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A simple and convergent way to synthesize 2-aminobromonaphthalenes involves condensation of free secondary amines with the corresponding 2-naphthol under Bucherer conditions. The amination protocol relies on common Teflon-capped pressure flasks and has been used to modify the tertiary aminonaphthalene core of DANPY, a biocompatible chromophore shown to be safe and effective for staining a variety of cellular targets. Following a Suzuki reaction with pyridine 4-boronic acid, additional diversity is introduced upon N -alkylation to install the pyridinium cation.
New DANPY derivatives and intermediates reported herein reflect the modularity of the dye nucleus, including the addition of groups useful for applications in membrane staining and DNA-based biophotonics. Dyes with nonlinear optical NLO activity 1 are of interest for both photonic systems 2 and a number of imaging techniques in living cells.
The core dialkylaminonaphthylpyridinium DANPY chromophore consists of a tertiary aromatic amine coupled to a para -substituted pyridinium cation. A large hyperpolarizability is conducive to NLO processes such as the electro-optic effect 14 , 15 and second harmonic generation.
After disclosing an extensive evaluation of the structural, photophysical, and DNA-binding properties exhibited by the trimethylated fluorophore DANPY-1, 5 we grew interested in changing substituents at both the naphthylamine and pyridinium units through synthesis. In the discovery phase of our study, 2-aminobromonaphthalene see 1 , Scheme 1 was an ideal starting material because of the convenience of forging two sp 3 C—N bonds by routine alkylation.
As an improvement, we report herein a more practical and versatile approach to DANPY variants made possible by an effort to expand the scope of the Bucherer synthesis of 2-aminonaphthalenes. The addition of groups that allow coating of DNA to yield an alcohol-soluble electro-optic material 17 , 18 is also disclosed. Another pursuit still under development is building amphiphilic dyes suitable for lipid staining e. Shifting the absorbance maximum or manipulating hyperpolarizability was not a major target of this study; the primary rationale for calculating these properties for derivatives of interest was to evaluate whether optical properties would be comparable to DANPY However, changes in side-chain functionalization induce a significant and desirable variation in hydrophobicity, ranging from a log P of 2.
The wide range of logP values suggests that the DANPY nucleus can be tuned for affinity to either hydrophobic or hydrophilic substrates with simple modifications to the naphthylamine substituents. The small bathochromic shift for 4 aligns with that predicted from DFT calculations and is likely due to the greater electron-donating power of pyrrolidine versus dimethylamine; the reduction of the Stokes shift in a polar methanol environment is likely due to the increased hydrophobicity larger log P of the ground state.
The photoluminescence quantum yield of 4 at nm in DMSO is 0. If 4 is added to a 0. The path of synthesis depicted in Scheme 1 is highly scalable due to the crystalline nature of 2 , 3 , and 4. An alternative strategy for installing the dialkyl naphthalene amine in 2 would be to construct its lone sp 2 C—N bond by either Pd-catalyzed cross-coupling or formal nucleophilic aromatic substitution.
As shown in Table 2 , we now report that tricycle 2 and five other 6-bromonaphthaleneamines 6 — 10 are readily obtained in a practical manner by simply mixing naphthol 5 with a secondary amine under Bucherer reaction conditions. A Bucherer reaction 27 , 28 involves thermal conversion of a naphthol to a naphthylamine, and it has also seen use for transamination events in the 2-aminonaphthalene series.
The transformation takes place in aqueous medium in the presence of sulfurous acid or any of its salts i. French chemist Robert Lepetit was the first to discover the transformation in Another report describes aminonaphthalene synthesis by use of microwave irradiation, 34 but neutral and electron-rich methoxylated naphthol substrates were explored, and only acyclic secondary amines were tested as nucleophiles.
Na 2 S 2 O 5 common name disodium, also called sodium pyrosulfite or sodium disulfite was chosen as the reagent because once dissolved in water, metabisulfite dianion releases sulfur dioxide as a pungent gas and leaves behind sulfite dianion, the most reactive of sulfurous acid salts known to mediate Bucherer transformation. For all entries in Table 2 , the reported yields represent an average of at least two runs conducted on gram scale in which reaction time was restricted to 1 day out of convenience; some combinations of reagents may benefit from prolonged heating.
In the event where minor amounts of unreacted 5 are present at workup given the reversible nature of the reaction, a simple flash filtration through a pad of silica gel is sufficient to deliver amine products in analytically pure form 36 because naphthol is considerably more polar. Two other advantages concerning the scope of this methodology are as follows: 1 success in the process is not limited to secondary amines that are water-soluble.
As shown in entry 1b, the use of diisobutylamine as nucleophile gives modest levels of conversion in just 24 h even though the reaction mixture remains biphasic. It is probable that an alternative synthetic route to 10 based on iterative N -alkylation would be much longer and require protecting group manipulations. Based on known literature precedents, 27 , 28 formation of products 2 and 6 — 10 involves a key bisulfite adduct derived from addition to the keto form of the starting naphthol see d , Scheme 2.
To begin, protonation at C1 commences a typical enol—keto tautomerization, yielding conjugated oxonium cation a. In either case, keto forms of 1- and 2-naphthols a and b are known 28 to behave differently than their nonaromatic counterparts.
Cyclic and acyclic alkanones can only furnish 1,2-bisulfite adducts, which are quite useful when conducting purification or isolation. After rate-determining formation of the tetralone sulfonate d , the course of product formation is straightforward. Amine condensation with the free carbonyl delivers iminium ion e and then enamine f after proton loss at C1. The final stage involves rearomatization by sodium hydrogen sulfite elimination.
With a mechanism established, it becomes clear why overamination of 5 does not occur under these reaction conditions: C—N bond formation is restricted to the hydroxylated position that serves as a latent carbonyl function. As a salt, the DANPY nucleus is subject to further diversification with respect to its counterion and pyridinium alkyl group. The identity of the anion stems from the choice of electrophile used to build the alkylpyridinium cation, and primary bromides have also proven effective.
As shown in Scheme 3 , N -alkylation of the pyridine derived from 6 5 , 36 with bromoalkanes linked to 7-hydroxy coumarin umbelliferone give multifunctional fluorophores 12 and 13 as red, amorphous solids. These dye molecules may be suitable for photonic devices that utilize DNA-derived polymer waveguides.
In summary, a short and convergent entry to DANPY dyes has been refined by extending the Bucherer amination of 2-naphthols to cyclic secondary amines. The methodology relies on a less expensive naphthalene precursor relative to earlier work and will facilitate study of structure—function relationships in the donor amine unit of the dye.
The synthetic pathway also tolerates modification within the acceptor pyridinium domain, with more elaborate chromophores 12 and 13 now available for DNA-based biophotonics. Additional results will be reported in due course. All reactions were carried out in oven- and flame-dried glassware under inert atmosphere in dry degassed solvents using Schlenk and vacuum line techniques.
Column chromatography was performed with high-purity Davisil grade silica gel. TLC was performed with 0. Infrared spectra were recorded on a Fourier transform IR spectrophotometer; peaks are reported in wavenumbers cm —1 as strong s , medium m , weak w , or broad br.
High-resolution mass spectra were recorded using electrospray ionization time-of-flight methods at the University of Illinois Urbana-Champaign. Fluorescence spectra were recorded in methanol using a fluorimeter with an excitation wavelength of nm and a grating width of 15 nm for both emission and excitation, subtracting the scattering contribution from a pure methanol reference.
Anhydrous acetonitrile was dispensed from a solvent purification system driven by compressed argon. Iodomethane, 1,6-dibromohexane, 1,8-dibromooctane, and all secondary amines were distilled to colorless oils in the absence of a drying agent and used immediately.
The organic layer was removed and the aqueous layer was washed twice with ethyl acetate 20 mL. The combined organic layers were washed three times with saturated sodium chloride to remove residual water and DMSO.
The resulting solution was dried over MgSO 4 , filtered, and concentrated by rotary evaporation. During this step, iridescent brown salt crystals were observed to precipitate out of solution. This substance proved to be TBAI and, if desired, could be removed with an additional filtration step. It is not necessary, however, because the salt does not migrate through the silica gel used for purification.
Concentration afforded a shiny, light brown solid. Found: C, The vessel was fitted with a rubber septum and a vent needle, evacuated, and purged with argon on the Schlenk line. At this point, the reaction mixture was less turbid and a Pd black precipitate was visible. A routine TLC analysis confirmed the absence of the starting bromoarene 2. The mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with water 75 mL and ethyl acetate 75 mL.
After removing the organic layer, the aqueous layer was washed two times with 50 mL of ethyl acetate, and the combined organic layers were washed three times with an equal volume of saturated sodium chloride in order to remove residual DMF. The purified extract was dried over MgSO 4 , filtered through a medium porosity glass frit, and concentrated by rotary evaporation to give an orange solid residue. The crude material can be purified by recrystallization from hot toluene.
Slow cooling of the hot filtrate delivered the product as light orange, flaky nodules and clusters. Rotary evaporation of the long-wave UV-active fractions results in spontaneous deposition of light orange crystals that were vacuum-filtered, washed with cold petroleum ether, and dried under high vacuum 0.
In a dry glass vial containing a magnetic stir bar and a Teflon-lined screw cap, To the resulting light orange solution, iodomethane After 10 min, the reaction mixture was more orange in color and gentle solvent reflux had begun. Upon 24 h of stirring at this temperature, a bright red solution and dark precipitate were observed. The solid is the pyridinium iodide, which can be recovered by microfiltration but in variable purity because of a potential for dimethylation to give a dicationic material.
An uncharacterized yellow-orange fraction elutes just before the desired product, which is bright red in solution and light blue to violet under long-wave UV irradiation. The column also removes a dicationic impurity, as the dimethylamine unit can also quaternize by methylation.
Pooling and rinsing of pure fractions with chloroform, followed by concentration on a rotovap connected to a high vacuum, gave a dark red, tacky residue. Prolonged exposure to high vacuum may be required to remove the less volatile acetic acid. The solid was then recrystallized from a boiling mixture of chloroform 25 mL and methanol 2—4 mL, just enough to promote dissolution using a hot filtration step to remove any insoluble material.
Water 18 mL, 1. Up to 5. Melting of the substrate leads to partial dissolution, and the heterogeneous mixture gradually turns dark brown in color. After cooling to room temperature and venting the flask, the reaction mixture was extracted three times with 50 mL portions of ethyl acetate. The combined organic layers were washed once with an equal volume of saturated sodium bicarbonate and sodium chloride and dried over MgSO 4.
Filtration to remove the drying agent and concentration by rotary evaporation gave a light yellow residue that can be passed through a pad of silica gel in hexane:Et 2 O to remove any trace of 5 present by TLC analysis or directly recrystallized from hexane to give a flaky, free-flowing white solid 4.
The representative Bucherer amination procedure described above was performed on a 1. Found C, A 50 mL round-bottom flask equipped with a magnetic stir bar was charged with umbelliferone 1.
These solids partially dissolved, forming a light yellow suspension that was treated with 1,6-dibromohexane A large excess of electrophile is used in order to discourage dietherification by the phenoxide anion. Thus, a stream of nitrogen was used to purge out over half of the solvent volume, and the mixture was partitioned between 50 mL of water and 50 mL of ethyl acetate:hexanes in a separatory funnel.
The organic layer was collected and the bright yellow aqueous layer was washed twice with 30 mL of ethyl acetate:hexanes. The pooled organic layers were dried over MgSO 4 and concentrated. Purification by silica gel chromatography with 2. The procedure given directly above for the bromohexyloxy chromenone 11a was repeated on a scale involving 1. An identical workup and purification gave 1.
A simple and convergent way to synthesize 2-aminobromonaphthalenes involves condensation of free secondary amines with the corresponding 2-naphthol under Bucherer conditions. The amination protocol relies on common Teflon-capped pressure flasks and has been used to modify the tertiary aminonaphthalene core of DANPY, a biocompatible chromophore shown to be safe and effective for staining a variety of cellular targets. Following a Suzuki reaction with pyridine 4-boronic acid, additional diversity is introduced upon N -alkylation to install the pyridinium cation. New DANPY derivatives and intermediates reported herein reflect the modularity of the dye nucleus, including the addition of groups useful for applications in membrane staining and DNA-based biophotonics. Dyes with nonlinear optical NLO activity 1 are of interest for both photonic systems 2 and a number of imaging techniques in living cells.
E-mail: absalimi uok. A simple and reliable method based on the Bucherer reaction is proposed for the functionalization of graphene oxide GO with amine —NH 2 groups. In the proposed method the chemical reaction between ammonia and GO, as precursor materials, is catalyzed with sodium bisulfite. The surface analysis and material characterization reveal the high percentage of amine functional groups that can be achieved via this method. The investigation of the electrocatalytic activity of the prepared amino-rGO toward the oxygen reduction reaction confirms the significant improvement in the catalytic activity of amine functionalized graphene surface in the vicinity of doped nitrogen in the same graphene framework.