N benzyl

N benzyl DEFAULT

N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues

SPECIAL ISSUE

This article is part of the special issue.

Introduction


Recently, an extremely potent hallucinogenic phenethylamine, 25I-NBOMe (N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine; “smiles”) 1 has been available on the illicit drug market. (1) For purposes of enforcement, it is presently considered by the Drug Enforcement Administration (DEA) to be an analogue of 2C-I (2), which is currently a Schedule I controlled substance. The procedure to classify 1 as a Schedule I substance has been initiated, and it has been placed temporarily into Schedule I. (2) Unfortunately, several deaths have been associated with the use of 1, (3-5) but it is not clear whether the deaths resulted from the ingestion of lethal amounts of pure solid drug, or whether the drug has some inherent toxicity that is not normally associated with other hallucinogens.

There has been increasing global interest in 1 and closely related analogues. For example, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has received a range of notifications from EU Member States about analytically confirmed nonfatal and fatal intoxications associated with 1. This was then followed by a risk assessment conducted by the Scientific Committee of the EMCDDA in order to assess health and social risks associated with this particular analogue. (6) In addition, the World Health Organization’s Expert Committee on Drug Dependence reviewed the status of a range of new substances for its 36th meeting in June 2014, which included 1 and its 4-bromo and 4-chloro analogues. (7) In September 2014, the Council of the European Union decided to subject 1 to control measures and criminal penalties throughout the European Union. (8)

Typically, simple N-alkylation dramatically attenuates or abolishes hallucinogenic activity in phenethylamines. (9, 10) The N-benzyl moiety, however, confers exceptionally high potency onto the molecule, (11-15) and we have presented evidence that the N-benzyl may engage F339 in the human 5-HT2A receptor. (14) We also examined various N-arylmethyl substituents and found that a variety of aryl groups were effective in enhancing potency. (16, 17) In addition, the presence of a polar substituent at the ortho position of the aryl ring (a possible hydrogen bond acceptor) further enhances activity. (18) Silva et al. (18) also have reported that in an in vitro cylindrical rat tail artery strip 1 had a pEC50 of 10.09 and an Emax of 30%.

Two decades ago, Glennon et al. (19) reported that the affinities of the N-benzyl compound 3a, as well as the 4-bromo- and 4-iodo-N-benzyl compounds, 3b and 3c, respectively, were 2–3 times higher than that of the parent primary amine. There have been no further reports on these compounds, and in our own work, we had never examined 3- or 4-substituted benzyl substituents in the phenethylamine series.

In addition to the phenethylamine type 5-HT2A agonists, certain simple tryptamines possess similar pharmacology, particularly 4- or 5-oxygenated molecules. In the report by Glennon et al., placing an N-benzyl moiety on the amine of 5-methoxytryptamine had essentially no effect on affinity. Interestingly, N-benzyl-5-methoxytryptamine previously had been reported to be an antagonist of serotonin-induced contraction in the rat stomach fundus, the isolated guinea pig uterus, and the isolated guinea pig taenia cecum. (20) In addition, Leff et al. (21) had shown that N-benzyl-5-methoxytryptamine had only weak partial agonist activity at 5-HT2 type receptors in rabbit aorta and rat jugular vein.

Surprisingly, however, in the Glennon report, (19) a 5-HT2A receptor affinity of 0.1 nM was reported for the N-4-bromobenzyl compound (compound 33 in the Glennon report, numbered here as 5f), with 1000-fold selectivity for 5-HT2A over 5-HT2C receptors. We found these data particularly intriguing. This degree of selectivity was overestimated, however, because affinity at the 5-HT2A receptor was measured by displacement of an agonist ragioligand, whereas affinity at the 5-HT2C receptor was measured by displacement of an antagonist radioligand. Nonetheless, no specific 5-HT2A-selective agonist has been available, although such a compound would be very valuable for serotonin neuroscience research.

Although it was reported (19) that 4-bromo compound 5f had 0.1 nM affinity at the human 5-HT2A receptor, the 4-fluoro-, 4-chloro-, and 4-iodo-substituted benzyl congeners had reported affinities of 40, 105, and 120 nM, respectively, in that same report. We found this discontinuity in the structure–activity relationship (SAR) puzzling, where the 4-bromo compound would be such an outlier in the family of halogen-substituted benzyls. Further investigation by Jensen, however, revealed that the authentic 4-bromo compound 5f actually had relatively low affinity for the 5-HT2A receptor, more consistent with the reported affinities of the other halogenated compounds. (22) Although spectroscopic data were not reported by Glennon et al. (19) that might explain the basis for this discrepancy, their publication indicated elemental analysis data to be consistent with the proposed structure. If the elemental analysis data were correct, the mostly likely explanation for the discordant biological data therefore seemed to be that 5f might have been an isomer other than the 4-substituted compound.

On the basis of the hypothesis that the original data were associated with an isomer other than the 4-bromo compound, we subsequently discovered that N-3-bromobenzyl compound 5e did have higher affinity for the 5-HT2A receptor (Ki 1.48 nM), compared to that of the 4-bromo congener 5f (Ki 11.2 nM). Further, the effect of an ortho-oxygenated N-benzyl appeared not to be significant for affinity in the tryptamine series, suggesting perhaps different binding orientations of the N-benzyltryptamines versus the N-benzylphenethylamines within the receptor. That is, compound 5a has been reported to have agonist potency (pEC50 7.08) in a rat tail artery assay not significantly different from the compound with an unsubstituted N-benzyl moiety (pEC50 7.00), although the Emax was slightly higher for the 2′-methoxy compound. (18) These findings prompted us to synthesize a small series of structurally related congeners to determine whether other substitutions might have even greater affinity and/or selectivity for the 5-HT2A receptor.

Thus, in this article we describe the facile synthesis of compounds 1, 4a4e, and 5a5l, preliminary screening at a variety of 5HT family receptors, and more detailed testing at human 5-HT2A, 5-HT2B, and 5-HT2C receptors, including affinity measurements using displacement of the agonist radioligand [125I]-DOI and functional effects in elevating intracellular calcium. We also present behavioral data for the mouse head twitch response (HTR) as a measure of in vivo 5-HT2A receptor activation. (23)

Compound 1 has been previously reported, (24) and the NMR and electron ionization mass spectra of 4a and 4b have been reported but without any biological data. (25) We thus decided to compare all of the series members at the same time to elucidate a consistent SAR.

Chemistry


All of the compounds were most easily prepared using a modification of the facile method first reported by Abdel-Magid et al. (26) The free base of 2 was stirred in 3 mL of MeOH for 30 min with the appropriate aldehyde, followed by reduction of the intermediate enamine with NaBH4. Following appropriate workup, the bases were converted to their HCl or maleate salts and crystallized in good to excellent yields.

Pharmacology


Affinities at a panel of 5-HT receptors were determined by the NIMH-sponsored PDSP program (http://pdsp.med.unc.edu/kidb.php). Affinities at both the human and rat 5-HT2A and 5-HT2C receptors also were determined, using both agonist and antagonist radioligands. As a measure of functional potency and efficacy, changes in intracellular Ca2+ levels were measured using a fluorometric imaging plate reader (FLIPRTETRA, Molecular Devices), at the human 5-HT2A, 5-HT2B, and 5-HT2C receptors, and at the rat 5-HT2A and 5-HT2C receptors. Finally, as a measure of in vivo 5-HT2A receptor activation, we assessed the ability of all compounds to induce the mouse HTR. (23) We hypothesized that functional potency at the rat 5-HT2A receptor might correlate best with the mouse head twitch behavioral data because ligand affinities at the rat 5-HT2A receptor correlate with the mouse 5-HT2A receptor but not with the human 5-HT2A receptor. (27)

Results


Further exploration of a small library of 3-substituted N-benzyl tryptamines allowed us to develop a tentative SAR for this series, and it is clear that substituents on the N-benzyl 3-position do modulate affinity in the tryptamine series. In the broad screening of 5-HT receptor types, all of the compounds had the highest affinity at the 5-HT2 family of receptors (Tables 1 and 2).

Table 1. Affinities of New Compounds for the Human 5-HT2A and 5-HT2C Receptors Using Both Agonist and Antagonist Radioligandsa

Table 2. PDSP Screening Affinities for All Compounds at Other Human Serotonin Receptor Typesa

At the 5-HT2A and 5-HT2C receptors, the highest affinity was observed in the competition displacements with [125I]-DOI. Except for 5c and 5f, all of the tryptamine compounds had low nanomolar or subnanomolar affinity for the human 5-HT2A receptor. The known phenethylamine 1 had by far the highest affinity at 5-HT2A/2C receptors, with subnanomolar affinity at both subtypes. We have previously reported an affinity for 1 at the human 5-HT2A receptor of 0.04 nM. (14) Of the tryptamines, only the 3-iodobenzyl compound 5i, had subnanomolar affinity at the 5-HT2A receptor, although all of the tryptamines had high affinity at this receptor. It should be noted that N-methylation of 5e completely abolished affinity at the 5-HT2A receptor (Ki > 10 μM; data not shown), indicating that tertiary amines are not tolerated in the N-benzyltryptamines.

The rank order of affinity of all compounds at the [125I]-DOI-labeled h5-HT2C receptor generally paralleled that measured at the 5-HT2A receptor, although the affinities tended to be somewhat lower. Again, among the tryptamines studied 5i had the highest affinity at this receptor, as well as at the 5-HT2B receptor. Affinities measured at the [125I]-DOI site tended to be on the order of 5–10 times higher than that at the antagonist labeled sites at both receptors.

Functional potencies at the rat and human 5-HT2A and 5-HT2C receptors and the human 5-HT2B receptor are shown in Table 3. Compound 1 was a nearly full agonist at both receptor types, with a 4.2 nM EC50 at the human 5-HT2A receptor and 11 nM EC50 at the rat 5-HT2A receptor. The most potent compound was 5a, with an EC50 of 1.9 nM and 85% efficacy at the h5-HT2A. Notably, this compound has the N-2-methoxybenzyl substituent, the same as the most potent phenethylamine 1, suggesting that it may be optimal for activation of the 5-HT2A receptor when placed at the 2-position of the N-benzyl moiety. Efficacies of the tryptamines at the rat and human 5-HT2A receptors and human 5-HT2C receptor varied from about 40% to 80%, with a few compounds that were full agonists (e.g., 5a and 5c), whereas at the rat 5-HT2C receptor all of the compounds were full agonists.

Table 3. Functional Data for New Compounds in Rat and Human 5-HT2A and 5-HT2C and Human 5-HT2B Receptorsa

It is noteworthy that the functional potencies in the rat and human 5-HT2A receptors are essentially identical for phenethylamine compounds 1, and 4a4e, yet the potencies for tryptamine compounds 5a5l are 4–10-fold higher at the human 5-HT2A receptor than at the rat 5-HT2A receptor. This finding may reflect the single amino acid difference in the orthosteric binding site of these two receptors at position 5.46. In the rat or mouse 5-HT2A receptor, residue 5.46 is an alanine, whereas in the human receptor it is a serine. We have previously shown that mutation of this residue in the human receptor from serine to alanine has little effect on affinity or function for phenethylamine 5-HT2A agonists but does have a significant effect for tryptamines. (28) One might infer, therefore, from these potency differences that the indole NH in the present series also engages this serine in the human receptor but not the alanine in the rat receptor, consistent with mutagenesis studies reported by others. (29, 30)

Figure 1 shows an illustrative dose–response curve for compound 5h in the mouse HTR. HTR data for all compounds are given in Table 4. Although some of the compounds failed to induce the HTR at doses up to 30 mg/kg, most of the “inactive” compounds displayed relatively low potency at 5-HT2A (see Figure 2), so it is possible that they would induce the HTR if tested at higher doses. Importantly, for the subset of compounds that induced the HTR, behavioral potency was significantly correlated with functional potency at the r5-HT2A receptor (r = 0.69, p < 0.03; Figure 2), but there was no correlation with functional EC50 values at the r5-HT2C receptor (r = 0.17, p > 0.1). Despite the overall correlation between mouse HTR and r5-HT2A potency, the relationship was not always orderly for individual compounds. Compound 1 was by far the most potent compound in that assay, with an ED50 of 0.078 mg/kg (data taken from Halberstadt and Geyer (31)). It is not clear why 1 should be so much more potent than any other compound because, for example, 4d is inactive but appears nearly comparable functionally, with an EC50 of 14 nM and efficacy of 69%, compared with an EC50 of 11 nM for 1 with an efficacy of 79%. The next most potent compounds in the mouse HTR are 4c and 5j, with identical ED50s of 2.31 mg/kg, about 300-fold less potent than 1. Although they have similar functional EC50 values (36 and 26 nM), nothing in the functional or binding data can explain their lower potency compared to that of 1. Further, compounds 5a, 5b, and 5g have virtually identical ED50 values in the mouse HTR, yet their functional EC50s at the rat 5-HT2A receptor are 21, 34, and 80 nM, respectively.

Figure 1

Table 4. Activity of New Compounds in Producing the Mouse Head Twitch

Figure 2

With the exception of 5k and 5l, which had relatively low functional potencies at the r5-HT2A (EC50 values of 770 and 120 nM, respectively), all of the meta-substituted N-benzyl derivatives of 5-methoxytryptamine induced the HTR. That included the 3-methyl (5j; ED50 = 2.31 mg/kg), 3-methoxy (5b; ED50 = 3.28 mg/kg), 3-fluoro (5g; ED50 = 3.33 mg/kg), 3-chloro (5h; ED50 = 4.43 mg/kg), 3-bromo (5e; ED50 = 5.18 mg/kg), and 3-iodo (5i; ED50 = 7.77 mg/kg) compounds.

The HTR produced by compounds 5b and 5j showed a biphasic bell-shaped dose–response function (the response peaked at 10 mg/kg and 30 mg/kg was inactive). Other 5-HT2A agonists, including DOI, DOM, 2C-T-7, and 5-MeO–DIPT, have been shown to produce similar nonmonotonic responses. (32-34) Fantegrossi et al. (34) have argued that the descending arm of the biphasic HTR dose–response is a consequence of 5-HT2C activation, which attenuates the response to 5-HT2A activation. Recently, however, it was reported that N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenethylamine (25CN-NBOH), a 5-HT2A agonist with 100-fold selectivity over 5-HT2C, also induces the HTR with a biphasic dose–response. (35) The fact that the descending arm of the response to 25CN-NBOH was not affected by a 5-HT2C antagonist (35) demonstrates that the inhibition of the HTR at high doses does not necessarily result from competing activity at 5-HT2C. One potential alternative explanation for the biphasic HTR is that high levels of 5-HT2A activation may produce competing behaviors that interfere with expression of head shaking. Along those lines, it has been reported that high doses of quipazine, 5-MeO-DMT, and (+)-LSD produce stereotypic behaviors that preclude head shakes and wet dog shakes in rats. (36, 37)

Discussion


Unfortunately, despite the report by Glennon et al., (19) compound 5e was not selective for the h5-HT2A receptor versus the h5-HT2C receptor. Using affinity at the [125I]-DOI-labeled receptors, the selectivity of 5e was slightly less than 4-fold. Even using affinity at the [125I]-DOI-labeled h5-HT2A receptor and the [3H]-mesulergine-labeled h5-HT2C receptor, “selectivity” was only about 18-fold. The most selective compound in the entire series, with respect to affinity, was 5d, but with only 6-fold selectivity.

With respect to selectivity in function at the h5-HT2A vs h5-HT2C, the most selective tryptamine was 5j, with 44-fold selectivity and less than a 3-fold difference in affinity at the agonist-labeled receptors. Indeed, we were disappointed that none of the compounds had high selectivity for the h5-HT2A receptor.

Overall, with the exception of compound 1, none of the compounds was particularly potent in producing the HTR. This low potency is somewhat surprising, given that many known hallucinogens with high affinity for the 5-HT2A receptor, such as 2,5-dimethoxy-4-iodoamphetamine (DOI), R-(−)-2,5-dimethoxy-4-methylamphetamine (R-DOM), R-(−)-2,5-dimethoxy-4-bromoamphetamine (R-DOB), 2,5-dimethoxy-4-propylthiophenethylamine (2C-T-7), psilocin, and 5-MeO-N,N-diisopropyltryptamine (5-MeO–DIPT) produce the head twitch in mice at doses of ≤1 mg/kg. (32, 33, 38-40) However, certain tryptamine hallucinogens, including 5-MeO-N,N-dimethyltryptamine (5-MeO-DMT) and α-methyltryptamine, are active within the same dose range (3–30 mg/kg) as the N-benzyltryptamines tested herein. (40-42) It is unlikely that the low in vivo potencies of the compounds studied here are related to the use of an automated HTR detection system because we have confirmed that the results obtained using this system are consistent with published data based on visual scoring. (23) For example, the potency of LSD measured using the automated system (ED50 = 0.13 μmol/kg) (23) is almost exactly the same as the potency assessed using direct observation (ED50 = 0.14 μmol/kg). (41) One possible explanation for the low potencies might be rapid first pass metabolism of N-benzyl-analogues in general (43) combined with a slow release from subcutaneous tissue due to the highly hydrophobic nature of the compounds.

Substitution on the N-benzyl ring has different effects, depending on whether the phenethylamines or the tryptamines are being studied. For example, ortho-bromo-substituted tryptamine congener 5d failed to induce the HTR when tested at doses up to 30 mg/kg (∼60 μmol/kg), yet N-3-bromobenzyl 5e is active. By contrast, N-2-bromobenzyl phenethylamine 4c is active, whereas N-3-bromobenzyl 4d is inactive in the HTR assay.

None of the phenethylamines or tryptamines with 4-substituted N-benzyl groups, 4b, 4e, 5c, or 5f, was active in the HTR. All of these compounds were partial agonists with relatively low potency in the r5-HT2A functional assay. Although 5e, with a 3-substituted N-benzyl, has an EC50 and Emax virtually identical to 4e, it is active in the HTR assay. It is possible that differences in pharmacokinetics or metabolic lability could explain these data. Nevertheless, if only the compounds active in the mouse HTR assay are compared, one finds a significant correlation between potency in the rat 5-HT2A receptor and potency in the HTR assay, as shown in Figure 3.

Figure 3

Taken together, these data show that for N-benzylphenethylamines the highest in vivo potency in mice is associated with an ortho-substituent on the benzyl group, whereas the N-benzyltryptamines are more active in vivo when a meta-substituent is present. Hence, there are SAR differences between the N-benzyltryptamines and the N-benzylphenethylamines for the induction of the HTR, which likely reflect different binding orientations in the 5-HT2A receptor. Obviously, the indole system is larger than a simple phenyl ring, something that would clearly affect the binding modes for the two different series at the orthosteric site. For example, the distance from the indole C(3) atom to the 5-oxygen atom is 4.94 Å, whereas the corresponding distance from the 5-methoxy oxygen to C(1) of the aryl ring is only 3.70 Å. Even the distance of 4.85 Å from C(1) of the aryl ring to the 4-iodo atom of the phenethylamines is less than the 4.94 Å distance measured from C(3) of the indole to the 5-methoxy.

One exception is that for both the N-benzyltryptamines and N-benzylphenethylamines, oxygenated substituents are tolerated at the ortho- and meta-positions of the benzyl moiety. For example, 1, 4a, 5a, and 5b are all active in the HTR assay, whereas 4d and 5d are inactive over a range of doses. This observation again would be consistent with some structural feature in the 5-HT2A receptor that could engage a polar oxygen atom at the ortho-position of the N-benzyl moiety. There has been speculation, based on virtual docking studies with phenethylamines and tryptamines, that an oxygen atom in the ortho-position of the N-benzyl moiety may interact with a hydrogen bond donor (possibly the OH of Tyr 370(7.43) in the h5-HT2A receptor. (14, 18) It is conceivable that an oxygen atom at the meta-position in N-benzyltryptamines also could form a hydrogen bond with Tyr 370, possibly involving a water molecule.

Unfortunately, a 5-HT2A selective agonist did not emerge from this small library of compounds. There are now only two selective 5-HT2A agonists reported, (44, 45) but they have not been available for extensive study. Thus, research on 5-HT2A receptor function has been forced to employ either a mixed 5-HT2A/2C agonist such as DOI in combination with a specific 5-HT2C antagonist, or to administer antagonists alone, the latter paradigm really being appropriate to study receptor function only when there are high levels of endogenous receptor activation or constitutive activity of the receptors. Genetic knockout mice have not revealed particular behavioral phenotypes and have served primarily to demonstrate that a particular drug depends on the presence of 5-HT2A or 5-HT2C receptors for its effect. Hence, the psychopharmacology of a “pure” 5-HT2A agonist remains completely unknown. Furthermore, the tremendous present interest in the role of the 5-HT2A receptor in normal brain function makes it imperative that scientists in the field gain access to a 5-HT2A specific agonist so that research into the roles of the 5-HT2A receptor can be more fully elucidated.

Methods


Chemistry

General Methods

Reagents were purchased from Sigma-Aldrich Co. (St. Louis, MO) or Alfa Aesar (Ward Hill, MA) and used as delivered, unless otherwise specified. Thin layer chromatography was carried out using J. T. Baker flexible sheets (silica gel IB2-F) with fluorescent indicator, visualizing with UV light at 254 nm or iodine stain. Melting points were determined using a Mel-Temp apparatus and are uncorrected. NMR experiments were carried out using a Bruker Advance 300 MHz instrument, and the chemical shift (δ) values are in parts per million (ppm) relative to tetramethylsilane at 0.00 ppm. The solvent was CD3OD. NMR samples were dissolved in MeOD. Ph = aromatic protons/carbons of benzyl group; In = aromatic protons/carbons of the indole nucleus; Ar = either phenyl or indole resonances, or phenyl in the case of compounds 1–4f. Coupling constants (J) are presented in Hertz. Abbreviations used in the reporting of NMR spectra include: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, and quint = quintuplet.

Mass spectra were performed by high resolution LC-QTOF-MS on protonated molecules [M + H]+. UHPLC-Q-TOF-MS conditions for UHPLC separation employed a mobile phase consisting of 100% MeCN that included 1% formic acid (organic phase) and an aqueous solution of 1% formic acid (aqueous phase). The column was maintained at 40 °C with a 0.6 mL/min flow rate and 5.5 min acquisition time. The elution was a 5–70% MeCN gradient ramp over 3.5 min, then up to 95% MeCN in 1 min and held for 0.5 min before returning to 5% MeCN in 0.5 min. Q-TOF-MS data were acquired in positive mode scanning from 100 to 1000 m/z with and without auto MS/MS fragmentation. Ionization was achieved with an Agilent JetStream electrospray source and infused internal reference masses. Agilent 6540 Q-TOF-MS parameters: gas temperature, 325 °C; drying gas, 10 L/min; and sheath gas temperature, 400 °C. Internal reference masses of 121.05087 and 922.00979 m/z were used.

For compounds 1 and 4a4e, 0.5 mmol of the free base of 4-iodo-2,5-dimethoxyphenethylamine (10, 46) was stirred for 30 min at room temperature with 0.55 mmol of the appropriate aldehyde in 3 mL of methanol. The reaction was then placed on an ice bath, and 48 mg (1.25 mmol) of NaBH4 was added in three portions over 15 min. The ice bath was removed and the reaction allowed to stir for an additional 15 min. The reaction was then transferred to a separatory funnel with 50 mL of EtOAc. The organic phase was washed three times with saturated NaCl, then dried overnight over Na2SO4. The drying agent was removed by suction filtration, and the filtrate was concentrated under reduced pressure. EtOH (1 mL) was added to the amber residue, and the HCl salt was prepared by acidification with 0.5 mL of 1 N HCl/EtOH. Dilution with EtOAc or diethyl ether then led to crystallization of the HCl salts, generally in good yields. In most cases, the supernatant was simply decanted from the crystalline product, followed by resuspension of the crystals in Et2O and decantation, then air drying to afford the products as white to off-white fine needles. No attempt was made to optimize the yields, but in one case the supernatant was reduced to dryness and the residue crystallized from EtOH/Et2O to afford an additional 6% of product. This small additional recovery was not deemed sufficient to warrant the extra effort. Thus, all reported yields are those obtained after the first crystallization.

The synthesis of tryptamines 5a5l followed essentially the same procedure, except that maleate salts were prepared. As an example, 1.0 mmol of 5-methoxytryptamine free base (Aldrich) was stirred for 30 min with 1.10 mmol of the appropriate aldehyde in 5 mL of methanol. The reaction was then placed on an ice bath, and 96 mg (2.5 mmol) of NaBH4 was added in three portions over 15 min. The ice bath was removed and the reaction allowed to stir for an additional 15 min. The reaction was then transferred to a separatory funnel with 50 mL of EtOAc and was washed three times with saturated NaCl. The organic phase was dried overnight over Na2SO4, then filtered and concentrated under reduced pressure. Maleic acid (116 mg, 1 mmol) and 1.0 mL of acetone were then added to the residual amber oil, and the solution swirled until all of the maleic acid had dissolved. The reaction was then diluted with 10 mL of EtOAc, and Et2O was added nearly to the cloud point. In most cases, crystallization occurred rapidly and spontaneously, and the product solution was stored overnight in a cold room. Crystalline products were collected by suction filtration, washed on the filter with EtOAc, and then air-dried to afford white to off-white fine needles.

N-(2-Methoxybenzyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethan-1-amine Hydrochloride (1)

Obtained as needles following crystallization from acetone/EtOAc/Et2O; yield 86%; mp 168–170 °C, Lit (24) mp 162–166 °C, 166. (13)1H NMR (300 MHz, CD3OD) δ ppm 7.46 (1H, td, J = 8.2, 1.7 Hz, Ar–H), 7.37 (1H, dd, J = 7.6, 1.6 Hz, Ar–H), 7.35 (1H, s, Ar–H), 7.09 (1H, d, J = 8.3 Hz, Ar–H), 7.02 (1H, td, J = 7.5, 1.0 Hz, Ar–H), 6.86 (1H, s, Ar–H), 4.24 (2H, s, NB-CH2), 3.88 (3H, s, OCH3), 3.81 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.20–3.25 (2H, m, α-CH2), 3.03–2.98 (2H, m, β-CH2). 13C NMR (CD3OD): δ ppm 159.37 (Ar–Cq), 154.44 (Ar–Cq), 153.60 (Ar–Cq), 132.81 (Ar–CH), 132.73 (Ar–CH), 126.99 (Ar–Cq), 123.19 (Ar–CH), 122.13 (Ar–CH), 120.29 (Ar–Cq), 114.98 (Ar–CH), 112.16 (Ar–CH), 85.04 (Ar–Cq-iodine), 57.59 (OCH3), 56.71 (OCH3), 56.24 (OCH3), 48.1 (NB-CH2), 48.0 (α-CH2), 28.49 (β-CH2). HRMS calculated for C18H23INO3 [M + H]+, 428.07171; observed [M + H]+, 428.07239. The EI mass spectrum also has been reported by Casale and Hays. (25)

N-(3-Methoxybenzyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethan-1-amine Hydrochloride (4a)

Obtained as needles following crystallization from acetone/EtOAc/Et2O; yield 85%; mp 171–2 °C. 1H NMR (300 MHz, CD3OD) δ ppm 7.38 (1H, t, J = 7.7 Hz, Ar–H), 7.34 (1H, s, Ar–H), 6.98–7.10 (3H, m, Ar–H), 6.86 (1H, s, Ar–H), 4.19 (2H, s, NB-CH2), 3.83 (3H, s, OCH3), 3.81 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.22–3.27 (2H, m, α-CH2), 2.99–3.04 (2H, m, β-CH2). 13C NMR (CD

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Electro-optical effects of organic N-benzyl-2-methyl-4-nitroaniline dispersion in nematic liquid crystals

Abstract

The dispersion of organic N-benzyl-2-methyl-4-nitroaniline (BNA) in nematic liquid crystals (LCs) is studied. BNA doping decreases the threshold voltage of cell because of the reduced splay elastic constant and increased dielectric anisotropy of the LC mixture. When operated in the high voltage difference condition, the BNA-doped LC cell has a fall time that is five times faster than that of the pure one because of the decrements in the threshold voltage of the cell and rotational viscosity of the LC mixture. The additional restoring force induced by the BNA’s spontaneous polarization electric field (SPEF) also assists to decrease the fall time of the LC cell. The decreased viscosity can be deduced from the decrements in phase transition temperature and associated order parameter of the LC mixture. Density functional theory calculation demonstrates that the BNA dopant strengthens the absorbance for blue light, enhances the molecular interaction energy and dipole moment, decreases the molecular energy gap, and thus increases the permittivity of the LC mixture. The calculation also shows that the increased dipole moment, polarizability, and polarizability anisotropy increase the dielectric anisotropy of the LC mixture, which agrees with the experimental results well. BNA doping has a promising application to the fields of LC devices and displays.

Introduction

Nematic liquid crystals (LCs) are extraordinarily responsive and optically uniaxial materials. Nematic LCs have been extensively used in diverse applications, such as optical nonlinearity, optical phase modulators, micro-displays, flat panel displays, optical antennas, and optical switching, due to their electro-optical property and other admirable features1,2,3,4,5. LCs with a fast response are vital in removing motion blur in moving pictures and resolving cross-talk in 3D displays6,7,8,9. The response time of LCs should be less than 3 ms to diminish motion blur and cross-talk. Several techniques have been proposed to resolve this issue, and they include tuning the viscosity of materials10, varying the anchoring energy11, changing the electrode shape and driving scheme12, changing the cell gap13, modifying the guest–host material14, and applying new switching modes15.

The improvements in the electro-optical properties of LCs with the dispersion of different gust entities were presented recently. For example, Y. Dai et al. demonstrated that the incorporation of γ-Fe2O3 nanoparticles into LCs results in a response time of 4.75 ms with the application of the overdriving scheme, which is three times faster than pure LCs16. A response time of around 4 ms was obtained with the addition of a small amount of dye to a polymer-dispersed liquid crystal (PDLC) or functionalized carbon nanotubes dispersed in optically isotropic LCs. However, in this case, the excellent response speed is valid only for operation at a relatively high voltage17,18. Blue-phase LCs have a response time of 0.5 ms, but they still have drawbacks, such as hysteresis, high operation voltage, and narrow temperature range19.

N-Benzyl-2-methyl-4-nitroaniline (BNA) is a polar N-derivative 2-methyl-4-nitroaniline (MNA) with a high electro-optical capability due to its relatively high nonlinear optics (NLO) coefficient (234 ± 31 pm/V) compared with other organic NLO materials20. It was developed by the Hashimoto group21. BNA belongs to an orthorhombic space group of Pna21 and exhibits high second harmonic generation (SHG) efficiency due to its proper phase match, which is 300 times higher than that of standard urea21,22. BNA can also be utilized for the realization of devices with maximized THz, NLO, and piezoelectric properties. The angle between the two benzene rings of BNA is around 80° and results in its L shape23. The precise L-shape of the BNA molecule in orthorhombic crystal results in the establishment of two N–HO hydrogen bonds (HBs) that enable intermolecular charge transfer (CT) to obtain high SHG efficiency24,25. These groups represent push–pull systems with intramolecular CT between the electron donor (-NH2) and acceptor (-NO2) by means of the conjugated benzene ring26. The nitro group in the BNA molecule plays an important role due to the establishment of HBs and contributes to fundamentals, overtones, and lattice vibration couplings with intermolecular CT25. Orthorhombic BNA obeys intermolecular and intramolecular CT that lie on the same plane but have opposite directions27. In our previous work, a BNA–LC mixture was used to fabricate a large-aperture hole-patterned LC lens to improve the response time for the first time28. The BNA-doped LC lens had a turn-off time that was ∼ 6 times faster than that of undoped LC lens because the BNA dopant decreased the rotational viscosity of the LC mixture. However, the important mechanism for the decrease in the rotational viscosity of LC mixtures with BNA doping has not been discussed in detail yet.

In the current study, we attempted to understand the effect of BNA doping on nematic LCs. The transmission spectrum of a BNA-doped LC cell was used to observe the absorbance caused by the BNA dopant. The dielectric spectrum and voltage-dependent transmission of the BNA-doped LC cell were measured to determine the threshold voltage of the cell and the dielectric anisotropy and birefringence of the LC mixture, and the results were used to calculate the splay elastic constant of the LC mixture. The phase transition temperature of the BNA-doped LC cell was observed to confirm the tendencies in the order parameter and splay elastic constant of the LC mixture. The decreased order parameter reduced the relaxation time and active energy and hence the rotational viscosity of the LC mixture. The response time of the BNA-doped LC cell was also measured and showed that the BNA-doped LC cell had a fivefold faster fall time than the pure one due to the decreased threshold voltage of the cell and rotational viscosity of the LC mixture and the additional restoring force by the BNA’s spontaneous polarization electric field (SPEF). Density functional theory (DFT) was utilized to demonstrate the molecular alignment geometry, polarizability, polarizability anisotropy, and dipole moment of the BNA-LC mixture and understand further the interactions between BNA and LC molecules. BNA doping increased the polarizability, polarizability anisotropy, dipole moment, and hence dielectric anisotropy of the LC mixture.

Methods

BNA was synthesized by adding commercially purchased reactants 2-methyl-4-nitroaniline (MNA) (20 g), hexamethyl phosphoric triamide (HMPA) (100 ml), sodium bicarbonate (22 g), and benzyl bromide (45 g) to a round-bottom flask, and the entire solution was refluxed for 30 h at 70 °C under a nitrogen atmosphere21. Subsequently, 500 ml of double-distilled water was added to the solution. The solution was extracted with diethyl ether and washed several times with saturated sodium chloride solution. The organic layer was then dried using anhydrous sodium sulfate powder, and diethyl ether was evaporated to obtain BNA powder (17 g, yield of 19.5%). The synthesized material was further purified by re-crystallizing it several times by using high-performance liquid chromatography (HPLC)-grade methanol as a solvent. The final compound yielded a single spot in silica-gel thin layer chromatography (TLC) (n-hexane: ethyl acetate = 7:3). The appearance of the synthesized BNA was yellow powder at room temperature (RT) and had a melting temperature of ~ 105 °C. Figure 1a shows the molecular structure of organic BNA.

Molecular structure of (a) BNA and (b) E7 LC.

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Figure 1b shows the molecular structure of the nematic LC E7 (Daily Polymer Corp., Taiwan) used in the experiment. The nematic LC E7 was mainly composed of LC monomers 5CB, 7CB, 8OCB, and a small quantity of triphenyl. It had a nematic–isotropic phase transition temperature (TNI) of 64 °C, birefringence (Δn) of 0.22, rotational viscosity (γ) of 232.6 mPas, dielectric anisotropy (Δε) of 14.1, and elastic constant K11, K22, and K33 values of 11.1, 5.9, and 17.1 pN, respectively, at 20 °C. A commercial 5-μm-thick empty cell composed of two indium–tin–oxide (ITO) glass substrates was prepared. The inner surfaces of the substrates were coated with homogeneous polyimide and rubbed in the antiparallel direction. The thickness of the empty cell was confirmed with the interference method. An LC mixture consisting of organic BNA and nematic LC E7 was prepared, the BNA powder was directly dissolved in LCs without any solvents; then the mixture was ultrasonically stirred for 10 min at RT. The BNA concentration was set to 0.5, 1.0, 1.5, 2.0, and 3.0 wt%. The LC mixtures were heated to the isotropic phase to fill in the empty cell uniformly via capillary action and subsequently cooled down to the nematic phase.

The optical texture of the LC cell was determined using a polarizing optical microscope (POM) (DM EP, LEICA, Germany) to observe TNI. The LC cell was heated from the nematic to isotropic phase at a rate of 0.25 °C/min by using a temperature controller (T95-PE, Linkam, UK). The electro-optical properties of the BNA-doped LC cell were measured using the following setup. A He–Ne laser with 632 nm wavelength was used as incident light, and a BNA-doped LC cell was placed between a pair of crossed polarizers to obtain the voltage-dependent transmission (V–T). The rubbing direction of the cell had an angle of 45° with respect to the transmission axes of the polarizers. The pre-tilt angles of the BNA-doped LC cells were measured through the crystal rotation method29, which revealed that the angles were almost below 3°. The polar anchoring energy coefficients Wpolar of the BNA-doped LC cells were estimated via the high electric field techniques30. The Wpolar of the BNA-doped LC cells remained constant at ~ \(1.3 \times 10^{ - 4}\) J/m2, as shown in Table 1. The dielectric spectra of the homogeneously aligned (HA) and vertically aligned (VA) BNA-doped LC cells were measured using an LCR meter (Hioki 3532-50, Japan) with an applied alternating current (AC) field of 0.01 V/μm to obtain permittivities that are perpendicular (\(\varepsilon_{ \bot }\)) and parallel (\(\varepsilon_{\parallel }\)) to the LC molecular axis, respectively. The Δε of the LCs was defined as the difference between \(\varepsilon_{\parallel }\) and \(\varepsilon_{ \bot }\) at a frequency of 1 kHz. The Δn of the LCs was derived with the phase retardation technique5.

Full size table

Results and discussion

Figure 2a shows the POM images of the BNA-doped LC cells, where the cell rubbing direction was placed at 45° with respect to the transmission axes of the polarizer and analyzer. The uniform colors throughout the cells confirmed that the LC molecules were aligned homogenously31,32,33,34. After BNA addition, we did not observe any significant defect aside from the slight color shift, indicating that BNA was well dispersed in the LC matrix and the Δn of the LC mixture slightly changed. Figure 2b presents the transmission spectra of the BNA-doped LC cells in the visible range between 400 and 700 nm. The light loss of around 12% (from 85 to 73%) was obtained because BNA doping changed the refraction index of the LC mixture and thus increased the refractive index mismatch among the surfaces between the glass substrates and LC layer. Notably, BNA has drastic absorbance at wavelengths less than 450 nm. Figure 2c shows a diagram of the International Commission on Illumination (CIE) 1931 chromatographic coordinates. It illustrates the stimuli-induced color change. Compared with the color coordinate of the used light source, those of the empty and BNA-doped LC cells exhibit slight shifts possibly because of absorbance by LC mixture and PI layers. The yellowish CIE chromatographic coordinates of the BNA-doped LC cells are related to the used light source and the short wavelength absorbance of the BNA doping (from Fig. 2b). The inset of Fig. 2c shows the enlarged CIE chromatographic coordinates and the sample photos, confirms that the small amount of BNA doping slightly contributes to the yellow tint in the CIE chromatographic coordinates. This experiment indicates that the BNA-doped LC cell successfully plays the role of a light intensity filter as it should be. For electro-optical components that require high color accuracy, more experiments are necessary for the collocation among light source, LC cell, and organic materials.

(a) POM photographs, (b) transmission spectra, and (c) CIE 1931 chromatographic coordinates of the BNA-doped LC cells. Inset shows the enlarged CIE chromatographic coordinates and the sample photos of the 3 wt% BNA-doped and pure E7 LC cells under daylight illumination. The solid arrows indicate the rubbing direction (R) and transmission axes of the polarizer (P) and analyzer (A).

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Figure 3a shows the V–T curves of the BNA-doped LC cells measured at RT. The curve shifted toward the low-voltage side as the BNA concentration increased, indicating that BNA doping decreased the operation voltage of the cell. A decrease in maximum transmission was obtained because BNA doping changed the refractive index of the LC mixture, resulting in refractive index mismatch between the interfaces or absorption of light by the BNA-doped LC mixture. The POM images of the BNA-doped LC cells with various voltages were measured to determine the threshold voltage (Vth) of the cell. Vth was defined as the voltage at which the color of POM image began to change, indicating the initial distortion of LCs in the middle of the cell. As shown in Fig. 3b, Vth decreased with increased BNA concentration because BNA doping decreased K11 and increased Δε according to Eq. (1)35,36,37. Fig. 3c shows the changes in \(\varepsilon_{\parallel }\) and \(\varepsilon_{ \bot }\) with BNA concentrations at a frequency of 1 kHz. BNA doping increased the permittivity of the LC mixture.

$$ V_{th} = \pi \sqrt {\frac{{K_{11} }}{{\varepsilon_{0} \Delta \varepsilon }}} $$

(1)

(a) V–T curves of the BNA-doped LC cells. (b) Vth as a function of BNA concentration. (c) \(\varepsilon_{ \bot }\) and \(\varepsilon_{\parallel }\) as functions of BNA concentration at 1 kHz. (d) Δε and Δn as functions of BNA concentration. (e) γ at various BNA concentrations.

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As shown in Fig. 3d, BNA doping increased the Δε and decreased the Δn of the LC mixture. When the BNA concentration exceeded 1.5 wt%, Δn was saturated. The increment in Δε can be explained as follows. First, a strong polar terminal group (e.g., Cyano) usually causes a large Δε. BNA is a strong polar molecule such that BNA doping helps increase Δε. Second, BNA doping increases polarizability anisotropy (Δα) and hence Δε. Moreover, it enriches the short-range intermolecular forces. The presence of phenyl rings in BNA also changes the absorbance, Δε, K11, and γ of LC mixtures37,38,39. Generally, the accurate determination of elastic constant of LCs is less straightforward. The elastic constant is a parameter characterizing the elastic interaction between the LC molecules. When BNA is dispersed in LCs, the K11 of LC mixture also reflects the interaction between the LC molecules and the BNA dopant40. For the BNA-LCs composite, K11 can be roughly estimated by substituting Δε and Vth according to Eq. (1). Table 2 shows that BNA doping decreases K11 of the LC mixture. Moreover, BNA doping decreases the TNI and hence the associated order parameter S and Δn of the LC mixture according to Eq. (2) and (3)41,42,43.

$$ S = (1 - T/T_{NI} )^{\upbeta } , $$

(2)

$$\Delta n =\Delta n_{0} (1 - T/T_{NI} )^{\upbeta } , $$

(3)

$$ \gamma { = }\left( {{\text{a}}_{0} {\text{ } + \text{ a}}_{1} {\text{S } + \text{ a}}_{2} {\text{S}}^{2} } \right)\exp \frac{{{\text{ES}}^{m} }}{{k_{b} \left( {T - T_{0} } \right)}}, $$

(4)

where S is the order parameter, T is ambient temperature, T0 is the melting point of the LC mixture, m is an exponent, ai are proportionality, Δn0 is the birefringence of the LC mixture at 0 K, kb is the Boltzmann constant, β is a material parameter, and E is the activation energy of molecule rotation. For many of the LC compounds studied, β are approximately 0.25 and insensitive to materials44.Eq. (2) is only valid for T sufficiently smaller than TNI45,46. The BNA molecule composed of biphenyl rings induced an interaction with the polar substituents of LCs and decreases TNI, Δn and S37,39,47. In this study, T/TNI is less than 0.5 and thus S can be estimated by substituting T = 298 K, β = 0.25, and TNI into Eq. (2). As shown in Table 2, with 3 wt% BNA doping, S decreased by ~ 5%. The decreased S also indicates the decrement in K11 because K11 is proportional to S248. In addition, γ is proportional to E and S. Meier and Saupe reported that relaxation time \(\tau_{\parallel }\) is related to the potential barrier parameter η in VA LC cells49.

$$ \tau_{\parallel } \sim \frac{\exp (\eta ) - 1}{\eta }, $$

(5)

where η can be estimated by substituting S into the equation50

$$ \eta \approx \frac{{{\text{3S(5 - }}\pi {\text{S)}}}}{{{\text{2(1 - S}}^{{2}} {)}}}. $$

(6)

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In this experiment, the estimated η and \(\tau_{\parallel }\) decreased with increased BNA concentration due to the reduced S (Table 2). E is related to \(\tau_{\parallel }\) according to Eq. (7)51.

$$ E = 2.303 \, RT \, \log \left( {\frac{{\tau_{\parallel } k_{b} T}}{h}} \right), $$

(7)

where R is the molar gas constant, and h is the Plank constant. The decreased \(\tau_{\parallel }\) reduced E with increasing BNA concentration. Consequently, BNA doping decreased γ due to the decrements in the S and E of the LC mixture. The γ of LC mixture is also experimentally determined by transient-current measurement52. As shown in Fig. 3e, γ is decreased by ~ 44% with the increased BNA concentration.

Figure 4a shows the fall times of the BNA-doped LC cells at various temperatures. Rise (fall) time was defined as the time required for the transmission to change from 90 to 10% (10–90%) of the maximum transmission when the cell is turned on from 2 to 10 V (turned off from 10 to 2 V). Rise time is significantly smaller than fall time because of the former’s electric torque-driven reorientation, whereas the latter has a free relaxation reorientation. The rise times of the BNA-doped LC cells were almost constant at ~ 3.23, 1.58, and 0.67 ms for − 10°, 0°, and RT, respectively, due to the same turn-on voltage. Meanwhile, the fall time of the BNA-doped LC cells decreased with increased BNA concentration because BNA doping decreased the γ of the LC mixture and the Vth of the cell. Notably, the 3 wt% BNA-doped LC cell showed a fall time that was five times faster than that of the pure one at RT. If the applied voltage (Vapp) is much higher than Vth, the relationships among fall time (τoff), rise time (τon), Vth, and γ can be expressed as follows:43

$$ \tau_{o} = \frac{{\gamma d^{2} }}{{K_{11} \pi^{2} }}, $$

(8)

$$ \tau_{on} = \frac{{\tau_{o} }}{{\left| {\left( {\frac{{V_{app} }}{{V_{th} }}} \right)^{2} - 1} \right|}}, $$

(9)

$$ \tau_{off} = \frac{{\tau_{o} }}{{\left| {\left( {\frac{{V_{bios} }}{{V_{th} }}} \right)^{2} - 1} \right|}}, $$

(10)

where τ0 is the relaxation time constant when the LC cell is turned off from Vapp slightly higher than Vth, K11 is the splay elastic constant, Vbios is the bios voltage, and d is the cell thickness. BNA doping significantly decreased τoff due to the reduced γ and Vth. Alkyl (methyl-CH3) and phenyl groups are known to decrease viscosity. BNA has a phenyl group, so BNA doping can reduce viscosity47,53.

(a) Fall times of the BNA-doped LC cells at different temperatures. (b) n at various BNA concentrations.

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The additional restoring force provided by the BNA’s SPEF also decreases the fall time of LC cell. If we consider BNA molecule as a dipole. The direction of the resultant dipole moment surrounding the BNAs (local regions) could be different from the director of LCs54,55. When no electric field is applied to the cell, the LCs near the local region orient along the resultant diploe moment direction, but other LCs still align parallel to the cell substrate. Consequently, BNA doping slightly disturbs the LC alignment and decreases the average S of the LC mixture. As a sufficient high electric field is applied to the cell, the LCs near in local regions as well as other regions reorient parallel to the applied electric field. Once the applied field is turned off, the LCs in local regions tend to return to their previously resultant dipole moment directions due to the BNA’s SPEF, creating stronger restoring force that significantly decreases the fall time of the cell.

The NO2 group in BNA makes the LC cell unstable, because of the increased ion density (n) in the LC cell. The increased n worsens the image sticking in the LC device. In this paper, the n of BNA-doped LC cell is determined by dielectric spectrum method56. As shown in Fig. 4b, as expected, the n increases from \({2}{\text{.16}} \times {10}^{{{17}}} \, m^{ - 3}\) to \({3}{\text{.83}} \times {10}^{{{17}}} \, m^{ - 3}\) with BNA concentrations. The doping of metallic/metal oxide NPs to suppress the ion density or operating the cell with high frequency is possible solution for the image sticking issue.

DFT is a potential tool to explain the electronic structure of molecules. As shown in Fig. 5a–c, the structure optimization of aligned geometry between the BNA and 5CB molecule was performed using DFT with Becke-3–Lee–Yang–Parr (B3LYP) at the 6–31 + G (2d, p) basis set using Gaussian 09 software57,58,59,60. It was also used to explain the effects of the BNA-E7 mixture due to the monomer 5CB being the major component of LC E7. Several parameters, such as ultraviolet–visible (UV–vis) absorption spectrum, highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), molecular electrostatic potential, Δε, Δα, μ, and polarizability (α), were further obtained from the aligned geometry.

Geometry structures of (a) BNA, (b) 5CB, and (c) 5CB + BNA; (d) theoretical absorption spectra for BNA, 5CB, and BNA + 5CB.

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Figure 5d shows the calculated optical absorption spectra of 5CB, BNA, and 5CB + BNA, which provides an insight into the linear electronic absorption properties. The absorption peaks for 5CB and BNA appeared at 292 nm (π → π*) and 345 nm (n → π*), respectively, due to the presence of nitro and methyl groups61. The calculation results also indicated that BNA dopant shifted the absorbance wavelength of the LC cell toward 400 nm, confirming the partial contribution of BNA dopant to the yellowish CIE chromatographic coordinate of the BNA-doped LC cell, as shown in the inset of Fig. 2c.

The molecular orbital transition between HOMO and LUMO was calculated from the UV–vis absorption spectrum in Fig. 5d. HOMO acts as an electron donor, whereas LUMO acts as an electron acceptor. Here, HOMO and LUMO were concentrated entirely over anionic and cationic moieties, respectively. The HOMO–LUMO energy gaps (ΔE) of BNA and 5CB molecules was calculated using DFT with B3LYP at the 6–31 + G (2d, p) basis set using Gaussian 09 software. As shown in Table 3, the calculated ΔE of BNA, 5CB, and BNA + 5CB were 3.79, 4.60, and 3.91 eV, respectively62. A low value of the ΔE pertains to the concluding CT interactions taking place within the molecule and causes a highly polarized electronic structure. The relationship between dielectric constant and the ΔE is determined by63

$$\upvarepsilon (q) = 1 + \frac{1}{V}\frac{16\pi }{{q^{2} }}\sum\limits_{i}^{occ.} {\sum\limits_{a}^{vir.} {\frac{{\left| {\left\langle {\Phi _{i} (r)\left| {\exp (iq.r\left. ) \right|\Phi _{a} (r\left. ) \right\rangle \left| {^{2} } \right.} \right.} \right.} \right.}}{{E_{i} - E_{a} }}} } , $$

(11)

where the indices i and a represent the occupied and virtual (unoccupied) orbitals, respectively; ε is the dielectric constant; q is the wave vector; Ei and Ea are the orbital energies for occupied and virtual orbitals of \(\phi_{i}\) and \(\phi_{a}\), respectively; and V is the volume of the target molecule. ΔE is the difference between the occupied (Ei) and virtual (Ea) orbital energies, which appears in the denominator of Eq. (11). Therefore, a decreased ΔE increases dielectric constant ε. As shown in Table 3, BNA doping decreased ΔE and hence increased the permittivity (\(\varepsilon_{\parallel }\) and \(\varepsilon_{ \bot }\)) of the LC mixture.

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The molecular electrostatic potential (MEP) is related to the charge distributions of molecules and is calculated using DFT with B3LYP at the 6–31 + G (2d, p) basis set using Gaussian 09 software. MEP can be used to determine molecular interactions and analyse the bonding nature. MEP is related to the electronic density sites for electrophilic attacks and nucleophilic reactions as well as halogen and hydrogen-bonding interactions64. In Fig. 6, the negative (red) and positive (blue) regions represent electrophilic reactivity and nucleophilic reactivity sites, respectively. NO2 and the cyano groups are located in negative regions, whereas NH2 and CH2 are located in the positive region. MEP represents the net electrostatic effect of a molecule generated from the total charge distribution. It is extensively correlated with partial charges, electronegativity, dipole moments, and chemical reactivity. The total atomic electric dipole moment (μ) for the halogen bond participants in the charge-transfer complexes Dm …X–Y of the group was determined. The result showed that the magnitude (from − 8.03 to + 8.03 a.u.) of the total atomic dipole moment |μ(D)| was the largest for the BNA + 5CB complexes, indicating that it exhibited the highest interaction energy (Eint)65,66. Consequently, BNA doping increased Eint and the dipole moment (μ) and significantly increased the permittivity of the LC mixture67, as shown in Fig. 3c.

MEPs of (a) BNA, (b) 5CB, and (c) BNA + 5CB.

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The Maier–Meier equation was used to calculate Δε in consideration of the anisotropy in molecular polarizability and the orientation of the permanent dipole moment, as shown in Eqs. (12) - (14)68.

$$ \varepsilon_{\parallel } = 1 + \frac{NFh}{{\varepsilon_{0} }}\left\{ {\alpha { + }\frac{2}{3}\Delta \alpha S + \frac{{F\mu^{2} }}{{3k_{b} T}}(1 - (1 - 3\cos^{2} \theta )S} \right\}, $$

(12)

$$ \varepsilon_{{ \bot }} = 1 + \frac{NFh}{{\varepsilon_{0} }}\left\{ {\alpha { - }\frac{1}{3}\Delta \alpha S + \frac{{F\mu^{2} }}{{3k_{b} T}}(1 + \frac{1}{2}(1 - 3(\cos^{2} \theta )S} \right\}, $$

(13)

$$\Delta \varepsilon = \frac{NFh}{{\varepsilon_{0} }}\left\{ {\Delta \alpha { - }\frac{{F\mu^{2} }}{{2k_{b} T}}(1 - 3(cos\theta )^{2} )} \right\}S, $$

(14)

where N is the molecular number density; ε0 is the vacuum permittivity; F and h are constants of proportionality called the reaction field factor and the cavity factor, respectively; and θ is the dipole moment orientation angle relative to the long principal axis of the molecular frame. α and Δα can be calculated as

$$ \alpha = \frac{{\alpha_{xx} + \alpha_{yy} + \alpha_{zz} }}{3}, $$

(15)

$$ \Delta \alpha = \alpha_{xx} - \frac{{\alpha_{xx} + \alpha_{yy} }}{2}, $$

(16)

where αxx is the molecular polarizability parallel to the molecular long principal axis and αyy and αzz are the molecular polarizabilities perpendicular to the molecular long principal axis.

As shown in Table 3, the μ, α, and Δα for 5CB, BNA, 5CB + BNA, and 5CB + BNA + 5CB were calculated by using DFT applying the B3LYP method with the 6–31 + G (2d, p) basis set of the Gaussian’09 software. The increments in μ, α, and Δα were more considerable than the decrement (only 5%) in S with BNA doping, indicating that the enhancement in Δε was mainly attributed to the increment in μ, α, and Δα according to Eqs. (12) - (14).

Conclusions

The electro-optical effects of organic BNA dispersed in nematic LCs were demonstrated in this study. In the experiment, the BNA dopant preserved the color performance but slightly decreased the transmission of LC cells due to the refractive index mismatch between the interfaces and BNA absorbance. When the BNA-doped concentration reached 3 wt%, the Vth of the LC cells decreased by 25% due to the decreased K11 and increased Δε of the LC mixture. The S and Δn of the LC mixture decreased by ~ 5% due to the decreased TNI. Moreover, BNA doping decreased the activation energy E of the LC mixture. Consequently, BNA doping decreased the γ of the LC mixture. Notably, the 3 wt% BNA-doped LC cell had a fall time that was five times faster than that of the undoped LC cell, due to the decreased γ and Vth, and the additional restoring force induced by the BNA’s SPEF. In the calculation, the BNA dopant increased the Eint, μ, α, Δα, and Δε of the LC mixture and decreased its ΔE. The decreased ΔE increased the permittivity of the LC mixture. For practical applications, the optimal combination of LC and organic molecules still needs more in-depth research.

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Acknowledgements

The authors would like to thank Prof. C. H. Hu from the Department of Chemistry, National Changhua University of Education, for his assistance in the DFT calculations.

Funding

Ministry of Science and Technology, Taiwan (MOST) (107-2112-M-018-003-MY3, 108-2811-M-018-502).

Author information

Affiliations

  1. Department of Physics, National Changhua University of Education, Changhua, 500, Taiwan

    Pravinraj Selvaraj

  2. Department of Physics, University College of Engineering, BIT- Campus, Anna University, Tiruchirappalli, 620 024, India

    Karthick Subramani & Brahadeeswaran Srinivasan

  3. Graduate Institute of Photonics, National Changhua University of Education, Changhua, 500, Taiwan

    Che-Ju Hsu & Chi-Yen Huang

Contributions

P.S. executed this experiment and wrote the manuscript; K.S. and B.S. provided the BNA material; C.J.H. and C.Y.H. provided the conception and design of the work, analysis and interpretation of data, and revised the manuscript.

Corresponding authors

Correspondence to Che-Ju Hsu or Chi-Yen Huang.

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The authors declare no competing interests.

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Synthesis of benzyl chloride by the free radical chlorination of toluene using TCCA

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