New Acylhydrazone Photoswitches with Quantitative Conversion and

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Functional Nanostructured Materials (including low-D carbon)

New Acylhydrazone Photoswitches with Quantitative Conversion and High Quantum Yield but without Hydrogen Bond Stabilizing (Z)-Isomer Ying-Xue Yuan, and Yan-Song Zheng ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b21719 • Publication Date (Web): 24 Jan 2019 Downloaded from http://pubs.acs.org on January 29, 2019

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ACS Applied Materials & Interfaces

New Acylhydrazone Photoswitches with Quantitative Conversion and High Quantum Yield but without Hydrogen Bond Stabilizing (Z)-Isomer Ying-Xue Yuan† and Yan-Song Zheng†* Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China. †

ABSTRACT: Hydrazones are recently attracting increasing interest due to their facile synthesis and high addressability, fatigue resistance and modifiability as molecular switches. However, this new class of switches generally suffer from low conversion from E to Z-configuration. Here novel benzoylhydrazones were synthesized by condensation of 2-methoxynaphthaldhyde and benzoylhydrazine. In this hydrazone system, both sides of the imine double bond had large steric hindrance, so that (E)-isomer of the benzoylhydrazones were less stable and easily converted into (Z)-isomer even without intramolecular hydrogen bond. Up to 99% conversion efficiency and 89% quantum yield were obtained, in addition to excellent addressability and high fatigue resistance. Outstandingly, crystal structure of one (Z)-isomer disclosed no intermolecular hydrogen bonds between molecules of (Z)-isomer but strong and sequential hydrogen bonds between those of (E)-isomer. Therefore, (E)-isomer was less soluble in solvent than (Z)-one. This molecular switch system could be easily modified by both hydrophilic pentaethylene glycol chains and hydrophobic octyl chain. Under light irradiation, the resultant amphiphilic acylhydrazone could be transferred from (E)-isomer to (Z)-isomer in more than 90% yield even in water after light irradiation. Meanwhile, the self-assembled big nanospheres could rearrange into much smaller vesicles due to solubility difference of (Z)- and (E)-isomers. After anticancer drug procarbazine (PCZ) was loaded by this kind of acylhydrazone in water, it could be released by light irradiation, showing potential application in photocontrollable drug release.

Keywords: Benzoylhydrazone Photoswitches; Quantitative E/Z Conversion; Significant Deformation of Isomers; Photocontrollable Nanoparticle Change; Photocontrollable Drug Release INTRODUCTION

(Z)-isomer is often very unstable and is inappropriate for photoswitches.29−30 Only after appearance of 1,2,3-tricarbonyl-2-arylhydrazones which make (Z)-isomers stabilization by intramolecular hydrogen bond, the hydrazone can be used as photocontrollable switches.31 Later, Lehn et al. report that arylhydrazones prepared from condensation of pridyl-2-aldehyde or quanoline-2-aldehyde with corresponding hydrides also form intramolecular hydrogen bond in their (Z)-isomer, leading to effective transformation of (E)-isomer to (Z)-isomers under light irradiation.32 In contrast, no E−Z isomerization is observed for pyridyl-4-hydrazones without intramolecular hydrogen bond. By connecting both 2-pyridyl and carbonyl groups at double bond carbon of one hydrazone, Aprahamian et al. entrusted two sets of intramolecular hydrogen bonds to the hydrazone.33−36 In this case, even pH can drive E−Z isomerization when nitrogen-involved intramolecular hydrogen bond is broken by added acid and carbonyl-involved one gets the run upon. By making use of H-bonding stabilization of (Z)-isomer, the hydrazone configural switches can be used as color manipulation of

Molecular photoswitches displayed great potentials in information storage,1−6 photoactuators,3−4,7−10 11−13 photopharmacology, remote-controllable reactions,14−15 single-molecule localization microscopy,16−17 photogated electrical devices,18−20 controllable drug transport and release,21−24 selective dual-channel imaging,25 acidic sensing materials26 et al., and attract more and more attentions. Among the switchable molecules, azobenzens,27 cyanostiblene,25-26 diarylethenes,2−3 and spiropyrans28 are extensively and successfully studied for smart materials responding to light. To address the challenges met in the development of molecular photoswitches, especially application bottleneck of molecular switches, recently, a new class of molecular photoswitches based on hydrazone compounds are blossoming due to their facile synthesis, modularity, functional diversity, and fatigue resistance.29−30 The E−Z isomerization of C=N bonds in hydrazone under light irradiation has been known for long time, but the 1

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liquid crystals,37 photocontrollable phase separation,38 small-molecule robotic arm,39 proton relays,40 waste management,41 dynamic signaling cascades,42 negative feedback loop,43 network switching process,44 45 multi-stimuli-responsive fluorescence switch, photo-gated transmembrane channel,46 programmable molecular machine,47 and so on. Very recently, by optimizing the intramolecular hydrogen bonding interactions, the hydrazone photoswitch was found to give exceptionally thermostable (Z)-isomer with half life of 2700 years.48 Noticeably, acylhydrazones, which were especially easily prepared on large scale, displayed widely tunable photoswitch performance besides high addressability, high fatigue resistance and high modifiability.49−53,32,38 Hecht et al. reported over 40 acylhydrazones and conducted a systematic study on their photochromic properties as structural change.49 It was found that some of them had high E-Z conversion efficiency from 51% to 82% when they possessed intramolecular hydrogen bond that could stabilized the (Z)-isomer. By forming rotaxane with tetramide macrocycle, acylhydrazone showed increase of E-Z conversion efficiency from 91% to 98%, which provided higher switch fidelity.50 Moreover, acylhydrazone photoswitches could even be controlled by redox reaction, demonstrating that acylhydrazone are robust as a switch.51 However, all the acylhydrazones used in these studies are ones with intramolecular hydrogen bond that can stabilize the (Z)-isomer. Most of them show low E−Z conversion under light irradiation if no intramolecular hydrogen bond existed. Up to now, for hydrazone photoswitches, to access very high and even quantitative E-Z isomerization is still a challenge, although several rare examples for other molecular photoswitches with high E/Z conversion have been reported.54−57 Moreover, even some molecular photoswitches display quantitative E/Z conversion in organic solvent, but the conversion is very low in water due to the large dielectric constant of water.54 In addition, the long distance and less hindrance between substituents at two ends of C=N double bond of hydrazone photoswitches resulted in small deformation of the molecules after light irradiation, which is not helpful for some applications such as actuator. Here, we report that acylhydrazones, with destabilization of their (E)-isomers due to large steric repulsive forces instead of (Z)-isomer stabilization by intramolecular hydrogen bond, can be used as molecular photoswitches with significant deformation and almost quantitative conversion both in organic solvent and in water, which could be used to load and controllable release of anticancer drug. RESULTS AND DISCUSSION The benzoylhydrazone photoswithches (Scheme 1) were straightforwardly synthesized by condensation of benzoylhydrazine and 2-methoxy-1-naphthaldehyde which were easily prepared from commercially available starting

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materials in excellent yield. Except for hydrazone 8 (Scheme S3) and 9 (Scheme S4) which was viscous liquid, all other hydrazones (Scheme S1 and Scheme S2) were purified only by recrystallization, meaning that they would easily be obtained on large scale. From 1H NMR spectrum measurement of hydrazone 1, the hydroxyl group showed signal at very low field of 12.80 ppm (Figure S1). This suggested a strong intramolecular hydrogen bond of hydroxyl with imine nitrogen. After hydroxyl group was methylated in hydrazone 2, the C=N double bond changed ponting direction from naphthoxyl oxygen atom to carbon atom at position 8 (C8) due to steric hindrance of methoxyl group although the benzo moiety also had repulsive force to the imine group (Figure S4 − S39). The NMR signal of proton at C8 displayed a distinct lower-field shift from 8.00 ppm to 9.44 ppm after methylation, indicating an intramolecular hydrogen bond between imine nitrogen and C8-H. But the intramolecular hydrogen bond should not be very strong because of less polarity of C-H bond than that of O-H bond, which could be proved by the not very large chemical shift change. The reported crystal structure of 6 corroborated that it existed in (E)-configuration with weak intramolecular hydrogen bond between imine nitrogen and C8-H (2.351 Å hydrogen bond and dihydral angle of 34.87o between imine double bond plane and naphthyl ring).58 For (E)-7, they were about 2.457 Å and 40.97o, respectively, as shown in Figure 3C. Therefore, the (E)-isomer of methylated hydrazones 2 − 9 had a large repulsive force between C=N double bond and methoxyl group. Scheme 1. Structure of benzoylhydrazone compounds. The numbers on the structure indicate the different carbon and corresponding hydrogen atoms of naphthyl moiety. F

O 8

HN N

NH N 1

7

O

O

OH

5

1

4

3

HN N

O

O

HN N

O

O

O

O O

HN N O

O O

7

O

O 5

HN N

5

5

O

HO 5OH

O 5

HN N

O

O

O

5 5OH

N N O

O 8

OH

O

OH

O

O HO

O

4

3

2

O

6

HN N

2

6

HN N

O

CN

12

O O

O 9

10

Under irradiation of a portable 365 nm UV lamp for 2 h, hydrazone 1 showed no any change in its 1H NMR spectrum (Figure S40), indicating that the (E)-isomer of 1 could not be transferred into (Z)-isomer. In sharp contrast, under the same condition, hydrazones 2, 3, 4, 5, 6, 7, 8 and 9 displayed obvious E−Z isomerization which could be identified by 1H NMR in DMSO-d6 (Figure S41 – S48). Almost all proton signals displayed distinct change after irradiation. Especially, the proton signals of amide, C8-H,


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imine, and benzoyl ring showed a significant up-field shift after 365 nm UV light irradiation (Figure 2 and Figure S41 – S48). For example, the signals of amide, C8-H, imine, and benzoyl ring in hydrazone 6 had an up-field shift from 11.83 to 10.18 ppm, 9.44 to 7.97 ppm, 9.16 to 8.02 ppm, and 7.08 to 6.91 ppm, respectively. Conspicuously, the C8-H signal came back to the normal aromatic proton resonance position after irradiation, suggesting that the C8-H-involved intramolecular hydrogen bond was broken (Figure 2a – 2b). 2D H-H COSY NMR spectra of as prepared and irradiated 6 confirmed the E to Z configuration change after irradiation by 365 nm light (Figure S51 – S52). R

11

HN10 O N 9 H H

8

7

1

O 10' N 9'

365 nm or 380 nm light  or 288 nm light

O

N H

11' 8' 7'

R

2 3

6 5

H

1'

O 2' 3'

6' 5'

4'

4

(Z)-hydrazone

(E)-hydrazone

8

10

11

9

11'

8' 10' 9'

8 10

9

11

N-methyl hydrazone 10 also showed 83% E−Z conversion although the N-methyl group resulted in more strain in (Z)-isomer due to large steric hindrance at both side (benzo moiety and methoxy group) of the imine double bond (Figure S49). Even with a long-chain tetradecyl group at C6 position that could increase isomerization difficulty, the E/Z conversion was up to 80%. When the (Z)-isomers of 6, 7, 8 and 9 were heated at 90 oC for 2 h, they could revert to (E)-isomer in 100% yield (Figure 1c and Figure S45 − S48). When the solution of (E)-isomers of the benzoylhydrazones in DMSO was irradiated by 380 nm UV light (which is from a fluorophotometer and is more efficient than 365 nm light from a portable UV lamp), the absorption band in absorption spectrum at long wavelength gradually decreased and one at short wavelength increased with irradiation time. When the concentration was at several mM or more, an obvious color change from light yellow to colorless in solution could be observed. As shown in Figure 2A − 2B, the absorption bands of (E)-6 between 305 nm − 400 nm (max 365 nm) displayed a gradually abated absorbance while one between 270 nm – 305 (max 275 nm) raised constantly when it was continuously exposed to 380 nm light. This result demonstrated that these benzoylhydrones were negative photochromic compounds, which would be helpful for E-Z conversion in bulk materials such as crystals, film and liquid crystals.59When the obtained (Z)-6 was irradiated by 288 nm, the band at max 365 nm raised while the band at max 275 nm decreased with irradiation time, indicating that (E)-6 could be regenerated under irradiation of UV light having shorter wavelength (Figure 2C). The separation between two absorption maximum wavelengths demonstrated that the hydrazones had good ability to address photochemically both Z/E isomers

By comparing the signal intensity of amide proton before and after irradiation, hydrazones 2, 3, 4, 5, 6, 7, 8 and 9 showed E−Z conversion of 90%, 60%, 58%, 96%, 99%, 99%, 98% and 80%, respectively (Figure S41 – S48). For hydrazones 6 − 8 with electron-donating benzoyl moiety, the E-Z conversion was in the range larger than 98%, which was almost quantitative and very rare among hydrazone photoswitches and even among all other molecular switches. For hydrazones 3 and 4 bearing electron-deficient substituent on benzoyl part, the conversion was obviously low probably due to excited state energy transformation from imine double bond to benzoyl ring. Upon replacement of hydrogen of amide group by methyl group, the resultant

1.2 0.8 0.4 0.0 250

300 350 400 Wavelength (nm)

1.10

B 0.8


450

0.6

1.05

0.4 1.00

0.2 0.0 0

10 20 30 40 50 60 70 80 Irradiation time (min)

0.95

Absorbance at 275 nm

Figure 1. Reaction equation of E/Z isomerization of the benzoylhydrazones and 1H NMR spectra of 6 in DMSO-d6 (a) as prepared, (b) irradiated by a portable 365 nm UV lamp for 2 h, and (c) heated at 90 oC for 2 h after (b).

Absorbance

A 1.6


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



1.14



C 0.6 0.5

1.11

0.4

1.08

0.3

1.05

0.2 0.1

1.02 0

5 10 15 Irradiation Time (min)

20

D 1.0 Absorbance (a. u.)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

0.8 0.6 0.4 0.2 0.0

0

2

4

6 Cycles

8

10

12

Figure 2. (A) Change in the absorption spectra of (E)-6 in DMSO with irradiation time by 380 nm UV light. (B) Absorbance change of (E)-6 at 365 nm (black) and at 275 nm (red) with irradiation time of 380 nm UV light. (C) Absorbance change of (Z)-6 at 365 nm (black) and at 275 nm (red) with irradiation time of 288 nm UV light. (D) Absorbance change of 6 in DMSO at 365 nm upon alternating irradiation and heating. [6] = 6.0 × 10-5 M.

Due to almost quantitative Z to E conversion, some photophysical performance of 6 − 8 was easily measured. The molar absorptivity of (E)-isomers of 6, 7, and 8 was 13083, 12576, and 12874 M-1∙cm-1 at max 365 nm and the quantum yield for E to Z isomerization under 380 nm light irradiation was 84%, 89%, and 87%, respectively. For (Z)-isomers of 6, 7, and 8, they had molar absorptivity of 12378, 11540, and 9364 M-1∙cm-1 at max 275 nm and quantum yield of 34%, 33%, and 42% for Z to E isomerization under 288 nm light irradiation, respectively. Although the (E)-isomers and (Z)-ones had a similar molar absorptivity, quantum yield was in a large difference for them. This difference suggested that (Z)-isomer was more stable photostationary state than (E)-one. When obtained (Z)-isomers were left to stand at room temperature in dark, the isomerization process from Z to E was monitored by absorption spectrum. A thermal isomerization rate constant was calculated to be 0.00415 h-1, 0.00434 h-1, and 0.00335 h-1 for (Z)-isomer of 6, 7, and 8, respectively, from the dynamic absorption spectrum data. From that, an isomerization half-life for (Z)-isomer of 6, 7, and 8 was 167 h, 160 h, and 207 h, respectively.

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(Z)-isomer, which was then reverted to (E)-isomer by heating for 60 min at 90 oC. This process was repeated for 12 times and no photodegradation was observed (Figure 3D), demonstrating high fatigue resistance and structure stability of the hydrazone switches. Under irradiation of 288 nm light rather instead of heating, the (Z)-isomer of 6 could be also reverted into (E)-isomer. Upon alternating irradiation by 365 nm light and 288 nm one instead of alternating irradiation and heating, the absorbance of 6 at 365 nm also underwent repeated decrease and increase, and showed no fatigue for 11 times (Figure S81−S84). Fortunately, single crystals suitable for X-ray diffraction analysis were obtained by slowly evaporating of solution of (Z)-7 formed from 365 nm light irradiation of as-prepared 7 in a mixed solvent of chloroform and ethanol for about one week. Crystal structure confirmed the (Z)-configuration of 7 after it was irradiated by 365 nm light (Figure 3A – 3B).60 Interestingly, (Z)-7 was in folding conformation with benzoyl moiety almost vertically pointing to naphthyl ring, resulting in a dihedral angle of 82.86o between benzoyl ring and naphthyl ring. Meanwhile, due to steric hindrance at both side of imine unit, the dihedral angle was up to 64.02o between C=N double bond plane and naphthyl ring. This conformation of (Z)-isomers was unique when comparing with other (Z)-hydrazones. In hydrazone photoswitches by hydrogen bond stabilizing (Z)-isomer, the C=N double bond plane are almost coplanar with aromatic ring due to less steric repulsion.49 The lessened conjugation of C=N double bond with naphthyl ring in (Z)-isomer should be the reason that the absorbance of (E)-isomer at long wavelength decreased with irradiation. This is contrary to the many reported acylhydrazone photoswitches, in which the absorbance of (E)-isomer at long wavelength increases with irradiation. Besides, the protons of amide, benzoyl ring and methoxyl group were placed in the shielding area of naphthyl ring, with a shortest distance of 2.449 Å, 3.037 Å, and 2.931 Å between these protons and naphthyl carbon, respectively. Therefore, these protons displayed obvious up-field shift in 1H NMR spectrum after irradiation. In crystal state, (Z)-7 molecules stacked by head to head to form 3D networks (Figure 3B). Noticeably, there were π- stacking interactions both between benzoyl rings (3.388 Å) and between naphthyl rings (3.536 Å), but no intermolecular hydrogen bond between amide groups was found due to amide hydrogen pointing to naphthyl ring that shielded the hydrogen.

Like other hydrazone photoswithes, benzoylhydrazones 6 − 9 were also highly reliable photoswitches. The diluted solution of (E)-6 was irradiated for 4 min by 365 nm portable UV lamp and could be fully transformed into its ACS Paragon Plus Environment

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hidden between naphthyl ring and benzoyl group and could not form intermolecular hydrogen bonds. The sequential hydrogen bonds, which closely pulled the molecules together, were probably the main reason why (E)-isomer usually had less solubility than (Z)-isomer in organic solvent. For example, the as-prepared 6 was almost insoluble and suspended in chloroform, but it became easily soluble and led to clear solution after (E)-isomer was transferred into (Z)-one by irradiation of 365 nm light.

c

a

b

c' a' b'

Figure 4. 1H NMR spectra of 8 in D2O (a) as prepared, (b) irradiated by a portable 365 nm UV lamp for 2 h.

Figure 3. (A) Crystal structure of (Z)-7. (B) Stacking of (Z)-7 molecules in crystal state. (C) Crystal structure of (E)-7. (D) Stacking of (E)-7 molecules in crystal state. The hydrogen atoms were removed for clarity in (B). The number in (D) denoted the intermolecular hydrogen bond length in Å.

In contrary to (Z)-7, (E)-7 was stretched and its crystal structure displayed intermolecular hydrogen bonds between amide groups in addition to the π- stacking interactions between naphthyl rings due to amide group which was both hydrogen bond donor and acceptor (Figure 3C – 3D). Meanwhile, the hydrogen of imine group (N=C-H) together with the amide hydrogen also formed hydrogen bonds with amide oxygen of the neighboring molecule. The sequential hydrogen bonds between amide groups and between amide and imine groups put (E)-7 in a column structure (Figure 3D). But not all hydrogen bonds in the sequence were in the same length. They were repeated according to the order from 2.002 Å, 2.080 Å to 2.025 Å between two amides groups and from 2.523 Å, 2.709 Å to 2.563 Å between amide and imine groups. Accordingly, π- stacking interactions between naphthyl rings in the column structure also showed a repeated distance order from 3.315 Å, 3.354 Å to 3.368 Å. However, no π- stacking interactions between benzoyl rings were found. For (Z)-isomer, due to folding conformation, the amide hydrogen donor was

Due to bearing three pentaethylene glycol chains, hydrazone 8 was amphiphilic and was soluble in both organic solvent and water. By comparing 1H NMR spectrum of 8 in D2O before and after 365 nm light irradiation, it was found that E−Z isomerization also occurred in water, just like that in DMSO-d6. Due to exchanging with deuterium of D2O, proton of amide group did not exhibit its resonance signal. However, the proton signals of C8-H, imine, and benzoyl ring showed an up-field shift from 8.93 to 7.88 ppm, 8.90 to 7.62 ppm, and 7.03 to 6.20 ppm, respectively (Figure 4). Similar to that in DMSO-d6, the obvious change of chemical shift of C8-H indicated that C8-H-involved intramolecular hydrogen bond was broken and the configuration of 8 was transferred from (E)-isomer to (Z)-isomer after it was irradiated by 365 nm UV light. After irradiation of 365 nm light, 98% of (Z)-isomer could be obtained. Interestingly, in a mixture of minor (E)-isomer and major (Z)-isomer, the (E)-isomer showed a little different chemical shift from that in a mixture of the major (E)-isomer and minor (Z)-isomer. Likewise, the (Z)-isomer displayed different resonance position in these two mixtures. For example, the proton signals of C8-H, imine, and benzoyl ring in (E)-isomer appeared at 8.93 ppm, 8.90 ppm, and 7.03 ppm but that of minor (E)-isomer in major (Z)-isomer showed at 8.81 ppm, 8.86 ppm, and 7.16 ppm, respectively. Compared with minor (Z)-isomer in major (E)-one, (Z)-isomer also had chemical shift change from 7.88 to 7.80 ppm, 7.62 to 7.56 ppm, and 6.20 to 6.22 ppm, respectively (Figure 4). This result was not observed in DMSO-d6 and suggested intermolecular interaction between molecules of 8 in water. Probably, 8 existed in tiny aggregates.



Dynamic light scattering (DLS) measurement showed that hydrazone 8 did not completely disperse into water at molecular level but in nanoparticles (Figure S85). Remarkably, the as-prepared 8 aggregated into nanoparticles with diameters of about 150 nm  172 nm (major) and 669 nm (minor) in water but the irradiated 8 by 365 nm light existed in much smaller aggregates with a diameter of only about 10 nm. After the solution of 8 in water was vitrified at −180 oC, the obtained Cryo-TEM images disclosed that 8 truly existed in nanoparticles. While the as-prepared 8 aggregated into nanoparticles with a diameter of 100 nm – 200 nm, the solution of 8 irradiated by 365 nm light was composed of vesicles with a diameter of 8 nm – 16 nm and shell width of about 5 nm (Figure 5). This result confirmed that the big nanoparticles assembled by 8 in water could be cracked into smaller ones after irradiation. The length of (Z)-isomer of 8 was 2.1 nm calculated by HperChem software (Figure S86). Therefore, the vesicle formed by (Z)-isomer of 8 should be composed of one bilayer of (Z)-isomer molecules, which led to a shell width of about 5 nm. The bilayer was formed by head to head π-π stacking of naphthyl rings of two (Z)-isomer molecules. For the big nanoparticles from (E)-isomer of 8, they should be made up of multi-bilayers of (E)-isomer molecules (Figure 6). The bigger nanoparticles of (E)-isomer should be ascribed to the intermolecular hydrogen bonds in (E)-isomer aggregates which pulled the molecules more closely and aroused less solubility of 8 in water.

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Figure 5. Cryo-TEM images of as-prepared 8 (A) and irradiated 8 (B) by 365 nm UV portable lamp for 2 h in water. Inset (27×27 nm), one magnified versicle. [8] = 2 mM.

Figure 6. Constitution sketch of nanospheres formed by aggregation of 8 in water before and after light irradiation. The red belt and green belt denote hydrophilic pentaethylene glycol chains and naphthyl moiety, respectively. The molecular conformation of (E)- and (Z)-8 was mimicked by HyperChem software and put them together according to the packing mode in crystal structure of 7.

The test for using 8 as carrier of guest molecules was made. Unfortunately, it failed to increase the solubility of the tested guests in water. For bestowing the amphiphile with capability of accommodating guest molecules, compound 9 that possessed one additional long alkyl chain was synthesized. Just like 8, the tetradecylhydrazone 9 was also very sensitive to UV light even in water, and showed distinct change both in absorption spectra and in NMR spectra (Figure S49 and Figure S66). Under irradiation of UV light, up to 90% (E)-isomer could be transferred into (Z)-isomer in water. Moreover, DLS showed the as-prepared 9 aggregated into nanoparticles with diameters of about 1725 nm in water, which could be rearranged into smaller particles with a diameter of about 710 nm (Figure S87), indicating a potential in drug controllable release if the drug was included in the bigger nanoparticles. The cryo-TEM images disclosed that the as-prepared 9 existed in vesicles with a diameter of 18 nm  25 nm while the irradiated 9 self-assembled into smaller vesicles in water with a diameter of about 10 nm (Figure S88), which was in accordance with the DLS measurement. The reason for change of the vesicle size of 9 in water after irradiation should be similar to that of 8. Anticancer drug procarbazine (PCZ) was tested for inclusion and controllable release. PCZ is almost insoluble in water with a very little solubility of about 0.002 mg/mL. But in the presence of 9, the solubility in water was got to 0.45 mg/mL, having a 225 fold increase. After dissolution of PCZ, the resultant colloidal solution was transparent and


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could be stable for more than several weeks. DLS disclosed that the aggregates in the solution had a size of 110 nm  170 nm (Figure 7). It was also observed by SEM image that nanoparticles with a diameter of about 150 nm formed after the solution was dried up at room temperature (Figure 8). However, upon irradiation by 365 nm light, the transparent solution became a white turbid suspension. SEM image disclosed that the aggregates in the suspension were very big and had a diameter of 1.10 m  1.60 m. It could be inferred that PCZ molecules were released from the nanoparticles of 9 upon irradiation, which then aggregated into bigger particles due to its insolubility in water. At room temperature, 9 was a viscous liquid and could not be seen by SEM. Therefore, the particles that were seen in SEM images should be ones of PCZ because it was a solid. By using centrifuge method to collect the formed precipitates after irradiation, it was found that a 47.8% of loaded drug was released.

A 80

110-170 nm

q(%)

60

Figure 8. (A) SEM image of a mixture of as-prepared 9 and PCZ in water. (B) SEM image of the mixture in water upon irradiation by 365 nm UV light for 4 h. [9] = 1 mM, [PCZ] = 2× 10-4 M.

40 20 0 0

B

100 200 Diameter (nm)

300

400

50 1.10-1.60 um

40 q(%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Meanwhile, AFM images at room temperature also confirmed the above result (Figure S89). In the solution of the acylhydrazone 9, no particles but layered structures were observed, in which the layered structures should be ascribed to the melted nanoparticles of 9. In the colloid solution of a mixture of 9 and PCZ, nanoparticles with a diameter of 110 nm – 150 nm were seen in addition to the layered structure. However, upon irradiation, PCZ was released and aggregated into very big particles with a diameter of 1.10 m  1.50 m (Figure 8).

30

CONCLUSION

20 10 0 0

1000

2000 3000 Diameter (nm)

4000

Figure 7. Dynamic light scattering diagram of solution of (A) a mixture of as-prepared 9 and PCZ. (B) The mixture prepared 9 and PCZ was irradiated by 365 nm UV portable lamp for 4 h in water. [9] = 5 mM, [PCZ] = 1.0 mM. Inset: photos of the mixture solution before (A) and after (B) irradiation.

In conclusion, by increasing the steric hindrance at both sides of the imine double bond and destabilizing (E)-isomer, benzoyl hydrazone exhibited up to 99% E-Z conversion efficiency although no intramolecular hydrogen bond could stabilize (Z)-isomer. Due to large steric hindrance at two sides of imine group, the C=N double bond had less coplanar with naphthyl ring in (Z)-isomer than in (E)-isomer, which led to reducing absorbance at long wavelength upon irradiation by long wavelength light and making the benzoylhydrazone a negative photochromic systems. Meanwhile, also because of the steric hindrance, benzoyl ring and naphthyl ring were folded each other and amide hydrogen was hidden between these two aromatic rings in (Z)-isomer. This resulted in no intermolecular hydrogen bond between molecules of (Z)-isomer in solid state while (E)-one showed strong intermolecular hydrogen bonds. Therefore, (Z)-isomer was more easily soluble in solvent than (E)-isomer. These obvious differences in



structure, photophysical and physical properties between E/Z isomers gave this new class of benzoylhydrazones greater application potential including photocontrollable drug release in water that had been demonstrated. Other application research such as photochromism driven by visible light, solid photoactuators, chirality induction by polarized light, information storage, and so on are under investigations. ASSOCIATED CONTENT Supporting Information. Experimental details for the synthesis, 1H-NMR, 13C-NMR, 2D NMR, HRMS spectra, absorption spectra under UV light irradiation and heating, calculation of quantum yield and half-life. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author Yan-Song Zheng*, E-mail: [email protected]. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT The authors thank National Natural Science Foundation of China (21072067 and 21673089) and the Fundamental Research Funds for the Central Universities (HUST: 2015ZDTD055) for financial support, and thank the Analytical and Testing Centre at Huazhong University of Science and Technology for measurement.

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Graphical Abstract


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New Acylhydrazone Photoswitches with Quantitative Conversion and

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