The Solvatofluorochromism of 2,4,6-Triarylpyrimidine Derivatives

DR. CAROLINA ALIAGA (Orcid ID : 0000-0002-1352-3164)

Article type : Special Issue Research Article

The Solvatofluorochromism of 2,4,6-Triarylpyrimidine

Derivatives^†

1

1,2

José Rodríguez-Aguilar, Matías Vidal, Camila Pastenes, Carolina Aliaga,*

1

Marcos Caroli Rezende and Moisés Domínguez*

1

Facultad de Química y Biología, Universidad de Santiago de Chile, Av. Bernardo

2

O´Higgins 3363, Santiago, Chile. Centro para el Desarrollo de la Nanociencia y la

Nanotecnología, CEDENNA, Chile

*Corresponding authors’ e-mails: carolina.aliaga@usach.cl (Carolina Aliaga) and

moises.dominguez@usach.cl (Moisés Dominguez)

^†THIS ARTICLE IS PART OF A SPECIAL ISSUE DEDICATED TO DR. EDUARDO

LISSI.

This article has been accepted for publication and undergone full peer review but has not

been through the copyediting, typesetting, pagination and proofreading process, which may

lead to differences between this version and the Version of Record. Please cite this article as

doi: 10.1111/php.12982

ABSTRACT

Seven new 2,4,6-triarylpyrimidines were synthesized and their solvatofluorochromism

investigated in 12 solvents and in an aqueous micellar solution of reduced Triton X-100. A

multiparametric analysis of their emission band showed that the solvent dipolarity and

basicity were mainly responsible for their solvatofluorochromism, which arose from an

internal charge-transfer from a donor fragment to the pyrimidine acceptor, confirmed by

theoretical calculations. In the micellar system, quenching of their fluorescence by addition

of derivatives of 2,2,6,6-tetramethylpiperidinoxyl (TEMPO) radical was investigated, and the

results were consistent with the spectral changes brought about by the micro-heterogeneous

system.

INTRODUCTION

Electron-accepting pyridimines conjugated with different donor groups have been employed

in the design of fluorescent probes. Such molecules, with a general formula A––D, exhibit

interesting properties as solvent-sensitive emitting dyes. By varying the pyrimidine acceptor

group A, the conjugating linkage  or the donor group D, the solvatofluorochromic

properties of these dyes can be widely varied. Examples of such variations include the direct

linking between a pyrimidine ring and an amino group (1–3), conjugation of a pyridimidine

system with a methoxyphenyl group (4), with an aminophenyl group linked through an

ethylene bridge (5–8) or through an arylene (9), or heteroarylene spacer (10).

In a series of papers, Achelle et al. have synthesized and described the optical properties of a

variety of fluorescent diazines of general formula A––D in homogeneous media (6–8, 11–

13), arriving at general structure-activity relationships for these compounds (14).

In the present report we describe the synthesis and optical properties of a series of novel A–

–D solvatofluorochromic dyes 1a–g (Scheme 1), investigating the effect of substituents X

and Y on their spectral behavior.

A multiparametric analysis of their emission spectra in 12 solvents revealed the main

properties responsible for the observed solvatofluorochromism. Their behavior was also

investigated in an aqueous micellar solution of reduced Triton-X 100, by recording their

spectra and by measuring the quenching of their fluorescence by addition of derivatives of

2,2,6,6-tetramethylpiperidinoxyl (TEMPO) radical.

MATERIALS AND METHODS

NMR spectra were recorded with a Bruker Avance 400 MHz equipment. IR spectra were

measured with a Spectrum two FT-IR (ATR) Perkin Elmer spectrophotometer. Melting

points were recorded with a Microthermal capillary melting-point apparatus and were not

corrected.

All solvents employed for the spectral measurements were of spectroscopic grade. All

reagents were analytically pure and were used without further purification. TLC analyses

were performed on TLC plates (silica gel 60, fluorescence indicator F254, 0.25 mm layer

thickness). Products were purified by column chromatography on silica gel 60 (0.063-0.200

mm). All reactions were carried out in standard oven-dried glassware.

The 4-acetoxy- and 4-hexanoyloxy-TEMPO derivatives were prepared following a reported

procedure (15) Bromochalcones 4a–c were synthesized according to literature procedures

(16-18).

General procedure for the synthesis of pyrimidines 6a–c. A 20 mL round-bottom flask was

charged with benzamidine hydrochloride 5 (440 mg, 2.8 mmol mmol) and the corresponding

chalcone 4a–c (2.8 mmol), potassium hydroxide (315 mg, 5.6 mmol) and ethanol (10 mL).

The resulting mixture was heated at 120^oC for 1.5 h. Upon the end of the reaction (as

observed on TLC, n-hexanes/EtOAc, 5:1), the solid that precipitated from the reaction

mixture was separated by filtration, washed with cold ethanol and water and recrystallized

from ethanol.

In this way, the following pyrimidines were prepared:

 4-(p-Bromophenyl)-2,6-diphenylpyrimidine (6a), obtained as a colorless solid (538

1

mg, 46%), mp 169–171 ºC (lit. (19) 168–170 ◦C). H NMR (400 MHz, CDCl₃) δ:

7.62–7.53 (m, 7H), 7.69 (d, J = 8.34 Hz, 1H), 8.30–8.34 (m, 4H), 8.64–8.81 (m, 3H).

 4-(p-Bromophenyl)-6-(p-fluorophenyl)-2-phenylpyrimidine (6b), obtained as a

1

colorless solid (715 mg, 63%), mp 127–129 ºC. H NMR (400 MHz, CDCl₃) δ: 8.73–

8.64 (m, 2H), 8.33–8.25 (m, 2H), 8.16 (d, J = 8.5 Hz, 2H), 7.92 (s, 1H), 7.69 (d, J =

13

8.5 Hz, 2H), 7.59–7.49 (m, 3H), 7.30–7.23 (m, 2H); C NMR (101 MHz, CDCl₃) δ:

not soluble enough to be recorded. FT–IR (ATR) ν: 3070, 2925, 1590, 1550, 1375,

1195; HRMS (ESI–TOF): m/z [M + H]⁺calcd for C H BrFN : 405.0397; found:

22 14

2

405.0417.

 4-(p-Bromophenyl)-6-(p-methoxyphenyl)-2-phenylpyrimidine (6c), obtained as a

1

light yellow solid (491 mg, 42%), mp 141-143 ºC. H NMR (400 MHz, CDCl₃) δ:

8.73-8.65 (m, 2H), 8.28 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.5 Hz, 2H), 7.92 (s, 1H),

7.69 (d, J = 8.5 Hz, 2H), 7.59–7.49 (m, 3H), 7.08 (d, J = 8.8 Hz, 2H), 3.92 (s, 3H);

13

C NMR (101 MHz, CDCl₃) δ: 164.5, 163.3, 162.1, 138.1, 136.6, 132.1, 131.5,

130.7, 130.3, 130.2, 129.8, 128.8, 128.8, 128.5, 128.4, 125.3, 114.3, 113.8, 109.1,

55.5; FT–IR (ATR) ν: 3070, 2925, 1585, 1535; HRMS (ESI–TOF): m/z [M + H]⁺

calcd for C H BrN O: 417.0597; found: 417.0612.

23 17

2

General procedure for the synthesis of dyes (1a–g). A microwave vial (10 mL) was charged

with the bromophenyl-4-pyrimidines 6a–c (0.7 mmol), Pd(PPh₃)₄(41 mg ,0.035 mmol, 5

mol%), K₂CO₃(97 mg, 0.7 mmol), N,N-dimethylformamide (5.0 mL), and 4-(N,N-

dimethyl)phenylboronic acid (139 mg, 0.84 mmol) or the and 4-(N,N-diphenyl)phenylboronic

acid (243 mg, 0.84 mmol). The resulting reaction mixture was heated for 1 h at 100 ºC. Upon

the end of the reaction (as observed on TLC, n-hexanes/EtOAc, 5:1), the mixture was diluted

with water (25 mL) and extracted with EtOAc (3 × 15 mL). The combined organic extracts

were dried over Na₂SO₄and all the volatile components were removed by rotary evaporation.

The desired products 1a–g were purified by column chromatography (n-hexanes:EtOAc, 20:1

→ 5:1).

In this way, the following pyrimidines were prepared:

 2-Phenyl-4-[4-(4-N,N-dimethylaminophenyl)phenyl]-6-phenylpyrimidine

(1a),

1

obtained as a yellow solid (180 mg, 60%), mp 209–211 ºC. H NMR (400 MHz,

CDCl₃) δ: 8.77 – 8.73 (m, 2H), 8.34 (d, J = 8.4 Hz, 2H), 8.31 (dd, J = 7.8, 1.9 Hz,

2H), 8.05 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.58 – 7.52 (m,

13

6H), 6.84 (d, J = 8.8 Hz, 2H), 3.03 (s, 6H).; C NMR (101 MHz, CDCl₃) δ: 164.6,

164.5, 150.4, 143.7, 137.7, 134.9, 133.2, 131.7, 130.7, 130.6, 129.3, 128.9, 128.7,

128.5, 128.4, 128.1, 127.8, 127.7, 127.3, 126.5, 112.7, 110.0, 44.7; FT–IR (ATR) ν:

3070, 2960, 2870, 2805, 1620, 1590, 1510, 1230, 1090; HRMS (ESI-TOF): m/z [M +

H]⁺calcd for C H N : 428.2121; found: 428.2133.

30 25 3

 2-Phenyl-4-[4-(4-N,N-dimethylaminophenyl)phenyl]-6-(4-fluorophenyl)pyrimidine

1

(1b), obtained as a yellow solid (160 mg, 50%), mp 172–174 ºC. H NMR (400 MHz,

CDCl₃) δ: 8.77 – 8.68 (m, 2H), 8.36 – 8.27 (m, 4H), 7.99 (s, 1H), 7.75 (d, J = 8.5 Hz,

2H), 7.62 (d, J = 8.8 Hz, 2H), 7.58 – 7.50 (m, 4H), 7.29 – 7.21 (m, 1H), 6.88 – 6.82

13

(m, 2H), 3.03 (s, 6H); C NMR (101 MHz, CDCl₃) δ: 164.7, 164.5, 163.5, 150.4,

143.7, 138.2, 134.8, 133.8, 130.9, 130.7, 129.4, 129.3, 128.8, 128.6, 128.5, 127.8,

127.7, 127.6, 126.5, 126.3, 116.0, 115.8, 112.7, 109.6, 40.5 (due to the very poor

solubility of the product, the unambiguous determination of J_C-Fwas not possible);

FT–IR (ATR) ν: 3055, 2965, 2870, 2800, 1615, 1595, 1520, 1230, 1085; HRMS (ESI-

TOF): m/z [M + H]⁺calcd for C₃₀H₂₄FN₃: 446.2027; found: 446.2031.

 2-Phenyl-4-[4-(4-N,N-dimethylaminophenyl)phenyl]-6-(4-

methoxyphenyl)pyrimidine (1c), obtained as a yellow solid (458 mg, 75%), mp 201–

1

203 ºC. H NMR (400 MHz, CDCl₃) δ: 8.78 – 8.69 (m, 2H), 8.32 (d, J = 8.4 Hz, 2H),

8.29 (d, J = 8.8 Hz, 2H), 7.97 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.8 Hz,

2H), 7.57 – 7.49 (m, 3H), 7.07 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 3H), 3.91 (s,

13

3H); C NMR (101 MHz, CDCl₃) δ: 164.4, 164.3, 164.1, 161.9, 150.4, 143.5, 138.5,

135.1, 130.5, 130.2, 128.8, 128.5, 128.4, 128.1, 127.8, 127.6, 126.4, 114.3, 112.7,

109.1, 55.6, 40.5; FT–IR (ATR) ν: 3065, 2955, 2860, 2795, 1630, 1585, 1500, 1250,

1105; HRMS (ESI-TOF): m/z [M + H]⁺calcd for C₃₁H₂₇N₃O: 458.2227; found:

458.2237.

 2-Phenyl-4-[4-(4-N,N-diphenylaminophenyl)phenyl]-6-phenylpyrimidine

(1d),

1

obtained as a yellow solid (162 mg, 42%), mp 207–209 ºC. H NMR (400 MHz,

CDCl₃) δ: 8.79 – 8.70 (m, 2H), 8.36 (d, J = 8.1 Hz, 2H), 8.33 – 8.28 (m, 2H), 8.04 (s,

1H), 7.76 (d, J = 8.1 Hz, 2H), 7.60 – 7.50 (m, 8H), 7.30 (d, J = 7.8 Hz, 2H), 7.26 (d, J

13

= 8.2 Hz, 2H), 7.20 – 7.13 (m, 6H), 7.09 – 7.02 (m, 2H).; C NMR (101 MHz,

CDCl₃) δ: 164.7, 164.5, 164.4, 147.6, 143.0, 138.2, 137.7, 135.8, 133.9, 130.8, 130.6,

129.4, 129.0, 128.5, 128.5, 127.8, 127.7, 127.3, 127.0, 124.7, 123.6, 123.2, 110.1.;

FT–IR (ATR) ν: 3075, 2965, 2865, 2800, 1615, 1600, 1525, 1235, 1080; HRMS (ESI-

TOF): m/z [M + H]⁺calcd for C H N : 552,2434; found: 552.2441.

40 29 3

 2-Phenyl-4-[4-(4-N,N-diphenylaminophenyl)phenyl]-6-(4-fluorophenyl)pyrimidine

1

(1e), obtained as a yellow solid (279 mg, 70%), mp 163–165 ºC. H NMR (400 MHz,

CDCl₃) δ: 8.77 – 8.69 (m, 2H), 8.40 – 8.32 (m, 2H), 8.33 – 8.25 (m, 2H), 7.99 (s, 1H),

7.80 – 7.72 (m, 2H), 7.62 – 7.50 (m, 5H), 7.34 – 7.26 (m, 4H), 7.21 – 7.14 (m, 6H),

13

7.11 – 7.04 (m, 4H); C NMR (101 MHz, CDCl₃) δ: 164.4, 164.2, 1623.0 (d, J¹=

218 Hz), 147.8, 147.6, 142.9, 140.5, 138.4, 136.0, 133.9, 131.5, 130.5, 130.3 (d, J³=

5 Hz), 130.1, 129.4, 128.6 (d, J²= 35 Hz), 128.4, 127.8, 127.7, 127.0, 124.7, 123.6,

123.2, 114.3, 113.8, 109.2, 55.5; FT–IR (ATR) ν: 3065, 2975, 2870, 2795, 1620,

1595, 1520, 1220, 1075; HRMS (ESI-TOF): m/z [M + H]⁺calcd for C H FN :

40 28

3

570.2340; found: 570.2349.

 2-Phenyl-4-[4-(4-N,N-diphenylaminophenyl)phenyl]-6-(4-

methoxyphenyl)pyrimidine (1f), obtained as a yellow solid (191 mg, 47%), mp 166–

1

168 ºC. H NMR (400 MHz, CDCl₃) δ: 8.77 – 8.70 (m, 2H), 8.38 – 8.33 (m, 2H), 8.30

(d, J = 8.8 Hz, 2H), 7.99 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.60 – 7.50 (m, 5H), 7.32 –

7.27 (m, 4H), 7.20 – 7.14 (m, 5H), 7.10 – 7.05 (m, 3H), 3.92 (s, 3H); Due to its very

13

poor solubility, the C NMR spectrum of the product was not recorded. FT–IR

(ATR) ν: 3080, 2970, 2865, 2790, 1615, 1595, 1510, 1210, 1095; HRMS (ESI-TOF):

m/z [M + H]⁺calcd for C₄₁H₃₁N₃O: 582.2540; found: 582.2551.

 2-Phenyl-4-[4-(4-methoxyphenyl)phenyl]-6-phenylpyrimidine (1g), prepared by a

coupling reaction with 4-methoxyphenylboronic acid (128 mg, 0.84 mmol). The

1

product was obtained as a yellow solid (218 mg, 75%), mp 164-165 ºC. H NMR (400

MHz, CDCl₃) δ: 8.74 (dd, J = 7.9, 1.9 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.33 – 8.26

(m, 1H), 8.04 (s, 0H), 7.74 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.60 – 7.49

13

(m, 3H), 7.02 (d, J = 8.7 Hz, 1H), 3.87 (s, 3H); C NMR (101 MHz, CDCl₃) δ:

164.7, 164.5, 164.4, 159.7, 143.2, 138.3, 137.6, 135.8, 132.8, 130.8, 130.6, 128.9,

128.5, 128.5, 128.3, 127.7, 127.3, 127.1, 114.4, 110.1, 55.4; FT–IR (ATR) ν: 3080,

+

2975, 2870, 2795, 1620, 1590, 1510, 1215, 1075; HRMS (ESI-TOF): m/z [M + H]

calcd for C H N O: 415.1805; found: 415.1813.

29 22 2

Theoretical Calculations. All the quantum-chemical calculations were carried out with the

Gaussian 09 package (20). Geometries for all molecules were optimized at the CAM-

B3LYP/6-31+G(d) density-functional level of theory, and transition energies calculated with

the TDDFT option. The Polarizable Continuum Model (PCM) was employed to mimic

solvent effects for benzene, dichloromethane and dimethylsulfoxide.

Spectroscopic and photophysical measurements. UV–vis spectra were recorded on a Perkin Elmer

Lambda 35 spectrophotometer in the range of 250–700 nm. Emission spectra were measured at room

o

temperature (25 1 C) on a Perkin Elmer LS 55 spectrofluorometer or a FluoroMax 4CP (Horiba

Jovin Yvon). Fluorescence quantum yields were measured on a FluoroMax 4CP (Horiba Jovin Yvon)

spectrofluorometer equipped with the Quanta-Phi integrating sphere.

RESULTS AND DISCUSSION

Synthesis of the diazines

Two synthetic approaches for building the pyrimidine ring in compounds like diazines 1a–g

have been described. The first of them employs condensation reactions from carbonyl (21-23)

and carbonyl-masked compounds (24) of already functionalized starting materials. The

second approach, a more flexible one, is based on the use of palladium-catalyzed cross-

coupling reactions of chloropyrimidines (25-27) or pseudohalide derivatives (28).

The seven solvatofluorochromic diazines 1a–g studied here were prepared by a

combination of these two general approaches. The general synthetic route is shown in

Scheme 2. Condensation of 4-substituted acetophenones 2ac with 4-bromobenzaldehyde

provided the bromochalcones 4ac in very good yields (67-95%), which were cyclized to the

2,4,6-triphenylpyrimidine derivatives 6a-c by reaction with benzamidine hydrochloride in

moderate to good yields (42-63%). Finally, palladium-catalyzed Suzuki-Miyaura cross-

coupling

of

6ac

with

4-N,N-diphenylamino-,

4-N,N-dimethylamino-

or

methoxyphenylboronic acid provided the solvatofluorochromic diazines 1ag in moderate to

very good yields (42-75%).

Solvatofluorochromism of diazines 1a–g in pure solvents

The UV-Vis spectra of diazines 1a–g showed weak absorptions in the range of 400-330 nm,

with maxima that were not resolved in most solvents, similarly to reported spectra of

triarylpyrimidines (29, 30). These broad ICT bands were composite, as shown by the two

excitation bands at 331 and 371 nm, obtained from the emission spectrum of 1a in DMSO

(Figure 1). By contrast with the corresponding emission bands, the lower-energy absorption

band was not strongly solvent-dependent, with maxima at 358 nm in hexane, 363 nm in

methanol and 371 nm in DMSO. Following the suggestion of Kido et al. in their detailed

study of the emission spectra of some triarylpyrimidines (29), we assigned the more intense,

fluorosolvatochromic emission band with the lower-energy absorption to a normal ICT

process. The higher-energy band at 331 nm in DMSO possibly originated from a TICT

process (1-3). A detailed confirmation of this hypothesis in all employed solvents was

however beyond the scope of the present work.

In their emission spectra, the intense, solvent-dependent band shifted, in the case of

dyes 1a–c, from 425-430 nm in hexane to 550-565 nm in DMSO. In the case of the N,N-

diphenylamino derivatives 1d–f , this emission band shifted from 430-435 nm in hexane to

535-540 nm in methanol. Finally, for dye 1g, a shorter solvatofluorochromic range was

observed, from 379 nm in hexane to 461 nm in methanol. A representative example of their

behavior is reproduced for diazine 1a in Figure 2.

-1

em

Emission energy values in kcal.mol (E = 28590 / λ

) for all diazines 1a–g in

em

max

twelve solvents of a wide range of polarities are listed in Table 1. Water was excluded from

the set of studied solvents, because of the erratic behavior of the emission band of all diazines

in this rather acidic solvent, a probable reflection of the strong hydrogen-bonds between the

solutes and this medium.

In the search of the solvent properties responsible for the observed

solvatofluorochromism of the studied diazines, a multiparametric regression analysis of their

emission energies was performed employing Equation 1 and Catalán’s parameters for solvent

acidity (SA), basicity (SB), polarizability (SP) and dipolarity (SdP) (31).

calc

0

em

E

em

= E

+ a SA + b SB + c SP + d SdP

(1)

The resulting values from the regression analysis for the corresponding coefficients a,

b, c and d are given in Table 2.

According to the results of the multiparametric regression in Table 2, the

solvatofluorochromism of diazines 1a–g depends mainly on the solvent dipolarity SdP, being

also affected by the medium polarizability (SP) and basicity (SB). The medium acidity has

only a minor influence on the solvatofluorochromic behavior.

Diazines 1a–g can be described as resonance hybrids of the two canonical formulae

(I) and (II), where (I) is the major contributor to the ground state and (II) to the excited state

(Scheme 3). The canonical structure (II) is stabilized by dipolar, basic solvents, resulting in a

reduction of the emission energy from this new less energetic state.

Solvent dipolarity is the major contributor for the stabilization of canonical structure

(II), with the larger negative coefficient d that varies little in the analogous series 1a–f.

Replacement of the amino group by the less electron-donating methoxy group in 1g reduces

the contribution of (II) to the excited-state resonance hybrid. Accordingly, the absolute value

of coefficient d is also reduced.

The influence of the medium basicity and polarizability on the internal charge-

transfer of the amino derivatives 1a–1f depends on the nature of the electron-donor and of

substituent R. Both the NMe and the NPh₂donor groups stabilize the canonical structure

2

(II) by electrostatic attraction between the solvent and the positive end Y of the solute, which

is reflected in a high sensitivity to the medium basicity. Steric hindrance by the bulky phenyl

rings, which shields the positive end Y in structure (II) from the solvent, can nevertheless

reduce the sensitivity of compounds 1d–f to the medium basicity. In addition, as a more

polarizable group than NMe , the NPh₂donor leads to dyes with larger sensitivities to the

2

medium polarizability (coefficient c of equation 1) than dyes 1a–c, with a N,N-

dimethylamino donor.

The results obtained with the aid of Eq. 1 were validated by the good correlation

exp

em

obtained between the experimental (E

) and the calculated emission energy values

calc

em

(E

), obtained from the simplified equation 2, which considered only the two parameters

largely responsible for the observed solvatofluorochromism of these dyes, solvent basicity

SB and dipolarity SdP.

calc

0

em

E_e

= E

+ b SB + d SdP

(2)

m

0

em

Values for the fitting parameters E , b and d of equation 2 are given in Table 2. As

2

an example, Figure 3 illustrates the good correlation (r = 0.97) obtained by plotting the

calculated emission energies from equation 2 against the experimental values for diazine 1a.

0

em

The fitting parameter E

should correspond to emission energies from spectra of

dyes 1a-g in the gas phase. These values should be very similar to the E values in the least

em

0

em

polar solvent of the set (hexane). In fact, comparison of the E

values of equation 2 (Table

2) with the corresponding emission energy values in hexane (Table 1) reveals very small

-1

differences, with deviations that are not greater than  0.9 kcal.mol .

The rather small variation of the regression parameters a, b and c in the series of

diazines 1a–g is in agreement with the two structural features previously stressed by Achelle

et al. in a comprehensive study of structure-property relationships of different emitting

diazines (14). Both the nature of the Y group, which should affect the 1,3-diazine moiety, or

the nature of the X group, which should affect the 4-aminophenyl fragment, play a relatively

unimportant role in the solvatofluorochromism of these compounds.

Computational calculations in pure solvents

TDDFT calculations of the emission spectra of diazine 1a were carried out to shed light on

the nature of its solvatofluorochromic band. As suggested by Jacquemin et al. for similar

diazines (32) we have employed the range-separated hybrid CAM-B3LYP for the geometry

optimizations of the ground (S ) and excited state (S ). The structures of both states showed

o

1

a high coplanarity between the pyrimidine, the phenyl-linkage and the N,N-

dimethylaminophenyl rings.

The calculated emission energies of diazine 1a shown in Table 1 were obtained as the

energetic difference between the ground and the first excited state, after relaxation of the

excited structure. After optimization of the ground state structure at the CAM-B3LYP/6-

31+G(d) level of theory, the first excited state was obtained and relaxed with the aid of the

TDDFT method at the same level of theory. The Polarizable Continuum Model (PCM) was

employed to mimic the solvent effect for benzene, dichloromethane and dimethyl sulfoxide

(20).

The calculated emission energies in benzene, dichloromethane and dimethylsulfoxide

are given in Table 3.

The calculated emission energies of diazine 1a in the three solvents are very close to

-1

those observed experimentally, differing only by 2-6 kcal.mol . This good agreement

supports the idea of a planar excited state and of an ICT S  S transition as responsible for

1

o

the solvatofluorochromic band.

The nature of the emission band was studied by analysing the electron densities of the

ground and the excited state of diazine 1a. Figure 4 shows that charge is transferred from the

donor N,N-dimethylaminophenyl group to the pyrimidine acceptor ring. Internal charge-

transfer occurs along the main axis of the molecule, involving the substituent at the 4-

position of the pyrimidine system, with little participation of the 2- and 6- phenyl

substituents. A very similar charge flow could be observed in benzene and dimethylsulfoxide.

Fluorescence and quenching in a micellar system

The observed solvatofluorochromism of the pyrimidine dyes 1a–g suggested a comparison of

this behavior in pure solvents and in a micellar system. The poor solubility of these dyes in

water was an indication of their hydrophobicity, and of a more effective solubility in micellar

media. In fact, in an aqueous solution of a neutral micelle (reduced Triton X-100), the

solubility of dyes 1a and 1d increased significantly, allowing reliable emission spectra of

these two compounds to be recorded in aqueous media and compared with their fluorescence

spectra in pure solvents.

Table 4 lists the emission 

values for the two dyes in an aqueous solution of

max

Triton X-100, together with the corresponding quantum yields in this medium. For the sake

of comparison, quantum yields for the two dyes were also determined in methanol and in

benzene, and are included in the table.

Values for the fluorescence maxima of dyes 1a and 1d in the neutral micellar system (452

nm) are similar to the corresponding 

max

values obtained in benzene (454 nm for 1a and 444 nm for

1d), suggesting that the two dyes are located in the more hydrophobic core of the micelle, in a

microenvironment with a polarity similar to that of non-polar benzene. A similar conclusion is

reached by comparison of the quantum yields of the two dyes in the micellar system with those in

benzene. Quantum yields in this pure non-polar solvent were similar and only slightly larger (0.758 or

1a and 1.000 for 1d) than in the micro-heterogeneous system (0.559 for 1a and 0.878 for 1d).

An alternative approach for determining the location of the two dyes in the micellar micro-

environment was the application of a recently developed protocol for locating antioxidants in these

media. The protocol was based on the comparative quenching ability of an antioxidant in a micellar

medium vis-à-vis a series of radical TEMPO derivatives of increasing hydrophobicity (33).

In the present work the protocol was simplified to the use of only two analogous TEMPO

derivatives of different hydrophobicities, compounds 12a and 12b

Addition of increasing amounts of any of the two radicals quenched the fluorescence of dyes

1a and 1d in the micelle. Linear Stern-Volmer plots were obtained in all cases (Figure 5) allowing the

determination of quenching constants for the two dyes towards radicals 12a or 12b.

Table 5 lists the Stern-Volmer constants obtained for the two dyes in the micelle, in the

presence of radicals 12a and 12b.

For both dyes 1a and 1d, the more hydrophobic radical 12b was a more effective

quencher, suggesting a closer proximity between the dyes and this hydrophobic quencher in

the micelle. This was in agreement with the evidence from the data of Table 4, which

suggested that the two dyes were located in a hydrophobic environment within the micelle.

In addition, 1d showed a greater sensitivity to the hydrophobic nature of the quenchers than

1a. This is shown in a comparison of the Stern-Volmer constants of 1a and 1d in Table 5.

Changing from 12a to the more hydrophobic quencher 12b resulted in a 1.3-fold increase of

the Stern-Volmer constant for dye 1a and of a 1.6-fold increase for dye 1d. This observation

suggested that dye 1d, being more hydrophobic than 1a, was located in a more hydrophobic

micro-environment within the micelle than dye 1a. This conclusion too was in agreement

with the data of Table 4, which suggested a more hydrophobic micro-environment for dye 1d

(a larger quantum-yield value) than for dye 1a.

CONCLUSIONS

A series of 2,4,6-triarylpyrimidines were synthesized and their solvatofluorochromic behavior

investigated in pure solvents and in an aqueous micellar solution of reduced Triton X-100. The

existence of composite emission bands for all dyes was suggested by the emission spectrum of 1a in

DMSO and in micelle solutions. The major band in these media was ascribed to an internal charge-

transfer process, as revealed by theoretical calculations. This solvatofluorochromic band exhibited

variations of its Stokes shift as large as 124 nm, as shown, for example, by the spectra of compound

1a in hexane (shift of 67 nm) and in DMSO (shift of 191 nm). Quantum yields as large as 1.00 were

observed in non-polar benzene, decreasing significantly in protic solvents. In a micellar solution of

reduced Triton X-100, quantum yields were as large as in non-polar media.

A multiparametric regression analysis of their spectral behavior in 12 solvents, employing

Catalán’s parameters (31). revealed a major dependence of their emission band on the solvent

dipolarity and basicity, with some contribution in the case of the N,N-diphenylamino derivatives 1d–f

of the solvent polarizability. These trends were rationalized by the existence of a dipolar excited state,

stabilized by polarizable, basic solvents.

The poorly soluble dyes in water were readily solubilized in an aqueous micellar solution of

reduced Triton X-100. Two analogous dyes, 1a and 1d, with a N,N-dimethylamino- or a N,N-

diphenylamino substituent, had their fluorescence spectra recorded in this micellar system. Their

fluorescence quenching by two derivatives of the TEMPO radical was also studied in this neutral

micellar medium. The emission 

max

values and the quantum yield for the two dyes in this medium

were consistent with the corresponding Stern-Volmer quenching constants determined in the micelle.

These data pointed to slightly different locations of the two dyes within the micelle, with the more

hydrophobic N,N-diphenylamino derivative 1d lodging in a more hydrophobic microenvironment in

the micelle than its N,N-dimethylamino analog 1a.

ACKNOWLEDGEMENTS: Financial support from FONDECYT projects 11140497

and 1140212 is gratefully acknowledged. M. V. thanks USA1555 project from VRIDEI-

USACH. CA thanks CEDENNA PB0807 project. We thank Dr. N. Pizarro (UNAB) for

helping us with quantum-yield measurements.

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†

-1

Table 1. Emission energy values in kcal∙mol for diazines 1a–g in various protic and non

protic solvents.

Solvent

1a

1b

1c

1d

1e

1f

1g

Hexane

67.27

62.98

55.73

58.59

52.17

52.08

50.87

54.67

53.44

53.34

53.24

53.64

66.49

62.98

55.41

58.47

52.17

52.36

50.69

54.56

53.34

53.44

53.04

53.14

67.59

63.96

56.39

59.32

52.75

52.95

51.89

54.88

53.44

53.24

53.04

52.46

65.73

64.39

55.84

58.83

53.34

53.64

53.24

56.73

54.46

53.84

53.54

53.24

66.18

64.69

56.73

59.32

53.84

54.46

53.54

57.88

54.98

54.46

53.95

53.04

66.03

64.69

56.95

59.07

53.54

53.74

53.44

57.99

54.56

54.15

53.84

53.04

75.44

73.31

68.24

70.77

65.13

65.28

64.25

67.91

65.73

65.43

64.54

62.02

Benzene

Dichloromethane

Chloroform

Acetonitrile

DMF

DMSO

1-octanol

1-butanol

2-propanol

Ethanol

Methanol

†

Excitation λ

values were 365 nm for compounds 1a–f and 330 nm for compound 1g.

max

Table 2. Values for the fitting parameters a, b, c and d in the multiparametric Equations 1 and 2 (see

bellow), calculated by the regression analysis of the experimental energy values of Table 1.

0

em

2 †

Diazine

a

b

c

d

E

r

††

0.96

0.97

68.363.6

66.850.7

0.432.5

-6.171.3

-5.850.9

-2.155.0

-12.151.1

-12.261.0

1a

†††

1a

-

††

0.95

0.96

67.483.7

66.360.7

-0.312.5

-5.651.3

-5.661.0

-1.615.2

-11.831.1

-11.911.0

1b

†††

1b

-

††

0.97

67.103.4

67.470.7

62.323.2

66.350.8

-2.322.3

-5.741.2

-6.681.0

-3.681.2

-4.521.0

0.514.7

-12.141.0

-12.121.0

-11.671.0

-11.381.1

1c

†††

1c

-

††

0.96

0.95

-1.172.2

5.724.5

1d

†††

1d

-

††

0.97

0.95

63.082.6

66.880.8

-2.631.7

-2.790.9

-4.191.1

5.393.6

-11.900.8

-11.631.1

1e

†††

1e

-

††

0.98

0.95

62.032.5

66.890.7

-1.621.7

-3.160.9

-4.261.0

6.913.4

-12.190.7

-11.841.1

1f

†††

1f

-

††

0.98

0.90

73.962.1

76.160.9

-5.701.4

-2.190.7

-4.621.3

3.072.9

-9.810.6

-9.661.3

1g

†††

1g

-

†

††

Squared correlation coefficient between calculated and experimental values. Regression

†††

equation 1;

regression equation 2;

Table 3. Experimental and calculated emission energies, in kcal.mol^-1, for diazine 1a in three

solvents of different polarity.

exp

calc †

Entry

Solvent

E_em

1

2

3

Benzene

67.27

55.63

50.87

69.17

Dichloromethane

Dimethylsulfoxide

59.55

56.26

†

Calculated at the CAM-B3LYP/6-31+G(d) level of theory employing the SCRF=PCM

option for solvent effects.

Table 4. Emission _maxand quantum-yield values for compounds 1a and 1d in methanol,

benzene and an aqueous micellar solution of reduced Triton X-100.

Quantum yields in different media, 

Emission

Compound

†

micelle

methanol

benzene



max

in

micelle

452

1a

1d

0.559 0.005

0.878 0.001

0.0032 0.0013

0.0298 0.0009

0.758 0.003

1.000 0.001

452

†

In nm, excitation at 365 nm

Table 5. Stern-Volmer constants for the quenching of dyes 1a and 1d by radicals 12a-c in an aqueous

solution of Triton X-100.

Radical quencher

Dye

12a

12b

1a

1d

859 ± 26

737 ± 8

1125 ± 23

1150 ± 14

FIGURE AND SCHEME CAPTIONS

Scheme1. Structures of all studied diazines 1a-g

Scheme 2. General synthetic route for the preparation of diazines 1a–g.

Figure 1. Absorption (solid black,  = 380 nm), emission (dashed black 

=

max

563), excitation (solid red,

= 331 and solid blue 371 nm) and emission spectra

max

(dashed red,

= 432 and dashed blue 563 nm) of 1a in DMSO. In the inset, absorption

max

spectra of 1a in hexane (solid purple, 

= 358 nm), DMSO (solid black,

= 371

max

nm) and methanol (solid green,

= 363 nm)

max

Figure 2. Emission spectra of diazine 1a (λ_exc= 365 nm) in n-hexane (red), benzene (blue),

trichloromethane (dark green), dichloromethane (black), 1-butanol (pink), dimethylsulfoxide

(DMSO) (light blue) and aqueous micelle solution (light green).

Scheme 3. Canonical structures of the resonance hybrids of dyes 1a–g in the ground and in

the first excited state.

2

Figure 3. Linear correlation (r = 0.97) for compound 1a, between the emission energy

calc

em

values (E

), calculated with the aid of equation 2, and the experimental energy values

exp

em

(E

) in twelve solvents.

Figure 4. Electron densities of the ground (left) and excited (S₁) (right) states of dye 1a

calculated in dichloromethane.

Scheme 4. Structures of the 4-alkanoyloxyTEMPO radicals employed in the quenching

experiments.

Figure 5. Stern-Volmer plots for the quenching of (a) dye 1a by radical 12b, and (b) dye 1d by

radical 12a.

Article Doi

The Solvatofluorochromism of 2,4,6-Triarylpyrimidine Derivatives

DOI: 10.1111/php.12982

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