Octupolar chimeric compounds built from quinoline caged acetate moieties: A novel approach for 2-photon uncaging of biomolecules

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Octupolar chimeric compounds built from quinoline

caged acetate moieties: a novel approach for

2-photon uncaging of biomolecules†

Cite this: DOI: 10.1039/c3nj00833a

a

´

Sebastien Picard, Emilie Genin, Guillaume Clermont, Vincent Hugues,

Olivier Mongin^band Mireille Blanchard-Desce*^a

The present study describes the synthesis and investigation of chimeric structures where 6-quinoline

and 8-quinoline caging units are integrated in multipolar systems to yield ‘‘hybrid’’ molecular structures

for two-photon uncaging. These systems were demonstrated to exhibit strikingly enhanced (up to more

than 2 orders of magnitude larger for octupolar derivatives) two-photon absorption responses in the

NIR region compared to common caging groups. Whereas the quadrupolar compound shows the

lowest two-photon uncaging cross-section (d_u), octupolar chimeric derivatives display one-order larger

d_uvalues than their dipolar analogues. This opens a promising route for the design of eﬃcient

octupolar type derivatives for two-photon uncaging of biomolecules.

Received (in Montpellier, France)

25th July 2013,

Accepted 3rd September 2013

DOI: 10.1039/c3nj00833a

www.rsc.org/njc

external reagents in cells and living organisms. Numerous

examples of photo-induced release (also termed ‘‘uncaging’’)

Introduction

The use of light as an external trigger oﬀers a number of

advantages and has been widely applied in the past decades

both in multistep organic synthesis and in biology with ‘‘caged

compounds’’.¹Actually light has proven to be an invaluable tool

in organic synthesis (especially in solid-phase synthesis) allow-

ing the removal of protecting groups under neutral conditions,

without requiring additional chemical reagents. This has been

particularly useful to overcome some of the problems asso-

ciated with extremely sensitive targets, not compatible with

acids or bases.²Photochemically removable protecting groups

also have the advantage to be selectively cleaved in the presence

of other conventional protecting groups that are insensitive to

light. Moreover, possible diﬀerentiation between two photo-

labile protecting groups based on the fine tuning of the

irradiation wavelength led to the concept of chromatic ortho-

gonality.³The use of phototriggers has also emerged as a

particularly attractive tool for the control and investigation of

fundamental biochemical processes. This includes photo-

release of biomolecules, photoswitching and optogenetics.⁴The

use of a light pulse as the triggering event allows fine temporal

control and high selectivity, while it circumvents the use of

of various active molecules have been reported using standard

excitation (i.e. one-photon), leading to a well-established list of

associated requirements.^4a–cThe uncaging process should be

both efficient and fast (especially for applications in neuro-

sciences), produce non-toxic by-products while the photo-

activatable precursor (the so-called ‘‘caged’’ compound) should

display suitable stability in the dark and repressed biological

activity.

More recently, two-photon (2P) excitation has gained

increasing popularity in this field, due to the many advantages

it provides.^4d,fThese include an intrinsic 3D resolution when

used in microscopy (i.e. focused light). In addition, the use of

near-IR excitation wavelengths (instead of one-photon excita-

tion in the UV-blue visible region) leads to increased penetra-

tion depth and can be less photo-toxic. The important criterion

in the case of 2P uncaging is the 2P sensitivity of caged

molecules. This is quantified by the corresponding 2P uncaging

action cross-section (d_u= s₂Q_u), which is the product of the 2P

absorption cross-section (s₂) and of the uncaging quantum

yield (Q_u). Low d_uvalues require the use of high excitation

intensities which can be detrimental to the biological media.

Conversely large d_uvalues pave the way for more eﬃcient and

less damaging 2P uncaging under biological conditions. In that

perspective, d_uvalues higher than 3 Goeppert-Mayer (GM) have

been suggested as highly desirable for biological applications.⁵

This realisation has prompted the quest for novel uncaging

structures combining a large 2P absorption cross-section and

suitable uncaging eﬃciency. Yet 2P uncaging is still in the early

a

´

Univ. Bordeaux, Institut des Sciences Moleculaires, CNRS UMR 5255,

´

351 Cours de la Liberation, F-33405 Talence Cedex, France.

E-mail: m.blanchard-desce@ism.u-bordeaux1.fr; Fax: +33 5-40-00-69-94

^bInstitut des Sciences Chimiques de Rennes, CNRS UMR 6226,

´

Universite de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France

† Electronic supplementary information (ESI) available. See DOI: 10.1039/

c3nj00833a

c

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Fig. 1 Selected examples of TP photoactivable cages.

stages and current cages suitable for eﬃcient 2P photolysis are

only scarce (Fig. 1).

Most of the studies reported in the literature up to now have

focussed on the investigation and structural modification of com-

mon uncaging systems, initially optimised for near-UV excitation.

These structures can be classified into diﬀerent series: widely used

Fig. 2 Octupolar chimeric phototriggers built from a donor triphenylamine core

linked to acceptor quinoline caging moieties through an ethynyl spacer and their

dipolar analogues.

nitrophenylalkyl-based cages (d_uranging from 0.01 to 3.1 GM), allowed as in isolated dipolar branches).¹⁰Taking advantage of

coumarin-4-ylmethyl series (d_u= 0.35–3.1 GM), quinoline deriva- the earlier work on the caging activity of quinoline derivatives

tives (d_uup to 0.9 GM), nitroindoline analogues (d_uup to 0.06 GM), and related studies emphasising the influence of the substitu-

hydroxycinnamyl cages (d_u= 0.3–4.7 GM) and ruthenium bipyr- ents (nature and position) on the 2PA response and uncaging

idyl complexes (d_u= 0.01–0.1 GM).¹Very recently, modification of eﬃciency of the quinoline moiety,¹¹we investigated structures

the donor group in biphenyl derivatives in the nitro aromatic where the ethynyl spacer is grafted either at the 6- or 8-position.

series appeared to be quite successful and led to unprecedented Acetic acid was used as the caged (bio)molecule, allowing easy

d_uvalues (up to 11 GM).⁶This successful strategy, based on using monitoring of phototriggered release. For comparison purpose

dipolar-based compounds for enhancing the 2PA response,⁷was and evaluation of the potential benefit of the octupolar

also applied to quadrupolar-based derivatives by Goeldner and approach, we also investigated a quadrupolar analogue built

co-workers by designing a caging system based on a fluorenyl from a fluorenyl core and having similar linkers. We herein

core bearing two nitroaryl end-groups (BNSF) leading to large d_ureport the synthesis and detailed study of the photophysical

values (5 GM).⁸These results provided evidence that molecular properties of the series of dipolar, quadrupolar and octupolar

engineering of novel cages by enhancing the 2PA response in chimeric derivatives as well as their ability to release acetic acid

multipolar (i.e. dipolar or quadrupolar) derivatives is a promis- under one and 2P excitation in various media. Results are

ing strategy.

Following this line, we decided to investigate an alternative

discussed in terms of structure–property relationships.

route based on the design of octupolar, rather than quadrupolar,

derivatives for 2P uncaging. We chose to focus on dipolar and

octupolar derivatives built from a triphenylamine electron-

Results and discussion

Synthesis

donating moiety linked to electron-withdrawing quinoline 6-Substituted quinoline based dipolar and octupolar derivatives

caging moieties via an ethynyl spacer (Fig. 2). We named these (compounds 6 and 8, respectively) were prepared by means of a

structures ‘‘chimeric derivatives’’ as they are composed of parts Pd(0)-catalysed Sonogashira cross-coupling reaction between

taken from two diﬀerent types of molecules (i.e. a triphenyl- (4-iodophenyl)diphenylamine or tris(4-iodophenyl)amine core,

amine-based chromophore and a quinoline-based cage). As respectively, and 6-ethynylquinoline derivative 3 (Scheme 1).

demonstrated in earlier studies, triphenylamine-cored octupo-

The synthesis of the key intermediate 3 was achieved with a

lar chromophores can combine broad and intense two-photon satisfactory overall yield of 68% (in pure isolated compound)

absorption in the NIR region.⁹This originates from the eﬀective following a four-step sequence starting from the commercially

coherent coupling between the dipolar branches which is available 6-bromo-2-methylquinoline 1. Compound 1 was con-

responsible for the intense 2PA band located at higher energy verted by a known sequential two-step synthetic procedure^11a,c,h,12

(corresponding to an electronic state which is one-photon involving oxidation with selenium dioxide followed by the

forbidden but strongly two-photon allowed) than that corre- reduction of the intermediate aldehyde using sodium borohydride

sponding to the lower excited state (both one and two-photon which leads to the corresponding hydroxymethylene derivative 2

c

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Scheme 1 Reagents and conditions: (i) (a) SeO₂(1.3 equiv.), dioxane reflux 3 h;

(b) NaBH₄(2.0 equiv.), MeOH, 0 1C to RT, overnight, 86% (over 2 steps); (ii)

ethynyltrimethylsilane (1.5 equiv.), PdCl₂(Ph₃P)₂(0.05 equiv.), CuI (0.05 equiv.),

Ph₃P (0.2 equiv.), toluene–Et₃N (5 : 1), 60 1C, 16 h, then in situ at RT, TBAF (1 M in

THF, 2.0 equiv.), 2 h, 79% (2 steps); (iii) 3 (1.2 equiv.), PdCl₂(Ph₃P)₂(0.06 equiv.),

CuI (0.12 equiv.), THF–Et₃N (5 : 1), RT, 2 h, 84%; (iv) DMAP (0.1 equiv.), Et₃N

(2.0 equiv.), Ac₂O (2.0 equiv.), CH₂Cl₂, RT, 4 h, 99%; (v) 3 (3.6 equiv.), PdCl₂(Ph₃P)₂

(0.06 equiv.), CuI (0.12 equiv.), THF–Et₃N (5 : 1), RT, 2 h, then in situ, DMAP

(0.1 equiv.), Ac₂O (2.0 equiv.), RT, 2 h, 94%.

Scheme 2 Reagents and conditions: (i) n-BuLi (1.1 equiv.), THF, ꢀ70 1C, 1 h,

then I₂, ꢀ70 1C to rt, 97%; (ii) SeO₂(1.2 equiv.), dioxane 80 1C, 3 h, 91%; (iii) 10

(1.0 equiv.), Pd₂(dba)₃(0.05 equiv.), CuI (0.1 equiv.), Ph₃P (0.2 equiv.), THF–Et₃N

(20 : 1), RT, 3 h, 12%; (iv) 11 (1.0 equiv.), Pd₂(dba)₃(0.05 equiv.), CuI (0.1 equiv.),

Ph₃P (0.2 equiv.), THF–Et₃N (20 : 1), RT, 3 h, 51%; (v) NaBH₄, THF, RT, overnight;

(vi) DMAP (0.1 equiv.), Ac₂O : Et₃N (1 : 1, v/v); (vii) 11 (3.3 equiv.), Pd₂(dba)₃

(0.05 equiv.), CuI (0.1 equiv.), Ph₃P (0.2 equiv.), TBAF (3.3 equiv.), THF–Et₃N (5 : 1),

RT, overnight, 47%.

with an excellent yield (86%). Further Sonogashira coupling

reaction with ethynyltrimethylsilane, followed by a deprotection,

in situ, of the trimethylsilane group by addition of a solution of

tetrabutylammonium fluoride provided the 6-ethynylquinoline

molecule 3 very eﬃciently (79%). 3 was subsequently transformed

into compound 5a via a Sonogashira coupling reaction with the

known (4-iodophenyl)diphenylamine¹³4 with 84% yield. Next,

treatment of the resulting alcohol 5a with acetic anhydride led

quantitatively to the dipolar 6-substituted quinoline caged acetate

6. Following the same strategy and starting from the known tris-

(4-iodophenyl)amine¹⁴7, we conducted an eﬃcient one-pot

two-step sequence involving a threefold Sonogashira coupling

followed, in situ, by the acetylation reaction to access the octupolar

caged acetate 8. This modification of the initial route was required

due to the very low solubility of the intermediate triol in common

organic solvents, which hinders its isolation, purification and

further conversion.

Keeping in mind that the position of the substituent on the

quinoline moiety might influence the photochemical and

photophysical properties of the cage, we also prepared quino-

line based dipolar and octupolar derivatives substituted at the

8-position (16 and 19). In fact, it has been very recently reported

that 8-(N,N-dimethylamino)quinoline (DMAQ) is considerably

more sensitive to 2P photolysis than its 6-DMAQ analogue.^11h

In the course of the synthesis, we noticed an important

diﬀerence of reactivity between the 6-substituted and 8-substituted

derivatives that brought us to rethink the synthetic route

detailed above and successfully applied for the 6-substituted

derivatives (Scheme 2).

of caged acetate, the synthesis of a reference, non-photoactivatable

compound was performed for comparison purpose. The prepara-

tion of compound 13 was achieved via a Sonogashira coupling

between N-(4-ethynylphenyl)-N,N-diphenylamine¹⁵12 and quinal-

dine 10 in the presence of Pd₂(dba)₃, triphenylphosphine and CuI

in THF–Et₃N. The dipolar aldehyde 14 was obtained similarly from

alkyne 12 and 8-iodoquinoline-2-carboxaldehyde 11 with a reason-

able yield (51%). The aldehyde functional group was reduced into

the corresponding alcohol in the presence of NaBH₄and then the

acetyl group was introduced. The dipolar 8-substituted quinoline

caged acetate 16 was synthesised in two steps from its precursor 14

with a good overall yield (75%). The octupolar 8-substituted quino-

line caged acetate 19 was prepared using the same strategy.

Considering the relative instability of the tris[4-(ethynylphenyl)]-

amine core towards polymerisation, we chose to start from the

silylated precursor^9b17 and to use slightly modified Sonogashira

reaction conditions by adding tetrabutylammonium fluoride in

the reaction medium for in situ alkyne deprotection. This Sonoga-

shira coupling/deprotection one-pot protocol provided the

expected trialdehyde 18 with a satisfactory yield of 47% (corre-

sponding to an average yield of 78% for the three consecutive

coupling reactions). Sequential aldehyde reduction with sodium

borohydride followed by acetylation with acetic anhydride afforded

the targeted octupolar 8-substituted quinoline caged acetate 19

(90%). Once again, the corresponding triol was not isolated due to

its lack of solubility in common organic solvents.

We thus prepared the 8-iodoquinoline-2-carboxaldehyde 11

in two steps from the commercially available 8-bromoquinal-

dine 9. First, treatment of compound 9 with n-butyllithium

followed by the quenching of the metalated intermediate with a

diode gave rise to an eﬃcient exchange of the bromide atom

with an iodide atom and provided 8-iodoquinaldine 10 with 97%

yield. Classical oxidation with selenium oxide then aﬀorded the

corresponding aldehyde 11 with 91% yield. Parallel to the synthesis

In parallel, for comparison purpose, we prepared the quad-

rupolar analogue of derivative 8 built from a fluorenyl core

instead of a triphenylamine core and bearing 6-quinoline

uncaging end moieties (compound 21 in Scheme 3). Quadru-

polar derivatives built from a fluorenyl core and ethynyl linkers

have long been shown to provide an interesting route towards

2PA chromophores combining significant 2PA responses and

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Scheme 3 Reagents and conditions: (i) 3 (2.4 equiv.), PdCl₂(Ph₃P)₂(0.04 equiv.),

CuI (0.08 equiv.), THF–Et₃N (20 : 1), RT, overnight, then (ii) in situ, DMAP (0.1 equiv.),

Ac₂O (2.0 equiv.), RT, overnight, 95%.

transparency.¹⁶Compound 21 was successfully synthesised in a

one pot two-step sequence from the fluorenyl core¹⁷20 and

6-ethynylquinoline 3 by Sonogashira cross-coupling followed by

the acetylation reaction (Scheme 3).

All new compounds were fully characterised by ¹H, ¹³C NMR

spectroscopy, HRMS. Interestingly, from the splitting values

observed for acetylenic carbon in derivatives 8 and 19, we could

obtain an estimation of the Hammett constant values for

6-quinoline and 8-quinoline moieties using the linear relation-

ships previously established for octupolar fluorophores built

from a triphenylamine core and ethynyl linkers.^9fThe s values

derived using this methodology are 0.3 and 1.1 for 6-quinoline

and 8-quinoline respectively.¹⁸This suggests that these moieties

behave as good acceptors when connected via a conjugated linker

to a strong electron-donating group, the 8-quinoline showing a

stronger electron-withdrawing ability.

Fig. 3 Absorption and emission spectra of compounds 5a, 6, 8 (top) and 15, 16,

19 (bottom) in THF.

the UV region. The low-energy, broad and intense absorption

band in the near UV region (maxima between 368 and 385 nm)

is characterised by a high molar extinction coeﬃcient (up to

9.3 ꢁ 10⁴M^ꢀ1cm^ꢀ1) which is about one order of magnitude

larger than those reported for the DMAQ series.¹¹This band is

characteristic of an intramolecular charge transfer (ICT) transi-

tion, as corroborated by the large Stokes shift values. An addi-

tional, narrower, absorption band is observed in the UV region

(maxima around 300 nm), which can be ascribed to a higher

energy p–p* transition. As noted from Table 1, all derivatives

Photophysical properties

Absorption and fluorescence properties in organic environ-

ments. The photophysical properties of the chimeric and

reference compounds were first investigated in aprotic organic

solvents (where photolysis is reduced due to lack of water). The

experimental data obtained in THF are collected in Table 1. As

illustrated in Fig. 3, all compounds display strong absorption in

Table 1 Photophysical properties of the dipolar, quadrupolar and octupolar exhibit significant fluorescence in the visible region, with fluores-

compounds in THF

cence quantum yields ranging from 0.56 to 0.77 in THF.

Comparison of the properties of the one-branch (‘‘dipolar’’)

max

e

l

abs

log(e^max

)

l

Stokes shift^a

t^dk_r^e

k_nr

em

[nm] [M^ꢀ1cm^ꢀ1] [nm] [10³cm^ꢀ1

]

F_f^b,c[ns] [10⁹

s

^ꢀ1] [10⁹s^ꢀ1

]

and three-branch (‘‘octupolar’’) derivatives having the same

peripheral groups (6 versus 8 and 16 versus 19) confirms that

the triphenylamine core mediates electronic coupling between

the branches leading to a definite red-shift (15 nm and 16 nm

respectively) of the absorption band.¹⁹In contrast, a blue shift

(16 nm and 6 nm respectively) of the emission band is

observed. As a result,²⁰the radiative decay rates of the octu-

polar derivatives are increased compared to those of the dipolar

ones. This can be interpreted as a consequence of excitation

localisation on a dipolar branch prior to emission, leading to a

polarised excited state (vide infra) whose energy is slightly

increased by the proximity of the other dipolar branches, due

to destabilising dipole–dipole through-space interactions.²¹In

all cases, we also observe a decrease of the fluorescence lifetime

which results from the enhancement of the non-radiative decay

rate. This is consistent with additional vibrational deactivation

modes in the three-branched architectures. Interestingly the

larger radiative decay rates almost compensate for the increased

5a 368 4.58

465 5.7

473 5.8

457 4.1

0.64 2.4 0.27

0.65 2.5 0.26

0.56 1.7 0.32

0.15

296 4.48

371 4.53

296 4.46

385 4.97

292 4.73

6

8

0.14

0.26

13 370 4.46

300 4.43

15 373 4.45

300 4.41

16 376 4.38

301 4.39

19 392 4.85

305 4.63

459 5.2

486 6.2

488 6.1

482 4.8

0.77 2.5 0.30

0.60 3.4 0.17

0.63 3.6 0.17

0.59 2.6 0.22

0.09

0.12

0.10

0.16

21 366 4.95

392 1.8

0.68 0.7 0.97

0.47

a

b

Stokes shift = 1/l_absꢀ1/l_em

.

F = fluorescence quantum yields.

d

c

Standard: quinine (F = 0.546) in 0.5 M aq H₂SO₄. Fluorescence

lifetime determined using time-correlated single-photon counting.

e

Radiative (k_r= F/t and non-radiative k_nr= (1ꢀF)/t) decay rates.

c

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non-radiative decay rates leading to similar fluorescence quantum polarised (relaxed) excited state, and thus leads to lower transi-

yields for one-branch (dipolar) and three-branch (octupolar) tion energy. We also observe that the fluorescence quantum

related derivatives (Table 1).

yield and lifetime values of acetyl derivatives are maintained

The position of the donating substituent (4-ethynylphenyl)- (compared to their hydroxyl analogues), indicating that no

diphenylamine on the quinoline moiety is found to influence noticeable photochemical processes (i.e. uncaging of acetic

the photophysical properties of both dipolar (compounds 5a, 6 acid) occur in pure THF. This is consistent with a photorelease

versus 15, 16) and octupolar (compound 8 versus 19) derivatives. mechanism involving water molecules.^11b,d–g

A slight red-shift of the absorption spectra (5–7 nm) and a

Finally, it is interesting to note that the reference quadru-

hypochromic effect are observed for derivatives built from polar derivative 21 shows similar absorption properties (low-

8-quinoline terminal groups compared to their analogues having energy absorption band) as the related dipolar and octupolar

6-quinoline terminal groups. Interestingly, an even more pro- derivatives (i.e. 6 and 8) having the same uncaging moieties but

nounced red-shift (15–25 nm) of the emission spectra is observed markedly blue-shifted emission. The resulting markedly smaller

resulting in larger Stokes shift values. Hence 8-quinoline deriva- Stokes shift value suggests that the ICT phenomenon leading to

tives show lower energy gaps (E₀₀) in agreement with the esti- symmetry-breaking after excitation and subsequent emission

mated stronger electron-withdrawing character. Both radiative from a localised polarised excited state²²is not strongly opera-

rate and non-radiative rates are smaller leading to longer lifetimes tive in that case.²³Also both the radiative and non-radiative

but similar fluorescence quantum yields.

rates are found to be much larger than those of its dipolar

Comparing the data obtained for the 8-substituted com- and octupolar counterparts, suggesting larger delocalisation in

pounds 13 and 15, we also observed that the introduction of a the excited state and more eﬃcient vibrational deactivation

polar hydroxyl group on the quinoline side chain induces a processes.

bathochromic shift of the absorption spectrum and more

Solvatochromism. The influence of the environment was

strikingly of the emission band (Table 1). The decrease of the investigated by studying the photophysical properties of the

fluorescent quantum yield values can be ascribed to combined chromophores in organic solvents of various polarities (Fig. 4).

eﬀects of the reduction of the radiative decay rate (related to the The absorption spectra are found to be almost unaﬀected by

red-shifted emission) and the slight enhancement of the non- the change in solvent polarity (except for a high polarity solvent

radiative decay rate which parallels the increase of the fluores- like DMSO which leads to the decrease of the molar extinction

cence lifetime. Further red-shifts of both absorption and emission coeﬃcients probably due to inhomogeneous broadening). In

bands are observed on going from the hydroxyl to the acetyl contrast, increasing the solvent polarity induces a marked

group. This suggests that the close hydroxyl or acetyl dipoles bathochromic shift of the emission spectra (responsible for

adopt a relative orientation allowing the stabilisation of the lower radiative decay rates) and subsequently the Stokes shift

Fig. 4 Solvatochromic behaviour of 6-quinoline derivative compounds 5a (top left) and 8 (bottom left) and 8-quinoline derivatives 15 (top right) and 19

(bottom right).

c

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Table 2 Solvatochromism analysis and anisotropy data of dipolar chimeric

derivatives

Specific solvatochromic

t^c

y^d

v^e

a ^f

Dm^g

b

shift^a(10³cm^ꢀ1

)

r

[ns] [ns] (Å³) (Å) (D)

5a

6

8

19.7

21.4

19.5

0.22 3.2

0.21 3.2

3.9 930 6.1 20.9

3.5 842 5.9 20.7

—

15

16

19

17.6

17.1

18.0

0.15 4.7

0.15 4.8

2.8 670 5.4 16.7

2.9 690 5.5 16.7

—

a

Absolute value of the slope derived from the linear dependency of the

Stokes shift on the orientational polarisability (2Dm²/hca³). Fluores-

b

c

cence anisotropy in triacetin. Fluorescence lifetime in triacetin.

d

e

Longitudinal rotational correlation time in triacetin. Molecular

f

volume derived from fluorescence anisotropy. Onsager cavity radius

estimated from the molecular volumes. Photo-induced change of

g

dipole moment (Dm).

(from 17.6 to 19.7 ꢁ 10³cm^ꢀ1) indicative of a large increase of

dipole moment in the excited state for all investigated derivatives.

We observe that 6-quinoline derivatives show larger slope values

than their corresponding analogue having 8-quinoline moieties.

To further derive Dm values, accurate estimation of the Onsager

cavity radius (a) is required. In the case of dipolar derivatives, we

conducted anisotropy (r) and fluorescence lifetime measurements

(t) in a viscous solvent in order to gain more information on the

size of the molecules and estimate the Onsager cavity radius.²⁶

Using the Perrin equation²⁷(eqn (2)), we calculated the long-

itudinal rotational correlation time y from which we derived the

eﬀective molecular volume (v) and subsequently estimated the

Fig. 5 Lippert–Mataga correlations for compounds 5a, 6, 8 (top) and 15, 16, 19

(bottom).

increases. Such positive solvatochromic behaviour is consistent Onsager cavity radius (a):

with an ICT transition with a large dipole moment enhance-

0:4

Zn

kT

ment upon excitation. Interestingly both dipolar (compounds

r_max

¼

with y ¼

(2)

t

1 þ

5a, 6 and 15, 16) and related octupolar derivatives (compounds

8 and 19) did show similar pronounced solvatochromic behavi-

our. This can be ascribed to excitation localisation, after

excitation prior to emission, on the branches of octupolar

derivatives leading to polarised emissive states.^9cIn contrast,

the symmetrical quadrupolar derivative 21 does not show a

marked emission solvatochromism (see ESI†), which suggests

that in that case, excitation localisation on part of the molecule

does not occur in organic solvents.²⁴As shown in Fig. 5, the

solvatochromic behavior of dipolar and octupolar compounds

can be fitted with a Lippert–Mataga relationship²⁵(eqn (1)) as

the Stokes shift values are found to depend linearly on the

polarity–polarisability (or orientational polarisability) para-

meter of the solvent Df:

y

where Z is the solvent viscosity and T the temperature.

The data are collected in Table 2. As expected the caged

compound and their precursors (5a and 6, 15 and 16) show

similar Dm values. In contrast, the 6-quinoline derivatives show

larger Dm values (21 D) than 8-quinoline derivatives (16.5 D).

This may sound surprising since the electron-withdrawing

ability of the 8-quinoline has been estimated to be somewhat

larger. This can however be explained by the shorter distances

between the donating and accepting centres in the 8-derivatives

compared to the 6-derivatives. Indeed the distance between the

donating and accepting nitrogen atoms is 4 Å longer for

6-quinoline derivatives as compared to 8-quinoline analogues.

We also note that related dipolar and octupolar fluoro-

phores (6 and 8, 16 and 19) show similar slope values

(Table 2) providing evidence that excitation localisation on

the branches occurs prior to emission in octupolar derivatives

leading to similarly polarised emissive (relaxed) excited states

in octupolar derivatives and related dipolar derivatives.

n_absꢀ n_em= 2(Dm²/hca³)Df + const

(1)

where n_abs(n_em) is the wavenumber of the absorption (fluores-

cence) maximum, h is the Planck constant, c is the light velocity,

a is the radius of the Onsager cavity, and Df = (e ꢀ 1)/(2e + 1) ꢀ

(n²ꢀ 1)/(2n²+ 1), where e is the dielectric constant and n the

refractive index of the solvent while Dm is the change of dipole

moment of the solute between ground and excited states. The

Two-photon absorption (2PA)

corresponding slope values derived from the linear variations (i.e. Thanks to their fluorescence properties, we could experimen-

2Dm²/hca³) are collected in Table 2. Large values are obtained tally determine the 2PA characteristics of all compounds in the

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Table 3 Two-photon absorption properties of chimeric quinoline derivatives in

As observed from Fig. 6, dipolar derivatives 5a, 6, 13 and 15

exhibit a broad 2PA band (maxima range: 740–760 nm) occur-

ring at about twice the wavelength of the OPA band, which is

consistent with the fact that the lowest-energy excited state is

both one and two-photon allowed for dipolar chromophores.

We observe that maximum values ranging from 100 to 160 GM

are already much larger than those reported for quinoline

derivatives.^11h,27Octupolar chromophores 8 and 19 also pre-

sent this lowest-energy one- and two-photon allowed absorp-

tion band but a major broadening is observed due to the

overlap with a more intense 2PA band (maximum at 730–

740 nm) located at slightly higher energy and related to the

two-photon allowed, one-photon forbidden higher excited state

THF

max

abs

max

TPA

max

TPA

2l

[nm]

l

[nm]

s₂at l

[GM]

5a

6

8

736

742

770

740

750

730

160

163

480

13

15

16

19

740

746

752

784

750

730

100

130

110

390

21

732

710

75

NIR range (700–900 nm) using the well-known two-photon (Fig. 6). As a result the octupolar derivatives show major 2PA

induced fluorescence (TPEF) technique.²⁸Measurements were enhancement as compared to their dipolar analogues, leading

conducted in THF. Data are collected in Table 3. Interestingly, to a 2PA response as high as 480 GM and 390 GM for octupolar

all multipolar chimeric compounds were found to display much derivatives 8 and 19 built from 6-quinoline and 8-quinoline

larger (typically between one and two orders of magnitude larger) uncaging moieties respectively. The chimeric derivatives built

2PA cross section values compared to those reported for the most from 6-quinoline derivatives (both dipolar and quadrupolar)

common caging groups¹and quinoline derivatives.^11h,29

always show larger 2PA responses (by 25 to 45%) than their

Fig. 6 Compared one-photon absorption (black line) and two-photon absorption (red line) spectra of compounds 6 (top left), 8 (middle left), 21 (bottom left),

16 (top right) and 19 (middle right) in THF.

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8-quinoline counterparts (Table 3 and Fig. 6). This parallels the

hyperchromic effect observed for one-photon absorption (vide

supra and Table 1).

In contrast, we observe that the quadrupolar derivatives built

from the fluorenyl core show a much smaller 2PA response in the

700–900 nm spectral range (Fig. 6 and Table 3). These lower values

can be explained by symmetry reasons as well known for quadru-

polar derivatives.³⁰

In this case the lowest energy, one-photon allowed, excited

state is almost two-photon forbidden leading to low 2PA

responses in the NIR range.^16bThe higher excited-state (two-

photon allowed, but one-photon forbidden) is most probably

located in the visible region. Hence the quinoline derivatives

built from a triphenylamine core are more promising chimeric

structures than their quadrupolar analogues built from a

fluorenyl core in terms of 2P excitation eﬃciency in the NIR.

Interestingly, we observe that the presence of the hydroxyl

appendices leads to a definite increase of the 2PA response of

8-quinoline derivatives as indicated by comparison of the 2PA

responses of derivatives 15 and 16. This confirms that the

electric field created by local dipoles close to the chromophore

unit can aﬀect the 2PA response in a significant way.³¹

Fig. 7 ¹H NMR spectrum (400 MHz) of octupole 8 in CDCl₃at t = 0 h and t = 24 h

of irradiation.

of the caged compound simultaneously decreased in both cases

(Fig. 7).

This last observation proved that our compounds are able to

release the acetyl upon light irradiation. The mechanisms of

the photodeprotection reaction of quinoline-based photo-

triggers have been investigated in details in recent years.^11b,d–gIt

has been highlighted that quinoline caged acetates are classically

converted in aqueous media to their respective hydroxyl deriva-

tives upon UV-light excitation and that the photochemical reac-

tion is slower when an organic solvent is used. In these NMR

experiments, the formation of the remnant alcohol did not occur

due to the lack of water and we observed the formation of a

complex mixture which could be explained by the polymerisation

of the cationic intermediate species involved in the proposed

mechanisms. However the comparison of the integration of the

methyl NMR signals allowed us to monitor the time course of the

photochemical reaction for the derivative 6 and thus deduce a

kinetic profile as well as t_90%and Q_uvalues (Table 4).

The amount of acetic acid released from the photolysis of

the dipolar compound 6 against time fits a single exponential

rise to the maximum consistent with a classical photoheterolysis

S_N1 reaction mechanism. Estimated values for the uncaging

quantum yield (Q_u) and the consequent one-photon uncaging

eﬃciency (eQ_u) are very low in acetone-d₆, pointing to the crucial

role of water in the uncaging photochemical process.

Photo-uncaging studies

We then investigated the uncaging properties of the dipolar

and octupolar quinoline caged acetate derivatives in diﬀerent

environments. Samples were excited at 365 nm (using two

lamps, 2 ꢁ 6 W) and the time courses for the photolysis

reactions were monitored either by ¹H NMR analysis or by

HPLC-MS analysis. The irradiation time for 90% conversion

(t_90%in seconds) was deduced from the fit of the kinetic data

and the uncaging quantum yield Q_uwas then calculated using

the following relationship^11a,b,32(eqn (3)):

ꢀ1

Q_u= (I ꢁ e_(365nm)ꢁ 10³ꢁ t_90%

)

(3)

In all experiments, the one-photon photolysis of the CouOAc

in a pH 7 buﬀer was used as a reference to determinate the

irradiation intensity of the UV lamps (I in einstein cm^ꢀ2s^ꢀ1).^32a,33

We also confirmed that the photo-uncagers exhibit very good

stability in aqueous solution as no dark hydrolysis was observed

after a few days.

We thus turned our attention towards the photolysis of these

compounds under simulated physiological conditions using a

phosphate buﬀer titrated to pH 7. As quinoline caged acetate

derivatives were not soluble enough in this aqueous medium,

experiments were performed in mixtures of phosphate buﬀer

We decided to conduct preliminary studies on the photo-

chemical properties of these multipolar 6-substituted quinoline

derivatives by directly light inducing the photorelease of acetic

Table 4 Photochemical properties of chimeric caged acetate compounds

e_(365nm)

eQ_u

1

acid in NMR samples and monitoring it by H NMR analysis.

a

Solvent

(M^ꢀ1cm^ꢀ1

)

Q_u

(M^ꢀ1cm^ꢀ1

)

Either acetone-d₆(for the dipole 6) or CDCl₃(for the octupole 8)

was used as the solvent depending on the solubility of the

caged compounds. As a typical procedure, we dissolved few

milligrams of compound in a deuterated solvent (concentration

approximately 10^ꢀ3M) and then the NMR tube was irradiated

with two lamps of 365 nm (2 ꢁ 6 W) under dark conditions.

After several hours of irradiation, a significant signal corre-

sponding to the release of the acetic acid (dCH₃= 2.10 ppm)

appeared and the signal of the acetyl group (dCH₃= 2.21 ppm)

6

Acetone-d₆

3.4 ꢁ 10⁴

3.1 ꢁ 10^ꢀ60.10

1.4 ꢁ 10^ꢀ50.65

1.1 ꢁ 10^ꢀ40.43

7.0 ꢁ 10^ꢀ60.79

2.0 ꢁ 10^ꢀ41.6

1.7 ꢁ 10^ꢀ60.16

THF–buffer^b(3 : 7)

4.5 ꢁ 10⁴

CH₃CN–buffer^b(1 : 1) 4.1 ꢁ 10³

THF–buffer^b(1 : 1)

8

1.1 ꢁ 10⁵

16 CH₃CN–buffer^b(3 : 4) 8 ꢁ 10³

21 CH₃CN–buffer^b(1 : 1) 9.5 ꢁ 10⁴

a

b

Measured at 365 nm. Phosphate buﬀer adjusted at pH = 7.

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with a miscible organic solvent, either acetonitrile (classically

used in the literature) or THF depending on the solubility of the

phototrigger. Once again, samples were photolysed at 365 nm

(using two lamps, 2 ꢁ 6 W) and the time courses for the

photolysis reactions were monitored this time by HPLC-MS

analysis of aliquots taken at periodic intervals. When solutions

of dipoles in acetonitrile/phosphate buﬀer were irradiated, a

single new peak was observed in the HPLC chromatogram,

which corresponds to the expected remnant alcohols. These

identifications were confirmed by comparison with the HPLC-

MS analyses under identical conditions to the authentic sam-

ples. UV-detection of the elute fractions from the HPLC column

was performed either at 254 nm or 365 nm and the two

detection modes led to the same results. Analyses of known

mixtures of the caged compound and the corresponding alco-

hol allowed us to plot calibration curves with the classical

detection at 254 nm and thus to access quantitative analyses

of the time course of the reaction. According to previous

observations, the plot of the consumption of the photosensitive

dipoles against time fits a simple exponential decay, in agree-

ment with a S_N1 type mechanism. Uncaging quantum yields

(Q_u) are much higher than the values observed in organic

Fig. 8 The one-photon photolysis at 365 nm of the 6-substituted quinoline

dipole 6 performed in a THF–buffer pH 7 mixture (1.1 ꢁ 10^ꢀ4M): (top) HPLC

solvents but still remain very low with typical values of chromatogram obtained after irradiation of the sample; (bottom) plot of the

0.01% and 0.02% for dipolar derivatives having 6-quinoline

or 8-quinoline uncaging moieties respectively (i.e. compounds 6

or 16) in a CH₃CN–buffer mixture (Table 4). We also observe

remaining fraction of the photoactive compound against time. The solid line is a

least-squares fit of a simple decaying exponential (coefficient of determination

R²= 0.99).

that whereas 8-quinoline derivatives show reduced 2PA

response compared to 6-quinoline analogues, the uncaging

efficiency follows the reverse trend, as reported earlier for

DMAQ derivatives.^11hInterestingly we observe that the quadru-

polar derivative 21 shows a two orders of magnitude smaller

uncaging quantum yield than the dipolar derivative having the

same uncaging unit i.e. 6 (Table 4).

As the compounds (in particular octupolar derivatives) were

found to be more soluble in THF, we conducted the same

type of experiments with solutions in a THF–buffer mixture.

Under these conditions, the product of the photolysis of the

6-substituted quinoline caged acetate 6 was more complex and

HPLC analysis revealed the formation of two different photo-

Scheme 4 Proposed reaction routes of compound 6 in a THF–water mixture.

lysis products with t_R= 20.1 and 26.5 min (Fig. 8). The peak at

t_R= 20.1 min with m/z 427 for MH⁺clearly corresponds to the

expected remnant alcohol 5a. ESI-MS of the second peak

corresponding to the retention time 26.5 min showed a signal

Considering the nucleophilicity of the THF, we could now

at m/z 499 which was attributed to the MH⁺response of the expect the formation of nine remnant alcohols from the photo-

alcohol 5b (Scheme 4). It appeared that THF could play the role lysis of the octupolar 6-substituted quinoline caged acetate 8 in

of a competitive nucleophile during the photochemical process. a 1/1 THF–buffer pH 7 mixture. After optimisation of the

Trapping of the carbocationic intermediate might occur elution conditions, HPLC analysis of the irradiated sample

through the ring opening of the THF molecule prior to the revealed six well separated peaks with retention times of 20.0,

water addition, leading to the alcohol 5b (Scheme 4). The 23.7, 25.0, 29.3, 31.1 and 33.2 min. The correspondence

product outcome of the photolysis of the corresponding octu- between them and the different by-products was clearly estab-

poles under different solvent conditions and the associated lished thanks to the ESI-MS analysis of the elute corresponding

kinetic profiles are even more complex. The photochemical to each peak showing signals for MH⁺at m/z 789, 861, 831, 933,

reaction classically induces the release of acetic acid and 903 and 873, respectively. The search in the chromatogram for

produces at least three other products corresponding to the specific MH⁺signals allowed us to confirm that the three other

mono-, bis- and tris-deprotected molecules when non nucleo- remnant alcohols were not produced in sufficient amounts to

philic solvents are used (for example acetonitrile).

be detected by the UV sensor. Reasonably assuming that all the

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are one order of magnitude larger than those obtained for

dipolar derivatives demonstrating that octupolar derivatives

are more favourable for 2P uncaging than their quadrupolar

counterparts.

Conclusion

The present study conducted on a series of multipolar (dipolar,

quadrupolar and octupolar) chimeric derivatives of 6- and

8-quinoline demonstrates that the chimeric strategy is indeed

promising in terms of enhancing (by up to two orders of

magnitude) the two-photon absorption response in the NIR

region. Interestingly, the octupolar derivatives show larger two-

photon absorption responses than their dipolar analogues

whereas the quadrupolar derivative (built from a fluorenyl core

instead of having triphenylamine electron-donating moieties as

Fig. 9 Time course of one-photon photolysis of octupole 8 at 365 nm. Relative

concentrations of remnant alcohols were determined by HPLC. The deduced dipolar and octupolar derivatives) shows the smallest two-

relative amount of acetic acid released against time is plotted. The solid line is a

least-squares fit of a linear rise (coeﬃcient of determination R²= 0.99).

photon absorption response in the NIR region. However, the

chimeric derivatives show much lower uncaging quantum

yields than DMAQ-OAc derivatives optimised for one-photon

uncaging.¹¹The more pronounced – and dramatic – reduction

six identified remnant alcohols display similar absorption is observed for the quadrupolar derivative built from a fluorenyl

properties at 365 nm, we could calculate the relative amount core. In contrast, the octupolar derivatives are found to display

of released acetate in the different aliquots from the integration one-order larger two-photon uncaging cross sections (d_u) than

of the HPLC peaks. 90% of acetate release was achieved after their dipolar counterparts. This opens an interesting route

1 day of irradiation. The production of acetic acid against time towards an optimised ‘‘octupolar type structure’’ where two-

is plotted in Fig. 9 and the apparent kinetics seems to fit a photon absorption enhancement offered by the octupolar

linear profile.

scheme would be combined with satisfactory uncaging effi-

As reported in Table 4 for the dipolar derivative 6, the ciency. The uncaging quantum yields of quinoline derivatives

uncaging eﬃciency is observed to be reduced by almost one have been shown to be fairly dependent on the nature (and

order of magnitude in the THF–buffer mixture as compared to position) of substituents.¹¹We are thus currently exploring

the CH₃CN–buffer mixture. This emphasises that the polarity of other quinoline moieties, as well as alternative uncaging moieties

the environment as well as the amount of water significantly in order to further engineer octupolar chimeric structures where

influence and improve the uncaging efficiency. In that respect uncaging efficiency would be better retained while taking advan-

the lower uncaging yield of the octupolar derivative 8 with tage of the net two-photon absorption enhancement provided by

respect to its dipolar analogue 6 (by a factor of about 2) could the current octupolar scheme in the spectral range of interest for

also be related to the larger amount of THF (and subsequent biological applications (700–1000 nm).

lower amount of water) necessary to dissolve the octupolar

derivatives.

Experimental section

Synthetic procedures

The uncaging study thus reveals that the functionalisation

of the quinoline cage with an ethynylphenylamine moiety

(either in the 6- or 8-position) dramatically aﬀects its ability

General methods. Melting points were measured on a Stuart

to undergo photolysis both for dipolar and octupolar deriva- SMP 10. Infrared spectra were measured on a Perkin Elmer

1

tives. Using the hypothesis that one- and two-photon uncaging Spectrum 100 Optica. H and ¹³C NMR spectra were recorded

quantum yields are the same (i.e. originate from the same on a Bruker Avance III 200 spectrometer at 200 MHz and 50 MHz

lowest excited state and follow the Kasha rule), we could derive respectively and on a Bruker Avance I 300 spectrometer at

two-photon uncaging action cross-sections (d_u) from the experi- 300 MHz and 75 MHz, respectively. Shifts (d) are given in parts

mentally determined s₂values and using the uncaging values per million with respect to the solvent residual peak and

(Q_u) measured in CH₃CN–water mixtures. For dipolar deriva- coupling constants (J) are given in Hertz. Mass spectra were

tives 6 and 16, maximum d_uvalues of about 0.002 GM are performed by the CESAMO (Bordeaux, France) on a QStar Elite

obtained at 750 nm. Concerning octupolar derivatives, using mass spectrometer equipped with an ESI source. Elemental

an estimated minored value of the uncaging quantum yield Analyses were carried out by the ‘‘Institut de Chimie des

(i.e. half of that of the dipolar analogue, as derived from Substances Naturelles’’ (Gif-sur-Yvette, France). LC/MS analyses

comparison of compounds 6 and 8 in Table 4) d_uvalues of were performed on a Shimadzu LCMS-2020. Column chroma-

0.03 GM and 0.04 GM at 730 nm are estimated for octupolar tography was performed on Fluka silica gel 60 (40–63 mm).

derivatives 8 and 19 respectively. These values, although modest, Solvents were freshly distilled before being used over CaH₂

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(for toluene, CH₂Cl₂and Et₃N) or benzophenone–Na (for THF). (Na₂SO₄), and concentrated under reduced pressure. The crude

CDCl₃was neutralised with K₂CO₃prior to use. No melting product was purified on silica gel (gradient eluent, toluene : EtOAc

point value is indicated when compounds decomposed.

9 :1 to 4:1) to give compound 5a (190 mg 84%) as a yellow

(6-Bromoquinolin-2-yl)methanol (2)¹². A suspension of sele- powder. Mp 172 1C. IR (KBr) n (cm^ꢀ1): 3434, 3061, 3034, 2199,

1

nium oxide (1.33 g, 12 mmol) in dry dioxane (50 mL) was heated 1589, 1509, 1334, 1315, 1285, 1268, 1062, 834, 754, 696. H NMR

for 1 h at 60 1C, and then 6-bromo-2-methylquinoline (2.23 g, (CDCl₃, 300 MHz) d (ppm): 8.08 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.7 Hz,

10 mmol) was added in one portion. The resulting red mixture 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.81 (dd, J = 8.7 Hz, J = 1.7 Hz, 1H),

was heated at reflux for 3 h. After cooling to room temperature, 7.43 (d, J = 6.7 Hz, 2H), 7.26–7.33 (m, 5H), 7.01–7.16 (m, 8H), 4.93

the mixture was filtrated through celite, the solid part was (s, 2H). ¹³C NMR (CDCl₃, 75 MHz) d (ppm): 64.4, 88.4, 91.3, 115.8,

washed with dioxane and the filtrate was concentrated under 119.2, 122.0, 122.3, 123.9, 125.3, 127.6, 128.9, 129.6, 130.8, 132.8,

reduced pressure. The resulting yellow solid was dissolved in 136.6, 146.3, 147.3, 148.4, 159.7. ESIHRMS: C₃₀H₂₂N₂O calculated

methanol (100 mL), cooled to 0 1C, and sodium borohydride for [M + Na]⁺: 449.1624, found 449.1609. Anal. calcd for

(760 mg, 20 mmol) was added. The resulting mixture was C₃₀H₂₂N₂O: C, 81.72; H, 5.39; N, 6.35; found: C, 81.96; H, 5.15;

stirred overnight at room temperature, and then concentrated N, 5.98.

under reduced pressure. The residue was neutralised with

(6-[(4-(Diphenylamino)phenyl)ethynyl]quinolin-2-yl)-methyl

water and extracted with CH₂Cl₂. The combined organic layer acetate (6). To a solution of (6-[(4-(diphenylamino)phenyl)-

was dried (Na₂SO₄) and then concentrated under reduced ethynyl]quinolin-2-yl)-methanol 5a (100 mg, 0.23 mmol), DMAP

pressure. A short column of silica gel (eluent, CH₂Cl₂: EtOAc (2.8 mg, 23 mmol), and Et₃N (62.2 mL, 0.46 mmol) in dry CH₂Cl₂

8 : 2) gave compound 2 (2.05 g, 86%) as a white powder. (3 mL) Ac₂O (44 mL, 0.46 mmol) was added. The yellow solution

¹H NMR (DMSO-d₆, 200 MHz) d (ppm): 8.35 (d, J = 8.7 Hz, was stirred for 4 h at room temperature, quenched with an

1H), 8.25 (d, J = 1.8 Hz, 1H), 7.80 (m, 2H), 7.70 (d, J = 8.5 Hz, aqueous saturated NaHCO₃solution, and then extracted with

1H), 5.59 (t, J = 6.0 Hz, 1H, OH), 4.72 (d, J = 6.0 Hz, 2H).

CH₂Cl₂. The combined organic layer was dried (Na₂SO₄), and

(6-Ethynylquinolin-2-yl)-methanol (3). Argon was bubbled concentrated under reduced pressure. The crude product was

into a mixture of (6-bromoquinolin-2-yl)methanol 2 (730 mg, purified on silica gel (eluent, heptane : EtOAc 4 : 1) to give

3.06 mmol), in a dry mixture of toluene–Et₃N (30 mL, 5 : 1) for compound 6 (106 mg, 99%) as a brown powder. Mp 146 1C.

20 min. Then, copper iodide (29.2 mg, 0.15 mmol), PdCl₂- IR (KBr) n (cm^ꢀ1): 3056, 3036, 2926, 1739, 1590, 1507, 1492,

(Ph₃P)₂(107.4 mg, 0.153 mmol), Ph₃P (160 mg, 0.612 mmol), 1329, 1314, 1245, 1228, 1059, 834, 752, 694, 501. ¹H NMR

and ethynyltrimethylsilane (640 mL, 4.5 mmol) were added. The (CDCl₃, 300 MHz) d (ppm): 8.06 (d, J = 8.5 Hz, 1H), 7.95

resulting mixture was heated at 60 1C for 16 h. The mixture was (d, J = 8.7 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.72 (dd, J = 8.7 Hz,

cooled at 0 1C and TBAF (1M in THF, 6 mL, 6 mmol) was added. J = 1.7 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.7 Hz, 1H),

The reaction mixture was stirred for 1 h at room temperature, 7.17–7.25 (m, 4H), 6.92–7.07 (m, 8H), 5.31 (s, 2H), 2.13 (s, 3H). ¹³

C

and filtrated through celite. The filtrate was concentrated NMR (CDCl₃, 75 MHz) d (ppm): 21.1, 67.6, 88.4, 91.5, 115.7, 120.3,

under reduced pressure. The residue was diluted in EtOAc, 122.3, 122.4, 123.9, 125.3, 127.6, 129.5, 129.7, 129.8, 130.7, 132.8,

and washed with water. The combined organic layer was 132.9, 136.8, 147.1, 147.3, 156.8, 170.9. ESIHRMS: C₃₂H₂₄N₂O₂

washed with brine, dried (Na₂SO₄), and concentrated under calculated for [M + Na]⁺: 491.1729, found 491.1712. Anal. calcd for

reduced pressure. The crude product was purified on silica gel C₃₂H₂₄N₂O₂C, 81.40; H, 5.21; N, 5.93; found: C, 81.41; H, 5.17;

(eluent, CH₂Cl₂: EtOAc 9 : 1) to give compound 3 (440 mg, 79%) N, 5.84.

as an orange powder. Mp 129 1C. IR (KBr) n (cm^ꢀ1): 3333, 3264,

(6,6⁰,6⁰⁰-[(Nitrilotris(benzene-4,1-diyl))tris(ethyne-2,1-diyl)]-

3213, 1592, 1494, 1071, 1043, 883, 833. ¹H NMR (DMSO-d₆, tris(quinolone-6,2-diyl))-tris(methylene) triacetate (8). Argon

200 MHz) d (ppm): 8.37 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), was bubbled into a solution of tris(4-iodophenyl)amine 7 (131 mg,

7.93 (d, J = 8.7 Hz, 1H), 7.74 (dd, J = 8.7 Hz, J = 1.7 Hz, 1H), 7.70 0.21 mmol) and (6-ethynylquinolin-2-yl)-methanol 3 (140 mg,

(d, J = 8.5 Hz, 1H), 5.59 (t, J = 6.0 Hz, 1H, OH), 4.72 (d, J = 6.0 Hz, 0.76 mmol), in a dry mixture of THF–Et₃N (2.4 mL, 5 : 1) for

2H), 4.33 (s, 1H). ¹³C NMR (DMSO-d₆, 75 MHz) d (ppm): 64.7, 81.6, 20 min. Then, copper iodide (4.8 mg, 25.2 mmol) and

83.2, 119.1, 119.8, 126.6, 128.8, 131.8, 131.9, 136.3, 146.2, 163.7. PdCl₂(Ph₃P)₂(8.84 mg, 12.6 mmol) were added. The resulting

ESIHRMS: C₁₂H₉NO calculated for [M + Na]⁺: 206.0576, found mixture was stirred for 2 h at room temperature. The mixture

206.0567. Anal. calcd for C₁₂H₉NO: C, 77.90; H, 5.01; N, 7.57; was diluted with THF (1 mL) and then DMAP (2.6 mg, 21 mmol),

found: C, 78.10; H, 4.84; N, 7.30.

and Ac₂O (120 mL, 1.26 mmol) were added. The resulting

(6-[(4-(Diphenylamino)phenyl)ethynyl]quinolin-2-yl)-methanol mixture was stirred overnight at room temperature. The reac-

(5a). Argon was bubbled into a solution of (4-iodophenyl)diphenyl- tion was filtrated through Celite^s. The filtrate was diluted with

amine 4 (200 mg, 0.53 mmol) and (6-ethynylquinolin-2-yl)-metha- EtOAc, and washed with an aqueous saturated NaHCO₃

nol 3 (118 mg, 0.65 mmol), in a dry mixture of THF–Et₃N (6 mL, solution. The organic layer was dried (Na₂SO₄), and concen-

5 : 1) for 20 min. Then, copper iodide (12.1 mg, 63.6 mmol) and trated under reduced pressure. The crude product was purified

PdCl₂(Ph₃P)₂(22.3 mg, 31.8 mmol) were added. The resulting on silica gel (eluent, CH₂Cl₂: EtOAc 7 : 3) to give compound 8

mixture was stirred for 2 h at room temperature. The mixture (180 mg, 94%) as a yellow powder. Mp 112 1C. IR (KBr) n (cm^ꢀ1):

was filtrated through celite. The filtrate was washed with brine 3037, 2939, 2204, 1931, 1744, 1591, 1563, 1505, 1477, 1369, 1319,

and extracted with EtOAc. The combined organic layer was dried 1224, 1179, 1050, 888, 834, 744, 538. ¹H NMR (CDCl₃, 300 MHz)

c

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d (ppm): 8.13 (d, J = 8.5 Hz, 3H), 8.05 (d, J = 8.9 Hz, 3H), 8.00 ¹H NMR (CDCl₃, 400 MHz) d (ppm): 8.34 (d, J = 8.3 Hz, 1H), 7.93

(d, J = 1.9 Hz, 3H), 7.81 (dd, J = 8.9 Hz, J = 1.9 Hz, 3H), 7.46–7.52 (dd, J = 7.2 Hz, J = 1.4 Hz, 1H), 7.73 (dd, J = 8.0 Hz, J = 1.1 Hz,

(m, 9H), 7.12 (d, J = 8.7 Hz, 6H), 5.39 (s, 6H), 2.21 (s, 9H). ¹³C 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.42–7.47 (m, 1H), 7.27–7.34

NMR (CDCl₃, 75 MHz) d (ppm): 20.9, 67.4, 89.0, 90.7, 117.8, (m, 5H), 7.11–7.16 (m, 4H), 7.02–7.09 (m, 4H), 2.82 (s, 3H).

120.2, 121.9, 124.2, 127.3, 129.4, 130.7, 132.5, 133.0, 136.6, ¹³C NMR (CDCl₃, 100 MHz) d (ppm): 26.0, 87.0, 95.7, 116.8,

146.9, 147.1, 156.8, 170.7. ESIHRMS: C₆₀H₄₂N₄O₆calculated 122.4, 122.6, 123.1, 123.6, 125.1, 125.3, 126.7, 127.9, 133.0,

for [M + Na]⁺: 937.2996, found 937.2999. Anal. calcd for 133.7, 136.5, 147.4, 148.0, 160.1. ESIHRMS: C₃₀H₂₂N₂calculated

C

₆₀H₄₂N₄O₆: C, 77.24; H, 4.75; N, 6.00; found: C, 77.10; H, for [M + H]⁺: 411.1855, found 411.1850.

4.49; N, 5.95. 8-((4-(Diphenylamino)phenyl)ethynyl)quinoline-2-carbal-

8-Iodo-2-methylquinoline (10). To a cooled (ꢀ70 1C) solution dehyde (14). To a solution of (4-ethynylphenyl)diphenylamine

of 8-bromo-2-methylquinoline 9 (2.36 g, 10 mmol), in dry THF 12 (105.0 mg, 338.0 mmol), 8-iodoquinoline-2-carboxaldehyde

(75 mL), was added slowly a solution of n-BuLi (2.5 M in (100.0 mg, 350.0 mmol), Pd₂(dba)₃(16.0 mg, 17.0 mmol), CuI

hexanes, 4.4 mL, 11 mmol). The resulting brown solution (6.7 mg, 35.0 mmol), and Ph₃P (18.4 mg, 70.0 mmol) in a dry THF

was stirred for 1 h at ꢀ70 1C, and then, a solution of iodine (3 mL) was added 150 mL of dry Et₃N. The resulting mixture was

(in 25 mL of dry THF) was slowly added. The reaction was stirred overnight at room temperature. The reaction was filtrated

warmed slowly at room temperature, and stirred for 1 h at this through a patch of silica gel, and the filtrate was concentrated

temperature. The red mixture was quenched with an aqueous under reduced pressure. The crude product was purified on silica

Na₂S₂O₃solution. After neutralisation of excess of iodine (red to gel (eluent, toluene), to give 8-((4-(diphenylamino)phenyl)ethynyl)-

yellow solution), the aqueous layer was extracted several times quinoline-2-carbaldehyde 14 (76 mg, 51%) as a yellow powder.

with Et₂O. The combined organic layer was dried (Na₂SO₄), and Mp: 151 1C. ¹H NMR (CDCl₃, 400 MHz) d (ppm): 10.32 (s, 1H), 8.32

concentrated under reduced pressure. The crude product was (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H),

purified on silica gel (eluent, Et₂O : petroleum ether, 5 : 95) to 7.82 (d, J = 8.1 Hz, 1H), 7.65 (dd, J = 8.1 Hz, J = 7.2 Hz, 1H), 7.56

give 8-iodo-2-methylquinoline 10 (2.60 g, 97%) as a yellowish (d, J = 8.6 Hz, 2H), 7.27–7.33 (m, 4H), 7.12–7.17 (m, 4H), 7.04–7.11

1

powder. Mp: 65 1C. H NMR (CDCl₃, 400 MHz) d (ppm): 8.30 (m, 4H). ¹³C NMR (CDCl₃, 100 MHz) d (ppm): 86.0, 97.6, 115.9,

(dd, J = 7.4 Hz, J = 1.3 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.76 117.9, 122.2, 123.8, 125.3, 127.8, 128.9, 129.6, 130.3, 133.1, 134.4,

(dd, J = 8.0 Hz, J = 1.3 Hz, 1H), 7.76 (dd, J = 8.0 Hz, J = 1.3 Hz, 137.9, 147.2, 147.8, 148.5, 152.7, 194.1. ESIHRMS: C₃₀H₂₀N₂O

1H), 7.31 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.0 Hz, J = 7.4 Hz, 1H), calculated for [M]⁺: 424.1576, found 424.1581. Anal. calcd for

2.81 (s, 3H).¹³C NMR (CDCl₃, 100 MHz) d (ppm): 25.7, 103.4, C₃₀H₂₀N₂O: C, 84.88; H, 4.75; N, 6.00; found: C, 84.83; H, 4.74;

123.0, 126.9, 127.1, 128.6, 136.8, 140.0, 146.7, 160.8. ESIHRMS: N, 6.23.

C

₁₀H₈IN calculated for [M+H]⁺: 269.9774, found 269.9767. Anal.

calcd for C₁₀H₈IN: C, 44.64; H, 3.00; N, 5.21; found: C, 44.48; H, tris(quinoline-2-carbaldehyde) (18). To a solution of tris[4-(2-

3.01; N, 5.54.

trimethylsilylethynyl)phenyl]amine^9b17 (117.5 mg, 220 mmol),

8,8⁰,8⁰⁰-((Nitrilotris(benzene-4,1-diyl))tris(ethyne-2,1-diyl))-

8-Iodoquinoline-2-carbaldehyde (11). A mixture of 8-iodo-2- 8-iodoquinoline-2-carboxaldehyde (200 mg, 729.5 mmol), Pd₂-

methylquinoline 10 (430 mg, 1.60 mmol) and selenium oxide (dba)₃(10 mg, 11 mmol), CuI (4.2 mg, 22 mmol), and Ph₃P (11.6 mg,

(215 mg, 1.92 mmol) in 1,4-dioxane (10 mL) was heated at 80 1C 44 mmol) in a dry mixture of THF–Et₃N (5 : 1, 2.4 mL) was added a

for 6 h. The mixture was cooled to room temperature, filtrated solution of TBAF (1 M in THF, 780 mL, 780 mmol). The resulting

through celite, and the filtrate was concentrated under reduced mixture was stirred overnight at room temperature. The reaction

pressure. The crude product was purified on silica gel (eluent, was quenched with an aqueous saturated NH₄Cl solution, and

Et₂O : petroleum ether, 1 : 9) to give 8-iodoquinoline-2-carboxal- then extracted several times with EtOAc. The combined organic

1

dehyde 11 (410 mg, 91%) as a yellow powder. 165 1C H NMR layer was dried and concentrated under reduced pressure. The

(CDCl₃, 600 MHz) d (ppm): 10.31 (s, 1H), 8.45 (d, J = 7.3 Hz, 1H), crude product was purified on silica gel (eluent, Et₂O:CH₂Cl₂,

8.25 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.40 (dd, J = 8.0 Hz, 5 : 95), and the resulting brown powder was washed with pentane

J = 7.3 Hz, 1H). ¹³C NMR (CDCl₃, 150 MHz) d (ppm): 104.9, 118.3, to give 8,8⁰,8⁰⁰-((nitrilotris(benzene-4,1-diyl))tris(ethyne-2,1-diyl))-

128.8, 130.3, 130.9, 138.4, 141.3, 146.9, 153.5, 193.5. ESIHRMS: tris(quinoline-2-carbaldehyde) 18 (80 mg, 47%) as an orange

1

C₁₀H₆INO calculated for [M + Na]⁺: 305.9386, found 305.9392.

powder. H NMR (CDCl₃, 600 MHz) d (ppm): 10.34 (s, 3H), 8.34

4-((2-Methylquinolin-8-yl)ethynyl)-N,N-diphenylaniline (13). (d, J = 8.4 Hz, 3H), 8.05–8.11 (m, 6H), 7.88 (dd, J = 8.1 Hz, J = 0.6 Hz,

To a solution of (4-ethynylphenyl)diphenylamine 12 (60.0 mg, 3H), 7.63–7.71 (m, 9H), 7.16–7.22 (m, 6H). ¹³C NMR (CDCl₃,

222.7 mol), 8-iodo-2-methylquinoline 10 (53.6 mg, 200.0 mmol), 150 MHz) d (ppm): 86.8, 97.0, 118.0, 118.2, 124.3, 125.0, 128.1,

Pd₂(dba)₃(9.2 mg, 10.0 mmol), CuI (3.8 mg, 20 mmol), and Ph₃P 128.9, 130.4, 133.4, 134.6, 138.0, 147.2, 147.8, 152.8, 194.1.

(10.5 mg, 40 mmol) in a dry THF (2 mL) was added 100 mL of dry ESIHRMS: C₅₄H₃₀N₄O₃calculated for [M + Na]⁺: 805.2210,

Et₃N. The resulting mixture was stirred for 3 h at room temper- found 805.2223.

ature. The reaction was filtrated through a patch of silica gel,

(8-[(4-(Diphenylamino)phenyl)ethynyl]quinolin-2-yl)-methanol

washed with Et₂O, and the filtrate was concentrated under (15). To a solution of 8-((4-(diphenylamino)phenyl)ethynyl)quino-

reduced pressure. The crude product was purified on silica gel line-2-carbaldehyde 14 (44 mg, 103 mmol), in dry THF (1 mL) was

(eluent, toluene), to give 4-((2-methylquinolin-8-yl)ethynyl)-N,N- added NaBH₄(3.8 mg, 103 mmol). The reaction mixture was

diphenylaniline 13 (9.8 mg, 12%) as a brown powder. Mp: 125 1C. stirred overnight at room temperature, quenched with an aqueous

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saturated NaHCO₃solution and then extracted several times with 67.6, 87.2, 95.7, 118.4, 119.8, 123.6, 124.2, 126.3, 127.7, 128.0,

CH₂Cl₂. The combined organic layer was dried (Na₂SO₄) and then 133.3, 134.1, 137.3, 147.0, 147.6, 157.0, 170.9. ESIHRMS:

concentrated under reduced pressure. The crude product was

purified on silica gel (20% EtOAc in Petroleum Ether) to give (5-[(4-

C

₆₀H₄₂N₄O₆calculated for [M + H]⁺: 915.3177, found 915.3173.

(6,6⁰-((9,9-Bis(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-9H-

(diphenylamino)phenyl)ethynyl]quinolin-2-yl)-methanol 15 (35 mg, fluorene-2,7-diyl)bis(ethyne-2,1-diyl))bis(quinoline-6,2-diyl))-

82%) as a yellow powder. Mp: 147 1C. ¹H NMR (CDCl₃, 400 MHz) bis(methylene) diacetate (21). To a solution of 2,7-diiodo-9,9-

d (ppm): 8.16 (d, J = 8.5 Hz, 1H), 7.95 (dd, J = 7.3 Hz, J = 0.9 Hz, 1H), bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene¹⁷20 (142.1 mg,

7.79 (dd, J = 8.0 Hz, J = 1.0 Hz, 1H), 7.47–7.55 (m, 3H), 7.27–7.32 200 mmol), (6-ethynylquinolin-2-yl)-methanol 3 (88 mg, 480 mmol),

(m, 5H), 7.14 (d, J = 7.7 Hz, 4H), 7.02–7.09 (m, 4H), 4.96 (s, 2H). ¹³

C

PdCl₂(Ph₃P)₂(5.6 mg, 8 mmol), and CuI (3.1 mg, 16 mmol) in dry

NMR (CDCl₃, 50 MHz) d (ppm): 64.0, 86.1, 96.3, 116.4, 118.9, 122.5, THF (2 mL) Et₃N (0.1 mL) was added. The reaction mixture was

123.7, 125.2, 126.2, 127.8, 129.5, 132.9, 133.6, 137.4, 147.3, 148.2, stirred overnight at room temperature, and then DMAP (2.5 mg,

159.3. ESIHRMS: C₃₀H₂₂N₂O calculated for [M + Na]⁺: 426.1732, 20 mmol), and Ac₂O (57 mL, 600 mmol) were added. The reaction was

found 426.1728. Anal. calcd for C₃₀H₂₂N₂O: C, 84.48; H, 5.20; N, stirred overnight at room temperature, quenched with an aqueous

6.57; found: C, 84.24; H, 5.29; N, 6.55.

saturated NaHCO₃, and then extracted several times with EtOAc.

The combined organic layer was dried and concentrated under

(8-((4-(Diphenylamino)phenyl)ethynyl)quinolin-2-yl)methyl

acetate (16). To a solution of 8-((4-(diphenylamino)phenyl)- reduced pressure. The crude product was purified on silica gel

ethynyl)quinoline-2-carbaldehyde 14 (50 mg, 117.8 mmol), in (eluent, EtOAc), to give 20 (172 mg, 95%) as a yellow powder. Mp:

dry THF (4 mL) was added NaBH₄(4.9 mg, 129.6 mmol). The 85 1C. ¹H NMR (CDCl₃, 200 MHz) d (ppm): 8.18 (d, J = 8.5 Hz, 2H),

reaction mixture was stirred overnight at room temperature. 8.03–8.12 (m, 4H), 7.86 (dd, J = 8.8 Hz, J = 1.6 Hz, 2H), 7.64–7.73

Then, DMAP (1.4 mg, 11.8 mmol) was added followed by (m, 4H), 7.59 (dd, J = 7.8 Hz, J = 1.2 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H),

addition of a Ac₂O–Et₃N mixture (1 : 1, 1 mL). The reaction 5.41 (s, 4H), 3.36–3.55 (m, 12H), 3.31 (s, 6H), 3.20–3.26 (m, 4H), 2.83

was stirred overnight at room temperature, quenched with an (t, J = 7.0 Hz, 4H), 2.45 (t, J = 7.0 Hz, 4H), 2.21 (s, 6H). ¹³C NMR

aqueous saturated NaHCO₃solution and then extracted several (CDCl₃, 100 MHz) d (ppm): 21.1, 39.8, 51.6, 59.1, 67.0, 67.5, 70.2,

times with CH₂Cl₂. The combined organic layer was dried 70.6, 72.0, 90.0, 91.6, 120.4, 121.8, 122.2, 126.7, 127.5, 129.6, 131.0,

(Na₂SO₄) and then concentrated under reduced pressure. The 131.4, 132.7, 136.8, 140.3, 147.2, 149.7, 157.0, 170.8. ESIHRMS:

crude product was purified on silica gel (20% EtOAc in Petro- C₅₅H₅₆N₂O₁₀calculated for [M + Na]⁺: 927.3827, found 927.3795.

leum Ether) to give (8-((4-(diphenylamino)phenyl)ethynyl)qui-

7-Hydroxycoumarin-4-ylmethyl acetate (CouOAc). 7-Hydro-

nolin-2-yl)methyl acetate 16 (40 mg, 75%) as a yellow powder. xycoumarin-4-ylmethyl acetate was synthesised by using the

Mp: 156 1C. ¹H NMR (CDCl₃, 400 MHz) d (ppm): 8.17 (d, J = protocol reported by Furuta et al.^32aTo a stirred mixture of

8.4 Hz, 1H), 7.95 (dd, J = 7.1 Hz, J = 1.3 Hz, 1H), 7.77 (dd, J = 4-chloromethyl-7-hydroxycoumarin³⁴(1.0 g, 4.75 mmol) in

8.5 Hz, J = 1.3 Hz, 1H), 7.48–7.54 (m, 4H), 7.27–7.32 (m, 4H), toluene (48 mL) under an Argon atmosphere were added

7.12–7.16 (m, 4H), 7.03–7.09 (m, 4H), 5.49 (s, 2H), 2.21 (s, 3H). successively AcOH (0.8 mL, 14.3 mmol) and DBU (2.8 mL,

¹³C NMR (CDCl₃, 100 MHz) d (ppm): 21.1, 67.6, 86.6, 96.1, 116.6, 19 mmol). The reaction mixture was refluxed for 17 h. After

119.7, 122.4, 123.7, 123.8, 125.2, 126.3, 127.7, 127.8, 129.5, 133.0, being cooled down to room temperature, the mixture was

133.9, 137.3, 147.4, 147.5, 148.1, 156.9, 170.9. ESIHRMS: concentrated under reduced pressure. The residue was diluted

C₃₂H₂₄N₂O₂calculated for [M + Na]⁺: 491.1729, found 491.1709. in CH₂Cl₂then washed with a HCl solution (1N). The combined

(8,8⁰,8⁰⁰-((Nitrilotris(benzene-4,1-diyl))tris(ethyne-2,1-diyl))-

organic layers were dried (Na₂SO₄) and concentrated under

tris(quinoline-8,2-diyl))tris-(methylene) triacetate (19). To a reduced pressure. The resulting crude solid was washed with

solution of 8,8⁰,8⁰⁰-((nitrilotris(benzene-4,1-diyl))tris(ethyne-2, ether (10 mL) to give 0.84 g of 7-hydroxycoumarin-4-ylmethyl

1-diyl))tris(quinoline-2-carbaldehyde) 18 (53 mg, 67 mmol), in acetate (76%) as a yellow powder. Mp 148 1C. IR (KBr) n (cm^ꢀ1):

1

dry THF (2 mL), NaBH₄was added (8.3 mg, 221.1 mmol). The 3292.9, 3084.1, 2926.2, 1748.1, 1690.6, 1621.3, 1243.6. H NMR

reaction mixture was stirred overnight at room temperature. (acetone-d₆, 200 MHz) d (ppm): 7.59 (d, J = 8.8 Hz, 1H), 6.88

Then, DMAP (0.9 mg, 6.7 mmol) was added followed by the (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.20

addition of a Ac₂O–Et₃N mixture (1 : 1, 0.6 mL). The reaction (t, J = 1.4 Hz, 1H), 5.33 (d, J = 1.4 Hz, 2H), 2.18 (s, 3H). ¹³C NMR

was stirred overnight at room temperature, quenched with an (CDCl₃, 50 MHz) d (ppm): 21.6, 62.9, 104.7, 110.6, 111.7, 114.9,

aqueous saturated NaHCO₃solution and then extracted several 127.5, 152.0, 157.6, 161.8, 163.3, 171.5. ESIHRMS: C₁₂H₁₀O₅

times with CH₂Cl₂. The combined organic layer was dried calculated for [M + Na]⁺: 257.0420, found 257.0411. Anal. calcd

(Na₂SO₄) and then concentrated under reduced pressure. The for C₁₂H₁₀O₅: C, 61.54; H, 4.30; found: C, 61.18; H, 4.87.

crude product was purified on silica gel (40% EtOAc in Petro-

Photophysical methods

leum Ether) to give (8,8⁰,8⁰⁰-((nitrilotris(benzene-4,1-diyl))-

tris(ethyne-2,1-diyl))tris(quinoline-8,2-diyl))tris(methylene) tri- All photophysical studies have been performed with freshly-

1

acetate 19 (50 mg, 90%) as a yellow powder. H NMR (CDCl₃, prepared air-equilibrated solutions at room temperature (298 K).

400 MHz) d (ppm): 8.18 (d, J = 8.5 Hz, 3H), 7.97 (dd, J = 7.2 Hz, UV/Vis absorption spectra of 10^ꢀ5M solutions were recorded on

J = 1.3 Hz, 3H), 7.79 (dd, J = 8.1 Hz, J = 1.3 Hz, 3H), 7.61 (d, J = a Jasco V-670 spectrophotometer. The reported molar extinction

8.6 Hz, 6H), 7.49–7.54 (m, 6H), 7.16 (d, J = 8.6 Hz, 6H), 5.51 coeﬃcients are within ꢂ5%. Steady-state and time-resolved

(s, 6H), 2.22 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz) d (ppm): 21.2, fluorescence measurements were performed on dilute solutions

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(ca. 10^ꢀ6M, optical density o 0.1) contained in standard 1 cm peaks related to the photosensitive molecule and the remnant

quartz cuvettes using a Fluorolog spectrofluorometer. Emission alcohol correspond exactly to concentration ratios. This obser-

spectra were obtained, for each compound, under excitation at the vation proved to be crucial for our investigations when THF

wavelength of the absorption maximum. Fluorescence quantum was used.

yields were measured according to literature procedures.³⁵The

reported fluorescence quantum yields are within ꢂ5%. Fluores-

cence lifetimes were measured by time-correlated single photon

counting (TCSPC). The reported lifetimes are within ꢂ0.1 ns.

Acknowledgements

This work was supported by a grant from Agence Nationale

pour la Recherche (Grant 2010 ANR-10-BLAN-1436). MBD grate-

fully thanks the Conseil Regional d’Aquitaine for generous

Two-photon absorption

´

funding (Chaire d’Accueil grant). We thank M. Klausen

2PA cross sections (s₂) were determined from the two-photon

excited fluorescence (TPEF) cross sections (s₂F) and the

fluorescence emission quantum yield (F). TPEF cross sections

of 10^ꢀ4M solutions were measured relative to fluorescein in 0.01M

aqueous NaOH for 715–980 nm,²⁸using the well-established

method described by Xu and Webb^28aand the appropriate

solvent-related refractive index corrections.³⁶Reference values

between 700 and 715 nm for fluorescein were taken from

literature.²³The quadratic dependence of the fluorescence

intensity on the excitation power was checked for each sample

and all wavelengths. Measurements were conducted using an

excitation source delivering fs pulses. This allows avoiding

excited-state absorption during the pulse duration, a pheno-

menon which has been shown to lead to overestimated 2PA

cross-section values.⁷To span the 700–980 nm range, a Nd:YLF-

pumped Ti:sapphire oscillator was used generating 150 fs

pulses at a 76 MHz rate. The excitation was focused into the

cuvette through a microscope objective (10ꢁ, NA 0.25). The

fluorescence was detected in epifluorescence mode via a

dichroic mirror (Chroma 675dcxru) and a barrier filter (Chroma

e650sp-2p) by a compact CCD spectrometer module BWTek

BTC112E. Total fluorescence intensities were obtained by inte-

grating the corrected emission. The experimental uncertainty

on the absolute action cross-sections determined by this method

has been estimated to be ꢂ10%.

´

(ISM, Universite Bordeaux 1) for his contribution to CouOAc

synthesis.

Notes and references

ˇ

´

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3 C. G. Bochet, Synlett, 2004, 2268–2274.

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Photolysis measurements

A solution of compound 6 (1.65 mg, 3.52 mmol, 1.1 ꢁ 10^ꢀ4M),

in a mixture 21 mL–10 mL THF–buffer solution (pH 7.00), was

irradiated using two lamps of 365 nm (2 ꢁ 6 W). Between each

duration, a small aliquot (0.5 mL) of the solution was removed

and diluted with a solution of ammonium formate (5% in

MeOH w/w). The photolysis was followed by reversed-phase

HPLC-MS analysis eluted with a gradient mixture of methanol

and water using absorbance detection at 254 nm or 365 nm.

The ratio was estimated by analysis of the HPLC chromato-

gram, the mass completed the analysis to confirm the authen-

ticity of the products. The reported uncaging quantum yields

are within ꢂ3%.

´

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c

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Octupolar chimeric compounds built from quinoline caged acetate moieties: A novel approach for 2-photon uncaging of biomolecules

DOI: 10.1039/c3nj00833a

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