Quinone methide generation via photoinduced electron transfer

Article abstract of DOI:10.1021/jo102531f

Photochemical activation of water-soluble 1,8-naphthalimide derivatives (NIs) as alkylating agents has been achieved by irradiation at 310 and 355 nm in aqueous acetonitrile. Reactivity in aqueous and neat acetonitrile has been extensively investigated by laser flash photolysis (LFP) at 355 nm, as well as by steady-state preparative irradiation at 310 nm in the presence of water, amines, thiols, and ethyl vinyl ether. Product distribution analysis revealed fairly efficient benzylation of the amines, hydration reaction, and 2-ethoxychromane generation, in the presence of ethyl vinyl ether, resulting from a [4 + 2] cycloaddition onto a transient quinone methide. Remarkably, we found that the reactivity was dramatically suppressed under the presence of oxygen and radical scavengers, such as thiols, which was usually associated with side product formation. In order to unravel the mechanism responsible for the photoreactivity of these NI-based molecules, a detailed LFP study has been carried out with the aim to characterize the transient species involved. LFP data suggest a photoinduced electron transfer (PET) involving the NI triplet excited state (λ_max 470 nm) of the NI core and the tethered quinone methide precursor (QMP) generating a radical ions pair NI ^- (λ_max 410 nm) and QMP⁺. The latter underwent fast deprotonation to generate a detectable phenoxyl radical (λ_max 390 and 700 nm), which was efficiently reduced by the radical anion NI^-, generating detectable QM. The mechanism proposed has been validated through a LFP investigation at 355 nm exploiting an intermolecular reaction between the photo-oxidant N-pentylnaphthalimide (NI-P) and a quaternary ammonium salt of a Mannich base as QMP (2a), in both neat and aqueous acetonitrile. Remarkably, these experiments revealed the generation of the model o-QM (λ_max 400 nm) as a long living transient mediated by the same reactivity pathway. Negligible QM generation has been observed under the very same conditions by irradiation of the QMP in the absence of the NI. Owing to the NIs redox and recognition properties, these results represent the first step toward new molecular devices capable of both biological target recognition and photoreleasing of QMs as alkylating species, under physiological conditions.

Full text of DOI:10.1021/jo102531f

ARTICLE
pubs.acs.org/joc
Quinone Methide Generation via Photoinduced Electron Transfer
Claudia Percivalle,† Andrea La Rosa,† Daniela Verga,† Filippo Doria,† Mariella Mella,† Manlio Palumbo,‡
Marco Di Antonio,*,‡ and Mauro Freccero*,†
†Dipartimento di Chimica Organica, Universitꢀa di Pavia, Viale Taramelli 10, 27100 Pavia, Italy
‡Dipartimento di Scienze Farmaceutiche, Universitꢀa di Padova, Via Marzolo, 5, 35131 Padova, Italy
S Supporting Information
b
ABSTRACT: Photochemical activation of water-soluble 1,8-
naphthalimide derivatives (NIs) as alkylating agents has been
achieved by irradiation at 310 and 355 nm in aqueous acetoni-
trile. Reactivity in aqueous and neat acetonitrile has been
extensively investigated by laser flash photolysis (LFP) at
355 nm, as well as by steady-state preparative irradiation at
310 nm in the presence of water, amines, thiols, and ethyl vinyl
ether. Product distribution analysis revealed fairly efficient
benzylation of the amines, hydration reaction, and 2-ethoxy-
chromane generation, in the presence of ethyl vinyl ether,
resulting from a [4 þ 2] cycloaddition onto a transient quinone
methide. Remarkably, we found that the reactivity was dramatically suppressed under the presence of oxygen and radical scavengers,
such as thiols, which was usually associated with side product formation. In order to unravel the mechanism responsible for the
photoreactivity of these NI-based molecules, a detailed LFP study has been carried out with the aim to characterize the transient
species involved. LFP data suggest a photoinduced electron transfer (PET) involving the NI triplet excited state (λmax 470 nm) of
the NI core and the tethered quinone methide precursor (QMP) generating a radical ions pair NI•ꢀ (λmax 410 nm) and QMP•þ.
The latter underwent fast deprotonation to generate a detectable phenoxyl radical (λmax 390 and 700 nm), which was efficiently
reduced by the radical anion NI•ꢀ, generating detectable QM. The mechanism proposed has been validated through a LFP
investigation at 355 nm exploiting an intermolecular reaction between the photo-oxidant N-pentylnaphthalimide (NI-P) and a
quaternary ammonium salt of a Mannich base as QMP (2a), in both neat and aqueous acetonitrile. Remarkably, these experiments
revealed the generation of the model o-QM (λmax 400 nm) as a long living transient mediated by the same reactivity pathway.
Negligible QM generation has been observed under the very same conditions by irradiation of the QMP in the absence of the NI.
Owing to the NIs redox and recognition properties, these results represent the first step toward new molecular devices capable of
both biological target recognition and photoreleasing of QMs as alkylating species, under physiological conditions.
’ INTRODUCTION
and photocleavage25 processes have been extensively investi-
gated in the past few years. Furthermore, it has been demon-
strated that NIs directly tethered to double-stranded
oligonucleotides, provided with a variable length AꢀT base pair
spacer, are capable of undergoing intramolecular PET, generat-
ing a couple of radical ions, namely NI•ꢀ and A•þ. Although the
charge recombination process should be favored, the quick
reoxidation of NI•ꢀ by O2 and the possibility of a hole hopping
between A•þ and G to form G•þ can strongly compete with the
latter. By confirmation of that, it has been observed that DNA
damage is greatly affected by the rate of the reoxidation process,
both by the length of the AꢀT base pair linker and G oxidation
potential.26,27 On the other hand, several groups have achieved
covalent modification of DNA by direct photoactivation of
o-hydroxybenzylic alcohols (1) or Mannich base derivatives of
phenols (2) and binols (3), in water solution, and such a
1,8-naphthalimide derivatives (NIs) have been studied exten-
sively over the past few years because of their very interesting
photophysical properties1ꢀ5 as well as their wide biological
applicability. In fact, these compounds present two characteristic
features, namely, high and tunable fluorescence properties and
the excellent accepting character of the NI core, which has greatly
increased the use of NI-based molecules for the synthesis of new
devices with emission behavior, such as dyes,6 organic LEDs,7 pH
and metal cation sensors,8ꢀ11 as well as anions sensors.12ꢀ14
Moreover, it has been shown that such a class of molecules acts
both as effective DNA intercalating agents,15,16 and potent
topoisomerase II inhibitors.17,18 This has resulted in the wide
ranging applications of NI-based molecules for the development
and design of new antitumor drugs.19ꢀ23
The high tendency of the NI core to undergo photoinduced
electron transfer (PET), as well as the affinity toward biological
substrates such as DNA, has also been exploited to induce
selective DNA damage. In particular, selective photo-oxidation24
Received: December 21, 2010
Published: March 22, 2011
r
2011 American Chemical Society
3096
dx.doi.org/10.1021/jo102531f J. Org. Chem. 2011, 76, 3096–3106
|

The Journal of Organic Chemistry
ARTICLE
reactivity can also be triggered by thermal digestion, base
catalysis, and the presence of fluoride anions.28ꢀ41 More re-
cently, binol derivatives, functionalized with benzylic amino acids
side chains, showed DNA photoalkylation properties and photo-
cytotoxicity comparable to, and in some cases higher than,
psoralene.42 Moreover, purine selective alkylation toward DNA
has been achieved by direct photogeneration of naphthoquinone
methides.43
The key intermediates shared between all these processes are
the transient quinone methides (QMs). Their formation showed
a strong dependence on the leaving group attached at the
benzylic position of their precursor (QMP). Furthermore, the
generation of QMs has been proven to be highly responsive to
the presence of electron-withdrawing and electron-donating
groups. In more detail, electron-donating groups greatly facilitate
QM generation, whereas electron-withdrawing substituents
strongly suppress such a process.44 This peculiar feature of
QMP has been recently exploited to develop a brand new
reductive protocol for the release of the QM transient. In
particular, the monoelectronic reduction of a naphthalendiimide
(NDI) acts as a reactivity switch for the directly tethered QMP,
owing to the properties of the electron-donating group of the
stable NDI radical anion generated, as summarized in Schemes 1
and 2.45
Although the above mechanism represents an original and
biologically suitable activation protocol for generation of QMs,
very stable and long living radical anion intermediates are
required in order to trigger the reactivity, thus allowing the
formation of byproducts such as reactive oxygen species (ROS).
In our present work, we describe the synthesis and the
unexpected photochemical reactivity of a new class of NI
derivatives, bearing two different QMPs at the imide moiety
(Scheme 3) by irradiation of the NI core. Moreover, we
rationalize the photogeneration of the transient QM (6) through
a PET mechanism between the phenolic precursors and the NI
core. Such a reactivity represents the first case of non-direct
phototriggering of QMs via PET involving a tethered peripheral
moiety.
’ RESULTS AND DISCUSSION
Synthesis. Already published studies showed how the PET
mechanism in naphthalimideꢀdonor dyads is strongly affected
by the linker length between the NI accepting core and the
donor.2,4 In order to evaluate how this effect could be translated
in terms of photoreactivity, we decided to synthesize two
different NI derivatives. By tethering the (5-amino-2-hydroxy-
benzyl)trimethylammonium iodide, as QMP precursor, to the
1,8-naphthalene anhydride (8) we obtained molecule 11. The
latter represents a directly linked donorꢀacceptor system.
Scheme 1. Thermal and Photoinduced Generation of QM
and Substituent Effect on the Reactivity of QM Precursor
(QMP)
Scheme 3. Generation of QMs by PET Activation of Sub-
stituted NIs at 355 nm
Scheme 2. Generation of the NDI Radical Anion (NDI•ꢀ) as Electron-Donating Substituent, Triggering the QM Formation
3097
dx.doi.org/10.1021/jo102531f |J. Org. Chem. 2011, 76, 3096–3106

The Journal of Organic Chemistry
ARTICLE
Alternatively, using [5-(2-aminoethyl)-2-hydroxybenzyl]tri-
methylammonium iodide, we obtained molecule 14, which
allowed us to separate the donor QMP from the NI core with
a conformationally flexible spacer (Scheme 4).
absorptivity of the NI core in the 310 and 360 nm spectroscopic
window, compared to the negligible absorbance of the QMP
moiety, and (ii) the absence of photoreactivity of the amine
analogues (10, 13). In fact, it is widely known that QM generation
by directirradiation of Mannich bases also occurs, with very similar
photoefficiency to their quaternary ammonium salts.47 Despite
this, irradiation of molecules 11 and 14 showed high photoreac-
tivity toward basic nucleophiles such as piperidine, ethylbutyla-
mine, and tert-butylamine. In fact, both molecules upon irradiation
at 310 nm in a CH3CN:H2O 1:1 Ar purged solution gave
conversion into the corresponding alkylated adducts ranging
between 15 and 50%, after only 5 min of irradiation (using four
lamps, 15 W; Tables 1 and 2). A similar behavior toward neutral
nucleophiles, such as water and thiols, has been observed for
longer irradiation times (30 min; Tables 1 and 2), resulting in the
hydration adducts 15 and 21. This difference could easily be
explained by the higher electron donor character of the phenolate
anion generated in the presence of basic nucleophiles. Indeed,
performing the irradiation in carbonate buffered conditions
(pH >8.5) the hydration reaction became as efficient as the
trapping of basic nucleophiles. In fact, almost complete conversion
to the hydration adducts 15 and 21 was observed after 30 min
of irradiation under this condition (Tables 1 and 2), whereas
similar conversions to those observed for amines were obtained for
5 min irradiation. Notably, poor photoreactivity toward thiol-
based nucleophiles has been observed, which is in marked contrast
to the reactivity studied by generating the transient QM by direct
irradiation. Therefore, in order to clarify the conditions of the
photo- and thermal activation, a blank has been prepared for each
photoreaction batch, which was made and treated under the very
same conditions but not exposed to light. Alkylating adducts have
never been detected for the nonirradiated blank solutions, in the
presence of the same nucleophiles for equal or longer reaction
times (at least for an additional hour). This result confirmed that
the observed conversions weredue tophotochemicalprocess only.
Base Catalytic Activation. Activation by base catalysis takes
advantage of the low pKa (∼8) of the quaternary ammonium
salts of the Mannich bases, which allows the generation of a
Attempts to achieve a direct coupling between the anhydride 8
and (5-amino-2-hydroxybenzyl)trimethylammonium iodide, ac-
cording published procedures,6 were hampered by the thermal
instability of the quaternary ammonium salts. In fact, it is well-
known how such substrates can easily decompose into free QM
and amine in the presence of electron-donating groups on the
aromatic ring.44 Consequently, both the adduct 11 and 14 were
synthesized by a three-step procedure starting from the coupling
of the anhydride 8 to p-aminophenol or tyramine, respectively,
exploiting a microwave synthetic protocol herein discussed. The
above coupling was followed by a Mannich reaction and CH3I
methylation (Scheme 4). This synthetic route allowed us to
obtain NIs 11 and 14 by using only one chromatographic
purification step in excellent yield.
After the synthesis of 11 and 14 was accomplished, we started
to investigate photoactivation protocols under mild conditions,
in order to study the reactivity of such molecules as photoalk-
ylating agents. Moreover, to evaluate their thermal intrinsic
reactivity and to discriminate it from the photoreactivity, two
more activation pathways have been studied: (i) buffered neutral
thermal digestion and (ii) base-catalyzed thermal digestion. In
both cases, the reaction of 11 and 14 was performed at 45 °C in
the presence of several nucleophiles (thiols and amines), in
aqueous acetonitrile solutions (CH3CN/H2O 1:1).
Photoreactivity. The photoactivation of o-hydroxybenzyl al-
cohols, Mannich bases, and their quaternary ammonium salts as
alkylating agents via QM generation has been studied. In fact, it is
well-known how QMs could be efficiently generated by direct
irradiation of phenol-like chromophores. Indeed, the acidic QMPs
singlet excited state leads to a facile deprotonation, which even-
tually results in QM generation.31,46 Surprisingly, we found that
the photoreactivity observed for the NI derivatives herein synthe-
sized was not due to such a mechanism. This conclusion was
suggested by two key experimental observations: (i) the high
Scheme 4. Synthesis of the NI Derivatives (11 and 14)
3098
dx.doi.org/10.1021/jo102531f |J. Org. Chem. 2011, 76, 3096–3106

The Journal of Organic Chemistry
ARTICLE
Table 1. Reactivity of 11 by Base Catalysis and Irradiation at 310 nm
[a] Reaction time; T/°C. CH3CN:H2O = 1:1, [11] or [14] = 5 ꢁ 10ꢀ4 M, [HNu] = 5 ꢁ 10ꢀ3 M, kept in the dark. [b] Reaction time; T/°C. CH3CN:H2O
= 1:1, [11] or [14] = 5 ꢁ 10ꢀ4 M, [HNu] = 5 ꢁ 10ꢀ3 M, 310 nm irradiation. Reaction yields (%) are reported in parentheses. [c] Condition A, carbonate
buffered (pH g8.5). [d] Condition A, not buffered. [e] Condition B, not buffered. [f] Condition B, carbonate buffered (pH g8.5)
reactive zwitterionic form at pH g8 and generates alkylating QM
after mild thermal activation.
only by the formation of a QM transient capable of reacting with
EVE via [4 þ 2] hetero-DielsꢀAlder cycloaddiction, as depicted
in Scheme 5.
Basic amines such as piperidine, tert-butylamine, and ethylbu-
tylamine (pKa > 10.7) gave almost quantitative conversion after 1
h of digestion (45 °C, in CH3CN:H2O 1:1; reaction condition A,
Tables 1 and 2). Amines displaying lower basicity (pKa e8),
namely, morpholine, as well as neutral nucleophiles, such as
water and thiols, require carbonate-buffered conditions (pH
g8.5, reaction condition C) and longer reaction times
(Tables 1 and 2). Remarkably, under these conditions reactivity
toward thiols has been recovered. The results described above
suggest that the activation of 11 and 14 as alkylating agent is not
efficient at rt but only under strong basic conditions (pH >8.5,
45 °C), when the phenol is mainly deprotonated, and under
higher temperatures. Similarly to the prototype quaternary
ammonium salt 2a, also for 11 and 14, the zwitterionic form
has to be populated to lower the barrier for the QM generation.
Hetero-DielsꢀAlder Reactivity. In order to confirm that a
QM transient species was responsible of the alkylating reactivity
observed, irradiation in the presence of ethyl vinyl ether (EVE)
has been carried out. Although the QM-hydration pathway is
competitive in aqueous acetonitrile ([EVE] = 0.1 M), the
irradiation of the NIs 11 and 14 leads to the formation of the
2-ethoxychromanes 27 and 28. Such reactivity could be allowed
Photochemical Efficiency. Quantum Yield Measurements.
In order to evaluate the efficiency of NI derivatives 11 and 14 as
photoalkylating agents, quantum yield experiments have been
carried out. In more detail, we investigated the efficiency of the
QM generation in water, trapping the resulting QM (i) by water
in a buffered solution and (ii) by a nitrogen nucleophile, such as
ethylbutylamine. In particular, for both derivatives 11 and 14,
two diluted solutions of the NIs (2.5 ꢁ 10ꢀ4 M in H2O:CH3CN
1:1) have been prepared: (i) a phosphate-buffered one at pH 7
and (ii) an unbuffered one in the presence of freshly distilled
ethylbutylamine (2.5 ꢁ 10ꢀ3 M). Both solutions have been
irradiated for 10 min at 315 nm, and both the alcohols 15 and 21
together with the amines 17 and 23 have been detected and
measured by HPLC. In addition, it is worthy to underline that 2a,
which is the precursor of a QM by direct irradiation, is not
reactive under the conditions described above, as its absorbance
at 315 nm is negligible.
Although the quantum yields in Table 3 clearly suggest that
the photoactivation efficiency of these NIs is quite low (<0.07),
they can be activated at much longer wavelength (355 nm) than
the quaternary ammonium salt 2a (254ꢀ280 nm).
3099
dx.doi.org/10.1021/jo102531f |J. Org. Chem. 2011, 76, 3096–3106

The Journal of Organic Chemistry
ARTICLE
Table 2. Reactivity of 14 by Base Catalysis and Irradiation at 310 nm
a] Reaction time; T/°C. CH3CN:H2O=1:1, [11] or [14] = 5 ꢁ 10ꢀ4 M, [Hnu] = 5 ꢁ 10ꢀ3 M, kept in the dark. [b] Reaction time; T/°C. CH3CN:
H2O=1:1, [11] or [14] = 5 ꢁ 10ꢀ4 M, [HNu] = 5 ꢁ 10ꢀ3 M, 310 nm irradiation. Reaction yields (%) are reported in parentheses. [c] Condition A,
carbonate buffered (pH g8.5). [d] Condition A, not buffered. [e] Condition B, not buffered. [f] Condition B, carbonate buffered (pH g8.5)
Scheme 5. Generation of Ethoxychromanes 27 and 28 by Trapping QMs (QM 11 and QM 14)
Intermolecular QM generation by PET. Direct Evidence for
QM Generation. The well-known electron-accepting properties
of 1,8-naphthalimide derivatives described by Majima and
co-workers3 suggest that the photoalkylation reactions described
above may be initiated by a photoinduced electron transfer
(PET) involving the triplet excited NI and the phenol moiety.
In order to support such a hypothesis, we began a laser flash
photolysis (LFP) investigation on the model intermolecular
photoreaction between N-pentylnaphthalimide [NI-P (29); see
the Supporting Information] and the quaternary ammonium salt
of the mannich base 2a. The transient absorption spectra resulting
from flashing a diluted solution of NI-P (2 ꢁ 10ꢀ4 M) in the
presence of 2a by LFP using 355 nm laser excitation in both neat
CH3CN and aqueous CH3CN have been recorded (Figures 1
and 2). The NI-P triplet excited state (3NI-P*) at 470 nm48,49 was
efficiently quenched by 2a with second-order rate constants
k2 = 1.4 ꢁ 108 and 1.3 ꢁ 108 Mꢀ1 sꢀ1 in neat CH3CN and
aqueous CH3CN, respectively. In neat acetonitrile, a longer time
3100
dx.doi.org/10.1021/jo102531f |J. Org. Chem. 2011, 76, 3096–3106

The Journal of Organic Chemistry
ARTICLE
Table 3. Quantum Yields (Φ)[a] for NIs Photoreactivity,
Measured for 11 and 14 (2.5 ꢁ 10ꢀ4 M) in Aqueous
Acetonitrile Solutions (H2O:CH3CN 1:1) under Buffered
(Phosphate Buffered, pH 7) and Unbuffered Conditions
NI derivative
conditions
Φ[a]
11
11
14
14
H2O:CH3CN, pH 7
0.022[b]
0.069[c]
0.016[b]
0.043[c]
2.5 ꢁ 10ꢀ3 M ethylbutylamine
H2O:CH3CN, pH 7
2.5 ꢁ 10ꢀ3 M ethylbutylamine
[a] By potassium ferrioxalate actinometry (monitored by UVꢀvis).
[b] Quantum yield for the formation of 15 and 21 by hydration reaction
H2O:CH3CN 1:1, 10ꢀ2 M phosphate buffer, pH 7. [c] Quantum yield for
the formation of 21 and 23 in the presence of 2.5 ꢁ 10ꢀ3 M ethylbutyl-
amine in H2O:CH3CN 1:1.
Figure 3. Transient absorption spectrum of a solution of NI-P (2 ꢁ
10ꢀ4 M) and 2a (4 ꢁ 10ꢀ3 M) in argon-purged 1:1 aqueous acetonitrile
solution, recorded after 0.11, 0.18, 0.22, 0.29, and 0.36 ms the laser pulse
(355 nm). (Inset) Decay trace monitores at 400 nm.
Figure 1. Transient absorption spectra of a solution NI-P (2 ꢁ 10ꢀ4 M)
and 2a (2 ꢁ 10ꢀ4 M) in neat and argon-purged CH3CN, recorded 0.82,
1.14, 1.77, 2.09, 2.41, 2.73, and 3.37 μs after the laser pulse (355 nm).
(Inset) Overlapping decay traces at 410 and 470 nm recorded in neat
CH3CN under argon.
Figure 4. Transient absorption spectrum of 11 in oxygen-free CH3CN,
recorded 2.14, 2.55, 3.37, and 3.78 μs after the 355 nm laser pulse.
(Inset) 311* pseudo-first-order rate constants as a function of the
concentration of 11.
The transient species that was generated from the decay of the
triplet excited state, with a maximum absorbance at 410 nm,
exhibited a longer lifetime, decaying with a first-order kinetic. It
was partially quenched by O2. Literature data suggest that both
the phenol radical cation and NI radical anion absorb at similar
wavelength (410 nm).50,51 Therefore, in the absence of reactivity,
from product distribution analysis in neat CH3CN, such a decay
process may be assigned to back electron transfer.
In aqueous acetonitrile, the 3NI-P* absorbance (470 nm) and its
decay still are clearly visible, but the resulting intense transient at
410 nm has disappeared, been replaced by a much weaker and long-
living transient centered at 400 nm (Figure 2). The intensity of the
absorbance related to the last species has been enhanced by the
rising of the quencher (2a) concentration. Both the spectroscopic
and the kinetic properties of this long-living species suggest
assigning the above transient to a quinone methide (QM)
(Figure 3), which has been detected only in aqueous acetonitrile.
Laser Flash Photolysis on NIꢀQMP Dyads. Solvent Effect
on Intermolecular vs Intramolecular PET. We have been able
to infer the nature of the key transient species (QMs) by studying
the photoactivation of the NIs 11 and 14 by product distribution
analysis and by investigating the parallelism between the photo-
activation and the base-catalyzed process. In addition, the LFP
investigation on the intermolecular reactivity, described in the
Figure 2. Transient absorption spectrum of a solution of NI-P (2 ꢁ
10ꢀ4 M) and 2a (2 ꢁ 10ꢀ4 M) in argon-purged 1:1 aqueous acetonitrile
solution, recorded 0.79, 1.11, 1.42, 1.73, 2.36, 2.68, 3.31, and 3.62 μs
after the laser pulse.
scale (>1 μs) revealed the evolution of the triplet into a blue-
shifted transient absorption, centered at 410 nm with a broad
absorption around 700 nm. Figure 1 shows the parallel time
course of the absorbance at both wavelengths 470 and 410 nm. At
the shorter wavelength (410 nm), the formation kinetic of this
transient was seen, and this buildup was mirrored by the decay at
470 nm (inset of Figure 1).
3101
dx.doi.org/10.1021/jo102531f |J. Org. Chem. 2011, 76, 3096–3106

The Journal of Organic Chemistry
ARTICLE
Figure 5. (A) Decay traces of a CH3CN diluted solution of 11 (5 ꢁ 10ꢀ4 M) at 470 nm recorded flashing at 355 nm under argon (red), air (fuchsia), and
oxygen (blue line). (B) Overlapping decay traces at 410, 470, and 700 nm, under argon.
function of 11 concentration, in the absence of O2. Plotting the
311* pseudo-first-order rate constants in neat acetonitrile as a
function of 11 concentration, we have been able to calculate the
second-order rate constant k2 = 1.7 ꢁ 1010 Mꢀ1 sꢀ1 for the
3
intermolecular quenching of 11* by 11, which is diffusion-
controlled (see Figure 4 inset). Similarly to the intermolecular
reaction between NI-P and 2a, a longer time scale revealed the
3
evolution of the 11* into a blue-shifted transient absorption,
centered at 410 nm with a broad and weak absorption around
700 nm. Figure 5B shows the parallel time course of the
absorbance at wavelengths 470, 410, and 700 nm. At the shorter
wavelength, the formation kinetic of this transient was seen, and
this buildup was mirrored by the decay at 470 nm.
The transient that was generated from the decay of the triplet
Figure 6. Transient absorption spectrum of 11 in an oxygen-saturated
CH3CN solution recorded 2.7, 3.0, 3.3, and 5.3 μs after the laser pulse.
excited state, with a maximum absorbance at 410 nm, exhibited a
longer lifetime (k = 4.48 ꢁ 104 sꢀ1) and it was partially quenched
by O2 (air-purged CH3CN, k = 6.29 ꢁ 106 sꢀ1; O2 purged
CH3CN, k = 2.02 ꢁ 107 sꢀ1). The oxygen did not bleach
completely the transient centered at 410 nm, leaving a decay trace
that did not returned back to zero absorbance (Supporting
Information Figure S1). Upon recording a full transient spectra
in the presence of O2 (Figure 6), it became clear that a second
weaker transient centered at 390ꢀ400 nm (retaining the broad
band at 700 nm) was present, but it was partially hidden by the
intense absorbance at 410 nm in the absence of O2. The absorption
spectra of the transient centered at 410 nm was very similar to the
published NI radical anion spectra (NI•ꢀ, λmax 410 nm).54 This
spectroscopic evidence, together with its quenchingby O2, suggests
that the intense absorbance at 410 nm has to be ascribed mainly to
Figure 7. Transient absorption spectrum of 11 in an oxygen-free
CH3CN solution recorded from 36.4 to 363.5 μs after the laser pulse.
the radical anion of the NI 11 (11•ꢀ). It is also clear that 11•ꢀ
absorption partially overlaps to a second transient (centered at
390ꢀ400 nm), which became visible only in the presence of O2.
previous chapter, clearly suggests the role of a PET mechanism in
This species, which exhibits also broad absorption beyond 650 nm,
has been assigned to the phenoxyl radical of the Mannich base
moiety (11•), due to its similarity to phenoxyl radical spectra
already published.55,56 In spite of the fairly close similarities
between phenoxyl radical and phenol radical cation spectra,57 11•
cannot be mistaken for the phenol radical cation 11•þ because it is
stable on a microsecond time scale in the presence of O2
(Supporting Information, Figure S2). Conversely, phenol radical
cations decay within 1ꢀ2 μs in neat acetonitrile.57
the activation of the alkylating QM at 355 nm. Therefore, we
decided to investigate further such QM activation novelty, flashing
at 355 nmthe NIꢀQMP dyads 11 and 14 by LFP. Photolysis of an
argon-purged acetonitrile solution of 11 (5 ꢁ 10ꢀ4 M) resulted in
a transient spectrum exhibiting, at pulse end, an absorption
centered at 470 nm (Figure 4). This transient, decaying with a
pseudo-first-order rate constant kobs = 3.6 ꢁ 106 sꢀ1 in Ar-purged
CH3CN, was quenched by O2. The quantitative effect of O2 onthe
triplet lifetime is reported in Figure 5A (air-purged CH3CN, k =
6.33ꢁ 106 sꢀ1, τ = 158 ns; O2 purged CH3CN, k= 1.22ꢁ 107 sꢀ1
,
LFP of 11 was then carried out in diluted aqueous CH3CN
containing a variable amount of water from 5 to 100 mM. After
the laser pulse, all the transients due to (i) the triplet, (ii) the NI
radical anion 11•ꢀ, and (iii) the phenoxyl radical 11• were
observed at 470, 410, and 700 nm, respectively. In aqueous
τ = 82 ns). Therefore, it was assigned to the triplet state of 11
(311*), on the basis of both the published tripletꢀtriplet absorp-
tion spectra of similar NIs52,53 and the striking similarity to the
3NI-P* described above. Interestingly, the311* lifetime was a linear
3102
dx.doi.org/10.1021/jo102531f |J. Org. Chem. 2011, 76, 3096–3106

The Journal of Organic Chemistry
ARTICLE
Scheme 6. The Intermolecular and Intramolecular PET Mechanisms Triggering the QM Reactivity
CH3CN, with water concentration below 0.1 M, the 311* lifetime
was unaffected. Conversely, both the transients absorbing at
410 nm (11•ꢀ) and 700 nm (11•) showed a strong water
dependence on their lifetimes. In addition, water (from 5 to
50 mM) was responsible for a dramatic reduction of both their
lifetimes (Supporting Information, Figure S3). Nevertheless, for
75 mM water concentrations, the formation of a more stable third
species became detectable. In fact, longer time scale (>30 μs)
revealed the parallel evolution of both 11•ꢀ and 11•into a blue-
shifted (370ꢀ380 nm) stable absorption and a broad tail up to
450 nm (Figure 7). The striking similarity of all the transients
detected in the intermolecular reaction NI-P (29) þ 2a, includ-
ing the direct detection of the prototype o-QM, with those
characterized for the dyad NIꢀQMP (11) suggests that the last
forming species should be ascribed to the QM conjugated to the
NI core.
presence of a proximal quaternary ammonium salt moiety further
enhances the acidity of the phenolic radical cation, which under-
goes fast deprotonation, generating a phenoxy radical. The latter is
detectable only in the intermolecular process. Deprotonation
efficiently competes with the back electron transfer, only when
water is present in solution and the resulting phenoxy radical can
be reduced to the anion NIꢀQMPꢀ. Indeed, according to the
already reported reduction potentials of phenoxyl radicals,58 as
well as the good reductive character of the NI•ꢀ,59 the reduction of
the phenoxyl radical to phenolate results in a thermodynamically
favored process. Such a mechanism is consistent with the poor
reactivity observed in the presence of radical scavengers and
oxidants such as thiols and oxygen (see Scheme 6).
’ CONCLUSIONS
In conclusion, we have described a novel, mild QM generation
pathway, triggered by a PET mechanism involving a naphthalene
imide core and a tethered QMP. The transient species, as well as
the mechanism involved in different solvent conditions, have
been clarified by performing detailed LFP investigations on both
an intermolecular model reaction and on the dyads NIꢀQMP.
To the best of our knowledge, this reactivity represents the
very first case of alkylating QM photogeneration triggered by a
photoinduced electron transfer with a peripheral moiety. The
reactivity of the photogenerated QM toward several nucleo-
philes, together with a thorough LFP investigation, revealed the
generation of the QM as a key intermediate using a longer
wavelength than that required for direct irradiation of the
quinone methide precursors. Owing to the wide applicability of
NI-based molecules in selective biological targeting, such reac-
tivity represents the first step toward the development of
molecular devices capable of undergoing photodelivery of QM
using UVꢀvisible light.
Surprisingly, the intensity of the 311* absorption rapidly
decreased under aqueous solutions for water concentrations
higher than 0.1 M. We have not been able to detect the triplet
311* nor the following transient species in aqueous acetonitrile
1:1, with our LFP equipment. This aspect, together with the fact
that (i) in steady-state irradiations both photohydrationꢀalkyla-
tion reactions reach their maximum efficiencies and (ii) the
presence of amines does not quench the alkylating reactivity,
suggests an intramolecular quenching of the NI triplet excited
state, by the donor moiety, in aqueous acetonitrile 1:1.
The NI 14 exhibited a very similar LFP behavior, with the
generation of (i) the triplet excited state of 14, (ii) its NI radical
anion 14•ꢀ, and (iii) the homologuephenoxylradical14• observed
at 470, 410, and 700 nm, respectively (Supporting Information,
Figure S4). Therefore, according to the experimental evidence, we
could rationalize the observed QM generation within the dyads 11
and 14 mainly through an intermolecular PET process in diluted
aqueous acetonitrile (<0.1 M H2O), which generates a couple of
radical ions, NI•ꢀ and QMP•þ. Conversely, inaqueous acetonitrile
with water concentration >0.1 M the PET becomes mainly
intramolecular with a higher efficiency of the QM generation,
since the phenol radical cation deprotonation is faster. The
’ EXPERIMENTAL SECTION
Microwave Imidization of 1,8-Naphthalic Anhydride (9,
12). General Procedure. Although the synthesis of similar NI
3103
dx.doi.org/10.1021/jo102531f |J. Org. Chem. 2011, 76, 3096–3106

The Journal of Organic Chemistry
ARTICLE
derivatives has already been published,6 we developed a microwave-
based methodology suitable for aromatic amines. In this way, the
reaction has been carried out in 1 h instead of 16 h, with higher yields.
In more detail, 500 mg (2.5 mmol) of 1,8-naphthalic anhydride and 3.1
mmol of the respective amine (4-aminophenol, tyramine) were sus-
pended in 6 mL of pyridine. The mixture was irradiated for 1 h in a CEM
oven, kept at constant temperature (130 °C) with a maximal power
output of 200 W. After cooling, the pyridine was removed under reduced
pressure. The crude solid was then suspended in an HCl aqueous
solution, filtered, and washed first with acidic water and then twice with
anhydrous EtOH.
157.0, 163.8. Anal. Calcd for C22H21IN2O3: C, 54.11; H, 4.33; I, 25.99;
N, 5.74; O, 9.83. Found: C, 54,10; H, 4.38; I, 25.90; N, 5.72.
N-[(3-(Trimethylamino)methyl-4-hydroxyphenyl)ethyl]-
1,8-naphthalimide Iodide (14). Mp: 251ꢀ256 °C. 1H NMR
(DMSO-d6): δ 2.87 (t, 2H, J = 7.6 Hz), 2.97 (s, 9H), 4.22 (t, 2H, J =
7.5 Hz), 4.39 (s, 2H), 6.85 (d, 1H, J = 8.3 Hz), 7.18 (dd, 1H, J = 1.8, 8.3
Hz), 7.27 (d, 1H, J = 1.8 Hz), 7.82ꢀ7.88 (m, 2H), 8.42ꢀ8.46 (m, 4H),
10.14 (s, 1H). 13C NMR (DMSO-d6): δ 32.5, 41.1, 51.8, 63.0, 114.5,
116.1, 121.9, 127.2, 129.4, 130.7, 131.3, 132.4, 134.4, 134.7, 155.7, 163.3.
Anal. Calcd for C24H25IN2O3: C, 55.82.01; H, 4.88; I, 24.58; N, 5.43; O,
9.30. Found: C, 55.80; H, 4.90; I, 24.55; N, 5.45.
The crude imides 9 and 12 were obtained as gray-violet (97% yield)
and white-yellow solids (95% yield) respectively. These compounds
have been used without further purification. The spectroscopic data
found for the imide 9 were in agreement with those reported in the
literature. 60(See the Supporting Information.)
Photoactivation. General Procedure. The determination of
the photoreactivity of molecules 11 and 14 as alkylating agents has been
performed according the following procedure. A Pyrez tube was filled
with 10 mL of a 5 ꢁ 10ꢀ4 M solution of 11 or 14 in H2O/CH3CN 1:1.
To this solution the freshly distilled nucleophile was added until its
concentration reaches 5 ꢁ 10ꢀ3 M, and a purge with N2 flush was
performed for 5 min. After that time the tube was irradiated in a
multilamp reactor fitted with four lamps centered at 310 nm for the
required time (5ꢀ60 min). Conversion has been followed by analytical
HPLC (H2O added with 0.1% TFA and CH3CN as eluent system).
Activation by Base Catalysis. General Procedure. The
alkylating properties of molecules 11 and 14 toward different nucleo-
philes (amines, thiols, and water) have also been investigated under
thermal base catalysis. To a 5 ꢁ 10ꢀ4 M solution of 11 or 14 in a 1:1
mixture of H2O/CH3CN was added the freshly distilled nucleophile
until its concentration reaches 5 ꢁ 10ꢀ3 M. Basic catalysis has been
achieved according two different strategies: (i) by using strong basic
nucleophiles, such as amines, or (ii) by performing the reaction in a
carbonate buffered media (pH 10, NaHCO3/Na2CO3) with nucleophiles
displaying poor basicity. Conversion has been followed by analytical
HPLC (H2O added with 0.1% TFA and CH3CN as eluent system).
N-[4-Hydroxy-3-(hydroxymethyl)phenyl]-1,8-naphthalimide
(Adduct 15). Yellow oil. 1H NMR (DMSO-d6): δ 4.54 (s, 2H), 5.07
(bs, 1H), 6.88 (d, 1H, J = 8.4 Hz), 7.02 (dd, 1H, J = 2.4, 8.4 Hz), 7.23 (d,
1H, J = 2.2 Hz), 7.9 (t, 2H, J = 7.7 Hz), 8.49ꢀ8.51 (m, 4H), 9.6 (bs, 1H).
13C NMR (DMSO-d6): δ 58.0, 114.6, 122.7, 126.8, 127.2, 127.4, 127.6,
127.8, 129.2, 130.7, 131.4, 134.3, 153.7, 163.9. Anal. Calcd for
C19H13NO4: C, 71.47; H, 4.10; N, 4.39. O, 20.04. Found: C, 71.49;
H, 4.09; N, 4.41.
N-[4-Hydroxy-3-(piperidin-1-ylmethyl)phenyl]-1,8-naph-
thalimide (Adduct 16). Yellow needles. Mp: 214ꢀ215 °C. 1H NMR
(CDCl3): δ 1.66ꢀ1.74 (m, 6H), 3.20ꢀ3.24 (m, 4H), 3.75 (bs, 2H), 6.90
(d, 1H, J = 2.4 Hz), 7.0 (d, 1H, J = 8.5 Hz), 7.15 (dd, 1H, J = 2.5, 8.5 Hz),
7.76ꢀ7.82 (m, 2H), 8.25 (d, 2H, J = 8.0 Hz), 8.65 (d, 2H, J = 8.2 Hz).
13C NMR (CDCl3): δ 22.0, 25.6, 44.6, 53.8, 116.9, 121.9, 122.7, 126.0,
126.9, 128.4, 128.5, 128.5, 131.5, 131.6, 134.1, 158.2, 164.6. Anal. Calcd
for C24H22N2O3: C, 74.59; H, 5.74; N, 7.25; O, 12.42. Found: C, 74.40;
H, 5.85; N, 7.32.
N-[3-(Butylethylamino)methyl-4-hydroxyphenyl]-1,8-naph-
thalimide (Adduct 17). Pale yellow needles. Mp: 128ꢀ129 °C. 1H
NMR (CDCl3): δ 0.90 (t, 3H, J = 7.3 Hz), 1.20 (t, 3H, J = 7.2 Hz),
1,35ꢀ1.48 (m, 2H), 1.60ꢀ1.65 (m, 2H), 2.67ꢀ2.80 (m, 2H),
2.95ꢀ3.06 (m, 2H), 4.00 (s, 2H), 6.90 (d, 1H, J = 2.2 Hz), 7.0 (d,
1H, J = 8.5 Hz), 7.15 (dd, 1H, J = 2.3, 8.3 Hz), 7.78ꢀ7.84 (m, 2H), 8.30
(d, 2H, J = 8.2 Hz), 8.70 (d, 2H, J = 7.3 Hz). 13C NMR (CDCl3): δ 10.5,
13.8, 20.3, 27.9, 47.0, 52.5, 56.4, 117.36, 121.6, 122.8, 126.1, 126.9, 128.8,
129.0, 131.5, 131.6, 134.1, 158.1, 164.5. Anal. Calcd for C25H26N2O3: C,
74.60; H, 6.51; N, 6.96; O, 11.93. Found: C, 74.55; H, 6.72; N, 7.05.
N-[4-Hydroxy-3-(morpholin-4-ylmethyl)phenyl]-1,8-naph-
thalimide (Adduct 18). Yellow needles. Mp: 222ꢀ224 °C. 1H NMR
(CDCl3): δ 2.65 (bs, 4H), 3.77ꢀ3.80 (m, 6H), 6.90 (d, 1H, J = 2.3 Hz),
7.0 (d, 1H, J = 8.5 Hz), 7.15 (dd, 1H, J = 2.3, 8.5 Hz), 7.78ꢀ7.83 (m,
2H), 8.30 (d, 2H, J = 8.3 Hz), 8.70 (d, 2H, J = 8.3 Hz). 13C NMR
N-[(4-Hydroxyphenyl)ethyl]-1,8-naphthalimide (12). Mp:
1
225ꢀ227 °C. H NMR (DMSO-d6): δ 2.80 (t, 2H, J = 8.0 Hz), 4.17
(t, 2H, J = 8.0 Hz), 6.69 (d, 2H, J = 8.4 Hz), 7.06 (d, 2H, J = 8.4 Hz),
7.81ꢀ7.86 (m, 2H), 8.44 (m, 4H), 9.24 (s, 1H). 13C NMR (DMSO-d6):
δ 32.7, 41.3, 115.2, 121.9, 127.2, 128.7, 129.5, 130.6, 131.2, 134.3, 155.8,
163.2. Anal. Calcd for C20H15NO3: C, 75.70, H, 4.76; N, 4.41; O 15.13.
Found: C, 75.72, H, 4.73; N, 4.48.
Mannich Reaction (10, 13). General Procedure. A 500 mg
portion of the respective 1,8-naphthalimide (9, 12) was dissolved in
anhydrous toluene (60 mL), and 1.2 equiv of N,N-dimethylmethyleni-
minium chloride and 1.6 equiv of K2CO3 were added to the solution.
This mixture was allowed to reflux with vigorous stirring under nitrogen
atmosphere for 4 h. After TLC control (EtOAc/MeOH 8:2), the solid
suspension was filtrated and washed with 30 mL of ethyl acetate. The
filtrated organic solution was dried under vacuum and the crude residue
was purified by flash chromatography (EtOAc/MeOH 8:2), affording
10 (59% yield) or 13 (40% yield).
N-[3-(Dimethylamino)methyl-4-hydroxyphenyl]-1,8-naph-
thalimide (10). Mp: 210ꢀ211 °C. 1H NMR (CDCl3): δ 2.30 (s, 6H),
3.70 (s, 2H), 6.90 (d, 1H, J = 2.3 Hz), 7.0 (d, 1H, J = 8.5 Hz), 7.15 (dd,
1H, J = 2.4, 8.5 Hz), 7.79ꢀ7.84 (m, 2H), 8.30 (d, 2H, J = 7.6 Hz) 8.70 (d,
2H, J = 7.3 Hz). 13C NMR (CDCl3): δ 44.3, 62.4, 108.3, 116.9, 122.2,
122.8, 126.0, 126.9, 128.2, 128.7, 131.5, 131.6, 134.1, 158.2, 164.6. Anal.
Calcd for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09; O,13.86. Found: C,
72.79; H, 5.27; N, 8.03.
N-[(3-(Dimethylamino)methyl-4-hydroxyphenyl)ethyl]-
1,8-naphthalimide (13). Mp: 185ꢀ188 °C. 1H NMR (CDCl3): δ
2.30 (s, 6H), 2.94 (t, 2H, J = 8.4 Hz), 3.61 (s, 2H), 4.37 (t, 2H, J = 8.4
Hz), 6.78 (d, 1H, J = 8.2 Hz), 6.97 (d, 1H, J = 2.0 Hz), 7.17 (dd, 1H, J =
2.1, 8.2 Hz), 7.74ꢀ7.80 (m, 2H), 8.22 (d, 2H, J = 7.4 Hz), 8.61 (d, 2H, J
= 7.0 Hz). 13C NMR (CDCl3): δ 33.3, 41.9, 44.3, 62.7, 115.8, 121.8,
122.6, 126.8, 128.0, 128.8, 128.9, 129.1, 131.0, 131.5, 133.7, 156.5, 164.0.
Anal. Calcd for C23H22N2O3: C, 73.78; H, 5.92; N, 7.48; O, 12.82.
Found: C, 73.79; H, 5.89; N, 7.45
Exhaustive Methylation of Mannich Bases (11, 14). Gen-
eral Procedure. A 500 mg portion of the respective Mannich base (10,
13) were dissolved in CH3CN (30 mL), and CH3I (5 equivalents) was
added dropwise. The solution was stirred at rt under nitrogen atmo-
sphere until precipitation of a white solid is observed. To enhance the
solid’s precipitation, 10 mL of Et2O could be added. The white solid was
collected by filtration and washed twice with cold CH3CN to give 11
(73% yield) or 14 (75% yield).
N-[3-(Trimethylamino)methyl-4-hydroxyphenyl]-1,8-naph-
thalimide Iodide (11). Mp: 256ꢀ257 °C. 1H NMR (DMSO-d6): δ
3.34 (s, 9H), 4.62 (s, 2H), 7.15 (d, 1H, J = 8.6 Hz), 7.35 (d, 1H, J = 2.4
Hz), 7.48 (dd, 1H, J = 2.3, 8.5 Hz), 7.90ꢀ7.95 (m, 2H), 8.50 (d, 2H, J =
7.8 Hz), 8.58 (d, 2H, J = 7.3 Hz). 13C NMR (DMSO-d6): δ 52.0, 62.8,
114.7, 116.3, 122.5, 126.8, 127.3, 127.8, 130.8, 131.4, 132.7, 134.5, 134.9,
3104
dx.doi.org/10.1021/jo102531f |J. Org. Chem. 2011, 76, 3096–3106

The Journal of Organic Chemistry
ARTICLE
(CDCl3): δ 52.9, 6.5, 66.7, 116.9, 121.2, 122.7, 126.4, 126.9, 128.4,
128.7, 128.9, 131.6, 131.5, 134.1, 157.7, 164.6. Anal. Calcd for
C23H20N2O4: C, 71.12; H, 5.19; N, 7.21; O, 16.48. Found: C, 71.35;
H, 5.10; N, 7.05.
N-[3-(tert-Butylamino)methyl-4-hydroxyphenyl]-1,8-naph-
thalimide (Adduct 19). Yellow needles. Mp: 153ꢀ155 °C. 1H NMR
(DMSO-d6): δ 1.30 (s, 9H), 4.00 (s, 2H), 6.90 (d, 1H, J = 8.5 Hz), 7.15
(dd, 2H, J = 2.3, 8.5 Hz), 7.88ꢀ7.93 (m, 2H), 8.51 (m, 4H). 13C NMR
(DMSO-d6): δ 26.6, 40.9, 42.1, 115.6, 122.0, 122.5, 126.5, 127.2, 127.8,
129.6, 129.9, 130.7, 131.4, 134.4, 157.0, 163.9. Anal. Calcd for
C23H22N2O3: C, 73.78; H, 5.92; N, 7.48; O, 12.82. Found: C, 73.53;
H, 5.98; N, 7.52.
27.9, 32.7, 41.4, 44.5, 50.5, 115.6, 121.9, 124.4, 126.9, 127.1, 127.7, 128.1,
128.2, 130.6, 131.2, 134.2, 156.6, 163.2. Anal. Calcd for C25H26N2O3: C,
74.60; H, 6.51; N, 6.96; O, 11.93. Found: C, 74.62; H, 6.49; N, 6.94.
N-[(4-Hydroxy-3-((2-hydroxyethylthiomethyl)phenyl)ethyl]-
1,8-naphthalimide (Adduct 26). White solid. Mp: 190ꢀ194 °C.
1H NMR (CDCl3): δ 2.56ꢀ2.60 (m, 2H), 2.97 (t, 2H, J = 7.3 Hz),
3.75ꢀ3.84 (m, 2H), 3.84 (s, 2H), 4.42 (t, 2H, J = 7.3 Hz), 6.5 (bs, 1H),
6.75 (d, 1H, J = 6.1 Hz), 7.07 (dd, 1H, J = 2.0, 6.0 Hz), 7.14 (d, 1H, J =
2.0 Hz), 7.75ꢀ7.81 (m, 2H), 8.25 (d, 2H, J = 8.8 Hz), 8.59 (d, 2H, J = 8.2
Hz). 13C NMR (CDCl3): δ 30.8, 32.0, 32.5, 33.1, 41.7, 61.5, 116.8,
122.4, 126.9, 129.7, 130.8, 131.2, 131.3, 131.5, 134.0, 143.5, 153.6, 164.1.
Anal. Calcd for C23H21NO4S: C, 67.79; H, 5.19; N, 3.44; O, 15.71; S,
7.87. Found: C, 67.82; H, 5.15; N, 3.42; S, 7.89.
N-[2-Ethoxychroman-6-yl]-1,8-naphthalimide (Adduct 27).
White needles. Mp: 273ꢀ274 °C. 1H NMR (CDCl3): δ 1.23ꢀ1.28 (m,
3 H), 2.01ꢀ2.09 (m, 2H), 2.67ꢀ2.72 (m, 1H), 2.95ꢀ3.06 (m, 1H),
3.65ꢀ3.68 (m, 1H), 3.93ꢀ3.99 (m, 1H), 5.32 (bs, 1H), 6.98ꢀ7.08 (m,
3H), 7.79ꢀ7.85 (m, 2H), 8.30 (d, 2H, J = 8.3 Hz), 8.67 (d, 2H, J = 7.3
Hz). 13C NMR (CDCl3): δ 15.0, 20.5, 26.1, 63.7, 97.0, 117.8, 122.8,
123.5, 126.9, 127.1, 127.5, 128.4, 128.9, 131.5, 131.6, 134.1, 152.4, 164.6.
Anal. Calcd for C23H19NO4: C, 73.98; H, 5.13; N, 3.75; O, 17.14.
Found: C, 73.85; H, 5.03; N, 3.70.
N-[(2-Ethoxychroman-6-yl)ethyl]-1,8-naphthalimide (Adduct
28). White needles. Mp: 168ꢀ170 °C. 1H NMR (CDCl3): δ 1.22 (t,
3H, J = 7.0 Hz), 1.95ꢀ2.06 (m, 2H), 2.60ꢀ2.71 (m, 1H), 2.92ꢀ2.97 (m,
3H), 3.63ꢀ3.69 (m, 1H), 3.88ꢀ3.94 (m, 1H), 4.35ꢀ4.40 (m, 2H), 5.26
(bs, 1H), 6.82 (d, 1H, J = 7.8 Hz), 7.10 (s, 1H), 7.15 (d, 1H, J = 8.2 Hz),
7.75ꢀ7.81 (m, 2H), 8.23 (d, 2H, J = 8.2 Hz), 8.63 (d, 2H, J = 7.2 Hz).
13C NMR (CDCl3): 15.0, 20.43, 26.5, 33.4, 42.0, 63.5, 96.8, 116.8, 122.4,
122.6, 126.8, 127.7, 128.0, 129.6, 130.7, 131.0, 131.5, 133.8, 150.7, 163.9.
Anal. Calcd for C25H23NO4: C, 74.79; H, 5.77; N, 3.49; O, 15.94.
Found: C, 74.82; H, 5.73; N, 3.52.
N-[4-Hydroxy-3-((2-hydroxyethylthio)methyl)phenyl]-1,8-
1
naphthalimide (Adduct 20). White dust. Mp: 215ꢀ216 °C. H
NMR (DMSO-d6): δ 2.79ꢀ2.82 (m, 2H), 3.55 (bs, 2H), 3.73 (s, 2H),
4.74 (bs, 1H), 6.93 (d, 1H, J = 8.4 Hz), 7.04 (dd, 1H, J = 2, 8 Hz), 7.16 (d,
1H, J = 2 Hz), 7.88 (t, 2H, J = 8 Hz), 8.45ꢀ8.48 (m, 4H), 9.7 (s, 1H). 13C
NMR (DMSO-d6): 33.4, 37.5, 60.5, 114.7, 122.1, 124.8, 126.1, 126.6,
127.2, 127.7, 129.8, 130.2, 130.9, 133.7, 154.3, 163.3. Anal. Calcd for
C21H17NO4S: C, 66.47; H, 4.52; N, 3.69; O, 16.87; S, 8.45. Found: C,
66.45; H, 4.55; N, 3.72; S, 8.43.
N-[(4-Hydroxy-3-(hydroxymethyl)phenyl)ethyl]-1,8-naph-
thalimide (Adduct 21). Yellow oil. 1H NMR (DMSO-d6): δ 2.81 (t,
2H, J = 8.3 Hz), 4.19 (t, 2H, J = 8.2 Hz), 4.47 (d, 2H, J = 5.3 Hz), 4.96 (t,
1H, J = 5.3 Hz), 6.71 (d, 1H, J = 8.0 Hz), 6.91 (dd, 1H, J = 2.4, 8.0 Hz),
7.25 (d, 1H, J = 2.4 Hz), 7.87ꢀ7.92 (m, 2H), 8.46ꢀ8.54 (m, 4H), 9.18
(s, 1H). 13C NMR (DMSO-d6): 33.0, 41.5, 58.2, 114.6, 122.1, 125.0,
127.2, 127.4, 127.5, 128.6, 129.5, 130.7, 131.3, 134.3, 152.6, 163.3. Anal.
Calcd for C21H17NO4: C, 72.61; H, 4.93; N, 4.03; O, 18.42. Found: C,
72.60; H, 4.95; N, 4.02.
N-[(4-Hydroxy-3-(piperidin-1-ylmethyl)phenyl)ethyl]-1,8-
1
naphthalimide (Adduct 22). White solid. Mp: 145ꢀ150 °C. H
NMR (CDCl3): δ 1.58ꢀ1.63 (m, 6H), 2.46 (bs, 4H), 2.89ꢀ2.94 (m,
2H), 3.62 (s, 2H), 4.32ꢀ4.37 (m, 2H), 6.76 (d, 1H, J = 8.2), 6.96 (d, 1H,
J = 1.8 Hz), 7.16 (dd, 1H, J = 2.0, 8.1 Hz), 7.72ꢀ7.77 (m, 2H), 8.19 (d,
2H, J = 7.6 Hz), 8.50 (d, 2H, J = 7.0 Hz). 13C NMR (CDCl3): δ 23.9,
25.7, 33.3, 41.9, 53.7, 61.9, 115.8, 121.5, 122.5, 126.8, 128.0, 128.9, 128.9,
131.0, 131.4, 133.8, 156.5, 163.9. Anal. Calcd for C26H26N2O3: C, 75.34;
H, 6.32; N, 6.76; O, 11.58. Found: C, 75.35; H, 6.30; N, 6.72.
’ ASSOCIATED CONTENT
Supporting Information. 1H NMR and 13C NMR for
S
b
the NIs 11 and 14, their synthetic precursors, and the adducts
15ꢀ28; further LFP data; and NI-P (29) synthetic procedure
and spectroscopic data. This material is available free of charge
via Internet at http://pubs.acs.org.
N-[(3-(Butylethylamino)methyl-4-hydroxyphenyl)ethyl]-
1,8-naphthalimide (Adduct 23). Yellow needles. Mp:
1
112ꢀ115 °C. H NMR (CDCl3): δ 0.92 (t, 3H, J = 7.2 Hz), 1.08 (t,
’ AUTHOR INFORMATION
3H, J = 7.2 Hz), 1.26ꢀ1.43 (m, 2H), 1.48ꢀ1.56 (m, 2H), 2.49ꢀ2.62 (m,
4H), 2.90ꢀ2.95 (m, 2H), 3.74 (s, 2H), 4.33ꢀ4.38 (m, 2H), 6.76 (d, 1H,
J = 8.1 Hz), 6.99 (s, 1H), 7.15 (dd, 1H, J = 1.5, 8.0 Hz), 7.73ꢀ7.78 (m,
2H), 8.21 (d, 2H, J = 8.2 Hz), 8.60 (d, 2H, J = 8.0 Hz). 13C NMR
(CDCl3): 10.8, 13.8, 20.4, 28.5, 33.3, 42.0, 46.5, 52.5, 57.3, 115.9, 122.0,
122.5, 126.8, 128.0, 128.9, 131.0, 131.5, 133.8, 156.6, 163.9. Anal. Calcd
for C27H30N2O3: C, 75.32; H, 7.02; N, 6.51; O, 11.15. Found: C, 75.35;
H, 7.00; N, 6.55.
Corresponding Author
marco.diantonio@unipd.it; mauro.freccero@unipv.it
’ ACKNOWLEDGMENT
This work was supported by MIUR, Grant FIRB-Ideas
RBID082ATK, and Grant AIRC 5826 (Associazione Italiana
per la Ricerca sul Cancro). Thanks to Dr. Luca Pretali for the
support concerning the LFP measurements and to Dr. Beth
Ashbridge for the support in the final revision of this paper.
N-[(4-Hydroxy-3-(morpholin-4-ylmethyl)phenyl)ethyl]-
1,8-naphthalimide (Adduct 24). White powder. Mp: 182ꢀ185 °C.
1H NMR (CDCl3): δ 2.48 (bs, 4H), 2.87ꢀ2.93 (m, 2H), 3.64 (s, 2H),
3.71 (bs, 4H), 4.29ꢀ4.35 (m, 2H), 6.76 (d, 1H, J = 8.2 Hz), 6.96 (d, 1H,
J = 1.8 Hz), 7.16 (dd, 1H, J = 2.0, 8.1 Hz), 7.70ꢀ7.75 (m, 2H), 8.18 (d,
2H, J = 8.2 Hz), 8.56 (d, 2H, J = 7.23 Hz). 13C NMR (CDCl3): 33.2,
41.8, 52.7, 61.7, 66.7, 115.9, 120.5, 122.5, 126.8, 128.0, 129.3, 129.4,
131.0, 131.4, 133.8, 155.9, 163.7. Anal. Calcd for C25H24N2O4: C, 72.10;
H, 5.81; N, 6.73; O, 15.37. Found: C, 72.15; H, 5.78; N, 6.70.
N-[(3-(tert-Butylamino)methyl-4-hydroxyphenyl)ethyl]-
1,8-naphthalimide (Adduct 25). Yellow solid. Mp 132ꢀ135 °C.
1H NMR (DMSO-d6): δ 1.07 (s, 9H), 2.77 (t, 2H, J = 7.3 Hz), 3.78 (s,
2H), 4.15 (t, 2H, J = 7.3 Hz), 6.59 (d, 1H, J = 8.2 Hz), 6.57ꢀ6.97 (m,
2H), 7.80ꢀ7.85 (m, 2H), 8.41ꢀ8.45 (m, 4H). 13C NMR (DMSO-d6): δ
’ REFERENCES
(1) Wintgens, V.; Valat, P.; Kossanyi, J.; Biczok, L.; Demeter, A.;
Berces, T. J. Chem. Soc. Faraday Trans. 1994, 90, 411.
(2) Cho, D. W.; Fujitsuka, M.; Choi, K. H.; Park, M. J.; Yoon, U. C.;
Majima, T. J. Phys. Chem. B 2006, 110, 4576.
(3) Cho, D. W.; Fujitsuka, M.; Sugimoto, A.; Yoon, U. C.; Mariano,
P. S.; Majima, T. J. Phys. Chem. B 2006, 110, 11062.
(4) Cho, D. W.; Fujitsuka, M.; Sugimoto, A.; Majima, T. J. Phys.
Chem. A 2008, 112, 7208.
3105
dx.doi.org/10.1021/jo102531f |J. Org. Chem. 2011, 76, 3096–3106

The Journal of Organic Chemistry
ARTICLE
(5) Takahashi, S.; Nozaki, K.; Kozaki, M.; Suzuki, S.; Keyaki, K.;
Ichimura, A.; Matsushita, T.; Okada, K. J. Phys. Chem. A 2008, 112, 2533.
(6) Cao, H.; Chang, V.; Hernandez, R.; Heagy, M. D. J. Org. Chem.
2005, 70, 4929.
(7) Kolosov, D.; Adamovich, V.; Djurovich, P.; Thompson, M. E.;
Adachi, C. J. Am. Chem. Soc. 2002, 124, 9945.
(8) Licchelli, M.; Biroli, A. O.; Poggi, A.; Sacchi, D.; Sangermani, C.;
Zema, M. Dalton T. 2003, 4537.
(38) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2002,
124, 6349.
(39) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2001,
124, 717.
(40) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2001,
123, 8089.
(41) Brousmiche, D. W.; Wan, P. Photochem. Photobiol. 2002,
149, 71.
(9) Bojinov, V. B.; Georgiev, N. I.; Bosch, P. J. Fluoresc. 2009,
19, 127.
(10) Tian, Y.; Su, F.; Weber, W.; Nandakumar, V.; Shumway, B. R.;
Jin, Y.; Zhou, X.; Holl, M. R.; Johnson, R. H.; Meldrum, D. R.
Biomaterials 2010, 31, 7411.
(42) Doria, F.; Richter, S. N.; Nadai, M.; Colloredo-Mels, S.; Mella,
M.; Palumbo, M.; Freccero, M. J. Med. Chem. 2007, 50, 6570.
(43) Verga, D.; Nadai, M.; Doria, F.; Percivalle, C.; Di Antonio, M.;
Palumbo, M.; Richter, S. N.; Freccero, M. J. Am. Chem. Soc. 2010,
132, 14625.
(11) Georgiev, N.; Bojinov, V. J. Fluoresc. 2010, 1.
(12) Duke, R. M.; Gunnlaugsson, T. Tetrahedron Lett. 2007,
48, 8043.
(44) Weinert, E. E.; Dondi, R.; Colloredo-Melz, S.; Frankenfield,
K. N.; Mitchell, C. H.; Freccero, M.; Rokita, S. E. J. Am. Chem. Soc. 2006,
128, 11940.
(13) Veale, E. B.; Gunnlaugsson, T. J. Org. Chem. 2008, 73, 8073.
(14) Veale, E. B.; Tocci, G. M.; Pfeffer, F. M.; Kruger, P. E.;
Gunnlaugsson, T. Org. Biomol. Chem. 2009, 7, 3447.
(15) Sami, S. M.; Dorr, R. T.; Alberts, D. S.; Remers, W. A. J. Med.
Chem. 1993, 36, 765.
(16) Wamberg, M. C.; Walczak, K.; Andersen, L.; Hassan, A. A.;
Pedersen, E. B. Helv. Chim. Acta 2006, 89, 1826.
(17) Chen, Z.; Liang, X.; Zhang, H.; Xie, H.; Liu, J.; Xu, Y.; Zhu, W.;
Wang, Y.; Wang, X.; Tan, S.; Kuang, D.; Qian, X. J. Med. Chem. 2010,
53, 2589.
(45) Di Antonio, M.; Doria, F.; Mella, M.; Merli, D.; Profumo, A.;
Freccero, M. J. Org. Chem. 2007, 72, 8354.
(46) Colloredo-Mels, S.; Doria, F.; Verga, D.; Freccero, M. J. Org.
Chem. 2006, 71, 3889.
(47) Modica, E.; Zanaletti, R.; Freccero, M.; Mella, M. J. Org. Chem.
2001, 66, 41.
(48) Le, T. P.; Rogers, J. E.; Kelly, L. A. J. Phys. Chem. A 2000,
104, 6778.
(49) Rogers, J. E.; Weiss, S. J.; Kelly, L. A. J. Am. Chem. Soc. 2000,
122, 427.
(18) Nitiss, J. L.; Zhou, J.; Rose, A.; Hsiung, Y.; Gale, K. C.; Osheroff,
N. Biochemistry 1998, 37, 3078.
(50) Tonokura, K.; Ogura, T.; Koshi, M. J. Phys. Chem. A 2004,
108, 7801.
(19) Brana, M. F.; Castellano, J. M.; Moran, M.; Perez de Vega, M. J.;
Romerdahl, C. R.; Qian, X. D.; Bousquet, P.; Emling, F.; Schlick, E.;
Keilhauer, G. Anti-Cancer Drug Des. 1993, 8, 257.
(20) Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay, G. J.; Baguley,
B. C.; Denny, W. A. Bioorg. Med. Chem. 2000, 8, 977.
(21) Li, F.; Cui, J.; Guo, L.; Qian, X.; Ren, W.; Wang, K.; Liu, F.
Bioorg. Med. Chem. 2007, 15, 5114.
(51) Benisvy, L.; Blake, A. J.; Collison, D.; Davies, S. E.; Garner,
D. C.; McInnes, E. J. L.; McMaster, J.; Whittaker, G.; Wilson, C. Dalton
T. 2003, 1975.
(52) Rogers, J. E.; Abraham, B.; Rostkowski, A.; Kelly, L. A. Photo-
chem. Photobiol. 2001, 74, 521.
(53) Rogers, J. E.; Le, T. P.; Kelly, L. A. Photochem. Photobiol. 2001,
73, 223.
(22) Yang, Q.; Yang, P.; Qian, X.; Tong, L. Bioorg. Med. Chem. Lett.
2008, 18, 6210.
(23) Zhu, H.; Miao, Z. H.; Huang, M.; Feng, J. M.; Zhang, Z. X.; Lu,
J. J.; Cai, Y. J.; Tong, L. J.; Xu, Y. F.; Qian, X. H.; Ding, J. Neoplasia 2009,
11, 1226.
(54) Gosztola, D.; Niemczyk, M. P.; Svec, W.; Lukas, A. S.; Wasie-
lewski, M. R. J. Phys. Chem. A 2000, 104, 6545.
(55) Land, E. J.; Porter, G.; Strachan, E. Faraday Trans. 1961,
57, 1885.
(56) Maki, T.; Araki, Y.; Ishida, Y.; Onomura, O.; Matsumura, Y. J.
Am. Chem. Soc. 2001, 123, 3371.
(24) Yang, Q.; Qian, X. H.; Xu, J. Q.; Sun, Y. S.; Li, Y. G. Bioorg. Med.
Chem. 2005, 13, 1615.
(25) Saito, I.; Takayama, M.; Sakurai, T. J. Am. Chem. Soc. 1994,
116, 2653.
(57) Gadosy, T. A.; Shukla, D.; Johnston, L. J. J. Phys. Chem. A 1999,
103, 8834.
(58) Surdhar, P. S.; Armstrong, D. A. The J. Phys. Chem. 1987,
(26) Kawai, K.; Osakada, Y.; Takada, T.; Fujitsuka, M.; Majima, T. J.
Am. Chem. Soc. 2004, 126, 12843.
(27) Kawai, K.; Osakada, Y.; Fujitsuka, M.; Majima, T. Chem.
Commun. (Cambridge) 2006, 3918.
91, 6532.
(59) Rogers, J. E.; Kelly, L. A. J. Am. Chem. Soc. 1999, 121, 3854.
(60) Paudel, S.; Nandhikonda, P.; Heagy, M. D. J. Fluoresc. 2009,
19, 681.
(28) Rokita, S. E.; Yang, J.; Pande, P.; Greenberg, W. A. J. Org. Chem.
1997, 62, 3010.
(29) Veldhuyzen, W. F.; Shallop, A. J.; Jones, R. A.; Rokita, S. E. J.
Am. Chem. Soc. 2001, 123, 11126.
(30) Veldhuyzen, W. F.; Pande, P.; Rokita, S. E. J. Am. Chem. Soc.
2003, 125, 14005.
(31) Richter, S. N.; Maggi, S.; Mels, S. C.; Palumbo, M.; Freccero, M.
J. Am. Chem. Soc. 2004, 126, 13973.
(32) Verga, D.; Richter, S. N.; Palumbo, M.; Gandolfi, R.; Freccero,
M. Org. Biomol. Chem. 2007, 5, 233.
(33) Wang, H.; Rokita, S. E. Angew. Chem., Int. Ed. 2010, 49, 5957.
(34) Di Antonio, M.; Doria, F.; Richter, S. N.; Bertipaglia, C.; Mella,
M.; Sissi, C.; Palumbo, M.; Freccero, M. J. Am. Chem. Soc. 2009,
131, 13132.
(35) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2001,
123, 8089.
(36) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2002,
124, 6349.
(37) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2002,
124, 717.
3106
dx.doi.org/10.1021/jo102531f |J. Org. Chem. 2011, 76, 3096–3106