigram quantities. 12A convenient modification was developed by Gobbi et al. 12 by performing the Knoevenagel condensation between the acetophenone derivative and malononitrile already in the first step.A subsequent nucleophilic addition under alkaline conditions to the tropylium ion followed by hydride and proton abstractions then generated the VHF, the immediate precursor for the DHA.This method was used to prepare 2-(4'-iodophenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile 2 in a ca.5-g scale (DHA with R = 4-iodophenyl in Scheme 2).We have optimized this procedure for large scale synthesis (ca.15 g) of the simple 2-phenyl-1,8a-dihydroazulene-1,1-dicarbonitrile 1 (DHA with R = phenyl in Scheme 2), which is the starting material for our regioselective functionalization of DHA. 8 In addition, its detailed characterization by both 2D-NMR spectroscopy and X-ray crystallography will be presented.Moreover, we have looked in more detail on the thermal conversion of VHF and the possibility for establishing a correlation with empirical solvent polarity parameters.

Results and Discussion
An optimization of the original cycloaddtionelimination route was deliberately avoided.The first step of this procedure is an oxidation of cyclooctatetraene by either Hg(OAc)2 13 or by electrolysis 14 (not shown in Scheme 2); one is toxic and the other inconvenient.Instead the first objective was to optimize the synthesis of the precursor for the VHF using the simple starting materials malononitrile 3, acetophenone 4, and tropylium tetrafluoroborate 5.It was found that the order of Knoevenagel and nucleophilic addition reactions was important.Thus, it was advantageous to prepare the crotononitrile derivative 6 before 7 (Scheme 3) since the latter is not stable under the required reaction conditions of the Knoevenagel condensation.On the other hand a Knoevenagel condensation between 3 and 4 in the presence of AcOH and NH4OAc gave 6 in high yield (Scheme 3).When following the analogous procedure of Gobbi et al., 12  Scheme 3. Synthesis of crotononitrile derivative.
The final steps leading to DHA 1 are shown in Scheme 4. Compound 7 was oxidized in two steps.Thus, hydride abstraction with tritylium tetrafluoroborate followed by elimination with Et3N gave the VHF 9. Heating this compound in the dark for 1 hour at 80 o C promoted ringclosure to furnish the DHA 1 as a pair of enantiomers.The synthesis can be done in large scale (15 g) and does not require purification before the last step.While optimizing and scaling up the synthesis, the total amount of solvents used for the three steps was reduced from 2.2 L to only 750 mL, and by using this convenient protocol the product (ca.15 g) can be purified using dry column chromatography. 16This chromatographic work-up can be done with less than 2-L of technical solvents and a subsequent recrystallization from either heptanes or ethanol (96 %) makes it overall an economical and efficient purification.The crystalline product is very stable and can be stored at ambient conditions for years with no need to exclude it from light.It can be kept in solution, in the dark, for months without decomposition.The compound can also be sublimed without decomposition.
The structure of crotononitrile derivative 7 was solved by 2D-NMR spectroscopy and X-ray crystallography (Figure 2).Because of overlapping signals, the proton signals could not be unambiguously assigned by COSY-NMR.But an NOE was seen between a singlet (assigned to H3) and a doublet (assigned to H4).By TOCSY1D H5, H8, and H8a were assigned as shown in Figure 4 (left).The structure of the DHA 1 was solved by 2D-NMR spectroscopy and X-ray crystallography.The seven-membered ring adopts a boat form where the C7-C8 double bond is twisted out of the plane (Figure 5), which is characteristic for DHAs.This conformation explains the similar absorption spectra, previously observed, for DHAs incorporating a substituent at position C-7.It remains a challenge when synthesizing new functionalized DHAs to unambiguously prove in which position a group is attached in the seven-membered ring.For this reason, we subjected DHA 1 to a detailed NMR analysis ( 1 H-, 13 C-, COSY-, 1 H / 13 C HMQC-and 1 H / 13 C HMBC-NMR, Figure 6) in order to assign all of the signals in the spectrum of this parent DHA as listed in Table 1.The simple DHA 1 and its corresponding VHF are conveniently used as reference compounds when comparing the rate constant for the thermal back-reaction of newly synthesized DHA/VHFs.For this reason the back-reaction of the VHF of 1 was restudied in our lab to make sure that the already reported values 7 are compatible under our precise conditions.A solution of DHA 1 was irradiated at its absorption maximum and according to UV-Vis and NMR the compound was completely converted to VHF 9. Heating the sample resulted in a clean conversion back to DHA and the thermal back-reaction was followed by UV-Vis and NMR using a kinetics program.The absorption spectra of DHA and VHF and the thermal backreaction in acetonitrile are shown in Figure 7.The rate constant at 25 °C was generally calculated by extrapolation from an Arrhenius plot or directly measured and for a series of solvents the activation energy and the pre-exponential factor was calculated using the Arrhenius equation.The data are collected in Table 2.In accordance to Daub's findings, 7 the back-reaction was faster in polar solvents than in non-polar solvents.In fact we found that the rate constant of the back-reaction was 12 times larger in the polar solvent EtOH than in the non-polar solvent cyclohexane.As shown in Figure 8 a linear trend was observed when plotting ln(k25°C) against the ET(30) value 17 of the solvent.This trend supports a mechanism via a zwitterionic structure as suggested previously by Daub and coworkers. 18Interestingly, the activation energy is only affected to a small degree by the solvent polarity (Table 2), which is, however, somewhat in disagreement with previously reported data. 7nstead, our data show that it is mainly the pre-exponential factor that causes the variation in the rate constant (i.e., an entropy effect).Thus, in a polar solvent there are smaller entropy constraints for the proper reaction geometry (more successful encounters).This is likely explained by the fact that electrostatic attraction between opposite charges in a zwitterionic structure (already promoted to some degree in the ground state by a polar solvent) results in some degree of preorganization (ion-pairing) for intramolecular cyclization.Another experiment was conducted by following the VHF conversion by 1 H-NMR spectroscopy.By plotting the change in the relative integral of a specific VHF-signal against time, the rate constant was measured in CD3CN.At 25°C, this rate constant (k25°C = 5.39 x 10 -5 s - 1 ) was almost identical to that measured by UV-Vis spectroscopy (k25°C = 5.36 x 10 -5 s -1 ).The rate constant was also measured in C6D6 at 40°C and the NMR-spectra are showed in Figure 9.A series of other control experiments were conducted, and a selection of these is explained in the experimental section.

Conclusions
In conclusion, we have developed a high-yielding route with easy work-up procedures for the preparation of 2-phenyl-1,8a-dihydroazulene-1,1-dicarbonitrile.This optimization is important as the compound serves as the parent compound for direct incorporation of a functional group in the seven-membered ring of DHA, using an earlier developed regioselective brominationeliminationcross-coupling protocol.Both this compound and its crotononitrile precursor were subjected to detailed NMR and X-ray crystallographic analyses.In this way, all NMR signals for the ring-protons were unambiguously assigned.The influence of solvent polarity on the thermal ring-closure of VHF was investigated in relation to solvent parameters, providing a linear correlation with the ET(30) parameter.Moreover, it is an increase in the Arrhenius preexponential factor that first of all causes fast ring-closure in polar solvents; this observation implies that entropy effects are in play.

Kinetic studies
A stock solution of DHA 1 was prepared by dissolving a sample in the given solvent (cf., Table 2).This stock solution was then further diluted until the absorption level was within the limits of the instrument.The sample was then irradiated with light at the DHA absorption maximum in the given solvent until no change in the absorption spectrum was observed.The sample was then heated and an absorption spectrum was measured against time (Figure 7) using a kinetics program, until at least three half-lives had passed.The cycle was repeated for at least four different temperatures.The change in absorption at the VHF absorption maximum was plotted against time, and the rate constant for the back-reaction at each different temperature was calculated (first-order kinetics).From an Arrhenius plot (shown in Figure 10 based on data given in Table 4), the activation energy Ea, the pre-exponential factor A, and the rate constant at 25 °C were calculated (if not measured directly at this temperature).We note that the small light irradiation from the UV-Vis apparatus (causing reformation of VHF) can be neglected.Thus, a series of control experiments were conducted in order to confirm that our setup did not tamper with the reaction conditions.The thermal back-reaction was followed by scanning both the VHF absorption decrease and the DHA absorption appearance by UV-Vis spectroscopy.Thus the calculated rate constant at 25 °C in acetonitrile (obtained at normal procedure, by extrapolation with an Arrhenius plot) was compared to the measured value (without scanning the DHA-absorption).No difference was found.In addition two almost identical experiments were conducted in toluene at 40 °C (scanning every 10 minutes), with and ARKAT-USA, Inc without scanning the DHA absorption region.This experiment showed only a small difference in the measured rate constant (k40°C = 4.00 x 10 -5 s -1 compared to k40°C = 3.89 x 10 -5 s -1 ).

X-Ray crystallography
A list of C-C and C-N bond lengths (except for the phenyl ring) for DHA 1 is provided in Table 5.

Figure 4 .
Figure 4. Coupling pattern and 1 H / 13 C HMQC-NMR spectrum of VHF 9 recorded in C6D6.Numbering according to DHA numbering.Assignment of signals can be found in the experimental section.

Figure 7 .
Figure 7. Absorption spectra of DHA 1 and its corresponding VHF 9 in MeCN (left).Absorption spectra for the thermal ring-closure (VHF→DHA) measured every minute at 60 °C in MeCN (right).

Figure 8 .
Figure 8. Rate constant dependency on solvent polarity; ln(k25°C) plotted against ET(30).The best straight line describing our data is inserted (i.e., data from Ref. 7 are not

Figure 9 .
Figure 9. Stacked 1 H-NMR spectra of the thermal conversion from VHF to DHA acquired in benzene-d6 at 40 °C (showed with 40 minutes interval).Note the decay of VHF signals at δ = 5.55 -5.37, 5.06 ppm and rise of DHA signal at δ = 3.45 ppm.

Table 2 .
Absorption maxima for DHA 1 and its corresponding VHF 9, and kinetic data for the thermal back-reaction in different solvents.Where Ea and A are left out, the rate constant was only measured at 25 °C a Quantum yields of light-induced ring-opening taken from Ref. 7. b Ref. 17. b Uncertainty less than ± 0.004.

Table 4 .
Measured rate constants (x 10 -5 s -1 ) for the back-reaction in different solvents, on which the Arrhenius plots are based

Table 5 .
List of DHA bond lengths for 1 (C-H and phenyl C-C / C-H not listed).For atom labeling, see Figure1