Reaction of nitrosonium cation with resorc[4]arenes activated by supramolecular control: Covalent bond formation

Article abstract of DOI:10.1021/jo400489m

Resorc[4]arenes 1 and 2, which previously proved to entrap NO⁺ cation within their cavities under conditions of host-to-guest excess, were treated with a 10-fold excess of NOBF₄ salt in chloroform. Kinetic and spectral UV-visible analyses revealed the formation of isomeric 1:2 complexes as a direct evolution of the previously observed event. Accordingly, three-body 1-(NO⁺)₂ and 2-(NO⁺)₂ adducts were built by MM and fully optimized by DFT calculations at the B3LYP/6-31G(d) level of theory. Notably, covalent nitration products 4, 5 and 6, 7 were obtained by reaction of NOBF₄ salt with host 1 and 2, respectively, involving macrocycle ring-opening and insertion of a nitro group in one of the four aromatic rings. In particular, compounds 4 and 6, both containing a trans-double bond in the place of the methine bridge, were oxidized to aldehydes 5 and 7, respectively, after addition of water to the reaction mixture. Calculation of the charge and frontier orbitals of the aromatic donor (HOMO) and the NO⁺ acceptor (LUMO) clearly suggests an ipso electrophilic attack by a first NO⁺ unit on the resorcinol ring, mediated by the second NO⁺ unit.

Full text of DOI:10.1021/jo400489m

Article
pubs.acs.org/joc
Reaction of Nitrosonium Cation with Resorc[4]arenes Activated by
Supramolecular Control: Covalent Bond Formation
Francesca Ghirga,† Ilaria D’Acquarica,*,† Giuliano Delle Monache,† Luisa Mannina,† Carmela Molinaro,†
Laura Nevola,†,‡ Anatoly P. Sobolev,§ Marco Pierini,*,† and Bruno Botta†
†Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita
̀
di Roma, P. le Aldo Moro 5, 00185 Roma, Italy
§Laboratorio di Risonanza Magnetica “Annalaura Segre”, Istituto di Metodologie Chimiche CNR Area della Ricerca di Roma, Via
Salaria km 29.300, 00015 Monterotondo, Italy
S
* Supporting Information
ABSTRACT: Resorc[4]arenes 1 and 2, which previously proved to entrap NO+
cation within their cavities under conditions of host-to-guest excess, were treated
with a 10-fold excess of NOBF4 salt in chloroform. Kinetic and spectral UV−visible
analyses revealed the formation of isomeric 1:2 complexes as a direct evolution of
the previously observed event. Accordingly, three-body 1−(NO+)2 and 2−(NO+)2
adducts were built by MM and fully optimized by DFT calculations at the B3LYP/
6-31G(d) level of theory. Notably, covalent nitration products 4, 5 and 6, 7 were
obtained by reaction of NOBF4 salt with host 1 and 2, respectively, involving
macrocycle ring-opening and insertion of a nitro group in one of the four aromatic
rings. In particular, compounds 4 and 6, both containing a trans-double bond in the
place of the methine bridge, were oxidized to aldehydes 5 and 7, respectively, after
addition of water to the reaction mixture. Calculation of the charge and frontier
orbitals of the aromatic donor (HOMO) and the NO+ acceptor (LUMO) clearly
suggests an ipso electrophilic attack by a first NO+ unit on the resorcinol ring, mediated by the second NO+ unit.
Chart 1. Resorc[4]arenes Studied as Hosts for Nitrosonium
Cation (NO+) Guest
INTRODUCTION
■
C-Nitroso compounds participate in various biological
processes: alkyl nitrites (RO−NO), nitrosoamines/amides,
organic nitrates, and nitrosothiols are used in medicine as
NO-releasing drugs,1−5 whereas toxic NOX gases, including
NO, N2O3, NO2/N2O4, and N2O5 may produce mutagenic
nitrosoamines/peptides and may nitrosate and deaminate DNA
as well.6−9 Nitrosonium cation (NO+), a close relative of NO, is
known to insert into metal complexes to give metal−nitrosyl
systems,10 and to react with calixarene platforms by forming
very stable host−guest complexes, both in solution and in solid
state.11−15 Such calixarene-based systems are now considered as
supramolecular materials for generation, detection, storage, and
release of NO.16,17
report the results obtained when resorc[4]arenes 1 and 2 were
treated with excess NOBF4 salt (up to 10-fold).
We previously reported that resorc[4]arene octamethyl
ethers 1, 2, and 3 (Chart 1), when treated with NOBF4 salt
in chloroform, entrap highly reactive NO+ species within their
cavities.18 The complexation process is proved by bathochromic
shifts of the UV absorbance and is reversible: addition of water
or alcohols leads in all cases to dissociation of the NO+
complexes and to a complete recovery of empty resorc[4]-
arenes. Stable 1:1 resorcarene−nitrosonium complexes of 1−3
were quantitatively isolated and fully characterized, using at
least a 10-fold excess of host to guest. Under the same
conditions, we also evaluated the role played by different side
chains in the resorc[4]arene hosts (1 vs 2) and conformations
(2 vs 3) for NO+ encapsulation by an integrated analysis of
spectral, kinetic, and molecular modeling data.18 We now
RESULTS AND DISCUSSION
■
Complexation of calix[4]arenes by NO+ cation under
conditions of guest-to-host excess, as reported in the literature,
may generate either complexes with stoichiometry greater than
1:112 or covalent side products.19 In a previous work,18 based
on monitoring the UV−visible spectra of resorc[4]arene/NO+
mixtures as a function of time, we found significant differences
in the corresponding kinetic profiles when the host/guest ratio
had been changed from 10:1 to 1:≥3. With the aim to clarify
Received: March 28, 2013
Published: June 20, 2013
© 2013 American Chemical Society
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Figure 1. Spectrophotometric changes for the reactions between resorc[4]arene 1 (top) and resorc[4]arene 2 (bottom) with NOBF4 salt in CHCl3
(molar ratios 1:10) at 298 K.
the role played by the NO+ cation in the interaction with
resorc[4]arenes, we carried out accurate experiments involving
spectral, kinetic, chromatographic, and molecular modeling
measurements.
equal to 10. Two bands at λmax = 561 and 626 nm (LEB zone),
after a fast initial growth, gradually decreased to achieve a
minimum at both wavelengths (Figure 2). A bit slower growth
was recorded at the wavelength range from 250 to 340 nm. The
shape of the growing spectral bands in the visible zone closely
resembles the analogous process already observed when
preliminary experiments were carried out under conditions of
1 to NO+ excess, which was rationalized as due to three
consecutive steps (denoted as steps I, II, and III).18 This
phenomenon at that time was attributed to the quick
generation of a 1/NO+ adduct of 1:1 stoichiometry, with the
nitrosonium cation located inside the cone cavity of the
resorcarene host (namely, the 1a−NO+ structure), which next
undergoes a slower evolution (a true first-order kinetics)
toward a new isomeric form of the complex (the 1b−NO+
adducts18). However, differently from that behavior, in the
present study, after the analogous initial growth of the
absorption bands in the LEB zone, a rapid stop followed by a
progressive decrease of their intensities was detected. These
observations suggest that, after the formation of the above 1:1
host−guest adduct (with NO+ inside the cone cavity), a new
supramolecular species, activated to undergo a spontaneous
intramolecular modification (reasonably a complex with a 1:2
host−guest stoichiometry), arises from the first. The emergence
of this species is indirectly monitored by the isosbestic point at
Because we demonstrated the prominent role played by the
nature of the resorcarene substituents in the complexation, with
respect to conformation,18 we directed our attention to
resorc[4]arenes 1 and 2, which share the same cone
conformation but feature different side chains (see Chart 1).
To figure out all the possible phenomena involved, resorc[4]-
arenes 1 and 2 were treated with an excess of NO+ cation (from
a saturated chloroform solution of NOBF4 salt), and the rate of
absorption changes of the resultant solutions were monitored in
the 300−800 UV−visible nm wavelength range at 298 K. As
compared with the spectra of the same resorc[4]arenes treated
with a host-to-guest excess,18 the UV−visible absorptions in the
low-energy bands (LEB) were drastically reduced and appeared
only by a strong magnification (Figure 1), whereas the growth
of the absorptions in the high-energy bands (HEB) zone took
place faster.
Kinetic Studies on Resorc[4]arene 1. The kinetic
pathway for the formation of 1−NO+ complexes was
monitored under pseudo-first-order conditions, recording in
the 250−800 nm UV−visible wavelength range spectra of
chloroform solutions containing a guest-to-host molar ratio
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Figure 2. Kinetic pathway of the interaction between resorc[4]arene 1 and NO+ cation monitored by UV spectroscopy in the LEB (λ = 561 and 626
nm) and in the HEB (λ = 313 nm) zones.
a
Table 1. First-Order Rate Constants (s−1) for the Interaction of Resorc[4]arenes 1 and 2 with Excess Added NOBF4 Salt
host
host concn (M)
NOBF4 concn (M)
kinetic event
λ = 313 nm
λ = 626 nm
λ = 339 nm
λ = 563 nm
1
2.7 × 10−3
2.5 × 10−2
process 1
process 2
process 1
process 2
process 1
process 2
1.8 × 10−4
4.2 × 10−4
−
−
−
−
−
−
−
−
1.2 × 10−5
1.3 × 10−5
1.0 × 10−3
5.3 × 10−4
2.5 × 10−2
5.6 × 10−3
−
−
−
−
6.2 × 10−4
−
−
−
2
9.2 × 10−4
1.5 × 10−6
2.2 × 10−4
1.5 × 10−6
a
Plots of the corresponding kinetic pathways (spectral changes as a function of time) are collected in Figures 2 and 6.
503 nm, visible in Figure 2. The next changes suffered by the
new hypothesized adduct would be, in fact, responsible for the
triggered loss of absorbance in the LEB zone. In other words,
the whole evolution of the spectral absorptions in the visible
zone would be the result of connected and partially
superimposed processes of supramolecular (in the first stage)
and covalent (in the next step) origin. The spectral changes,
collected as a function of time in the LEB zone, were processed
by nonlinear curve-fitting analysis according to a couple of
partially superimposed first-order processes (kinetic events 1
and 2 in Figure 2 and Table 1) and afforded good correlation
coefficients (in all cases >0.99). Nonlinear curve fitting was also
carried out on the spectral changes registered in the HEB zone
(λmax = 313 nm, see Table 1), which are again connected to two
consecutive processes, featuring very different rates (namely,
processes 1 and 2 of profile c in Figure 2). Again, according to
our previous results,18 the faster process (namely, process 1, λ =
313 nm, k1 = 1.8 × 10−4 s−1) should be associated with the
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coordination of a NO+ guest unit under the convex side of the
resorcarene lower rim defined by the side-chain substituents. In
principle, this insertion might involve either uncomplexed host
1 (a process that leads to the 1c−NO+ geometry discussed in
ref 18 and here reconsidered in the performed theoretical
approach, see Figure 3) or an already upper rim-complexed host
belonging to the starting resorcarene. The bleached solutions
were thus analyzed by normal-phase (NP) HPLC (for
experimental conditions, see the Supporting Information).
Figure 1S of the Supporting Information shows the chromato-
grams obtained after bleaching of 1/NO+ mixtures at 1:1, 1:2,
and 1:3 molar ratios. When bleached solutions from 1/NO+ =
1:1 mixtures were examined, the parent resorc[4]arene 1 was
recovered almost exclusively (peak A, 90%), as in previous
experiments with host excess.18 However, upon increasing the
NO+ concentration, two new products (peaks B and C, 60−
80%) were formed at the expense of the parent resorc[4]arene
(40−20%). Compounds 4 and 5 (corresponding to peaks B
and C, respectively) were first isolated by preparative TLC,
checked for purity by NP-HPLC (85−90%), and then fully
characterized by both 1D and 2D NMR techniques (HMBC,
HSQC, and TOCSY). Electrospray ionization−high resolution
mass spectrometry (ESI-HRMS) was used to complete
identification of compound 5 (see the Supporting Informa-
tion), while elemental analysis was performed for compound 4.
Identification of Compounds 4 and 5 by NMR
Spectroscopy. 1H NMR spectra of the new compounds
exhibited several signals for the aromatic protons (one for each
proton) instead of the two signals (one for type, Hi or He, of
proton) given by the parent resorc[4]arene 1. The same
happened for the eight singlet signals of the methoxyl groups
(only one signal in the precursor). Notably, whereas the He
signals (i.e., H-5, H-11, H-17, and H-23, see Chart 1) appeared
approximately in the same region for the two compounds, the
Hi signals (i.e., H-25, H-26, H-27, and H-28) were shifted
downfield, as compared with those of 1. Moreover, only the
signals for three bridge methines and relative substituents were
Figure 3. Structures obtained by DFT calculations for resorc[4]arene
1 and its two-body (1b−NO+ and 1c−NO+) and three-body (1a−
(NO+)2 and (1b−(NO+)2) adducts with NO+ cation (the counterion
−
BF4 was added to keep neutral the supermolecules).
(i.e., the 1b−NO+ structure), which would lead to three-body
adducts such as those depicted in the bottom of Figure 3 (vide
infra). However, the large excess of NO+ cation used with
respect to the corresponding formation of 1c−NO+ adducts18
preferentially account for a complex with a 1:2 host−guest
stoichiometry.
1
observed. In the H spectrum of 4, the doublet signals of two
coupled (J = 15.7 Hz) trans-olefinic protons (at δ = 6.81 and
6.21 ppm) and the appearance of a bromoethyl group
suggested the presence of a HCCH−CH2Br system, while
in the spectrum of 5 a new singlet at δ = 10.24 ppm was
attributed to an aldehyde group. Cumulatively, these findings
suggest for compounds 4 and 5 a rupture of one of the methine
bridges (e.g., C-2, see Chart 1) that leads to the loss of the C4v
symmetry of the cone conformation and to the plurality of
signals. As a result, the methine and its substituent are
converted to a 3-bromopropylene group in compound 4 and
oxidized to CHO in compound 5 (see Chart 2).
To understand the destiny of carbons 1 and 3 (see Chart 1),
we may consider that the above-mentioned downfield shifts,
caused by the loss of the deshielding due to the opponent
aromatic nucleus, were not comparable for the Hi protons: two
of them, indeed, reached the very high values of 7.15 (H-25)
and 7.79 (H-28) ppm in compound 4, and 7.60 and 7.75 ppm
Accordingly, the second and slower event (namely, process 2,
λ = 313 nm, k1 = 1.2 × 10−5 s−1), that was not detected at all in
host-to-guest excess conditions, takes place with a rate virtually
indistinguishable from that measured by the spectral changes in
the LEB zone (i.e., process 2, λ = 626 nm, k1 = 1.3 × 10−5 s−1).
Its linear kinetic profile, therefore, is consistent with the
hypothesized initial stage of a first-order transformation leading
to a product that is forming, which is devoid in its visible
spectra of the absorption band at 561 nm. Finally, a much
stronger absorption, running off-scale, was also registered in the
340−360 nm range (see Figure 2), exactly the UV zone
corresponding to the electron transitions for the NO+ species.
To summarize, after than a first NO+ unit has been
accommodated into the cone cavity of resorc[4]arene 1 (a
process that is allowed by the optimization of NO+−aromatic
charge-transfer interactions18); a second NO+ unit is
encapsulated within the lower rim of the host, leading to the
above 1:2 complex that, in turn, is ready to undergo a
spontaneous monomolecular modification. Such a process, that
in principle could be either supramolecular or covalent, is
evoked by a clear isosbestic point centered at 503 nm (Figure
2). To provide additional information on the species detected,
several experiments featuring changes in the reaction time and
in the [1]/[NO+] molar ratio were performed. Periodic
monitoring of the reaction mixtures was carried out by both
NMR and HPLC techniques, before and after the quenching of
the chloroform solutions with water. Notably, upon addition of
water, the solutions bleached (from deep purple to pale
yellow), as under conditions of host excess,18 but as the [1]/
[NO+] molar ratios changed from 1:1 to 1:3, the NMR spectra
showed the appearance of new signal resonances, beside those
Chart 2. Structures of Compounds 4 and 5 Obtained from
Resorc[4]arene 1
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Table 2. Charge and Frontier Orbital Properties Calculated for Uncomplexed Resorc[4]arenes 1 and 2 and for Their Two-Body
and Three-Body Adducts with NO+ Cation
charge on Cortho and Cipso atoms (electrons)
charge on N atoms
(electrons)
LUMO−HOMO
close to NO+
close to NO+
gap (eV)
up
down
a
host or NO+ adduct relative stability (kcal mol−1
)
BP (%) at 298 K NO+
NO+
Cortho
Cipso
Cortho
Cipso
NO+
NO+
up
down
up
down
b
b
1
−
0.0
−
100.0
0.0
0.205
0.562
−0.192
−0.197
−
−0.208
−0.198
−0.173
−0.197
−
−0.087
−0.087
−
−0.092
−0.088
−0.075
−0.087
−
−
−
−
−
2.4
1.4
1b−NO+
1c−NO+
1a−(NO+)2
1b−(NO+)2
2
−
0.520
−
0.7
6.4
8.5
0.0
−
−0.205
−0.208
−0.209
−
−0.086
−0.092
−0.040
−
−
0.0
0.569
0.570
0.205
0.561
0.530
0.402
1.2
1.3
1.9
1.2
0.7
2.8
100.0
−
0.1
b
b
−
2b−NO+
2c−NO+
2a−(NO+)2
2b−(NO+)2
4.4
0.0
0.0
0.5
−
−
−
−
99.9
69.9
30.1
−
0.567
0.639
0.639
0.628
−0.196
−0.200
−0.200
−0.091
−0.097
−0.088
−
1.3
0.9
1.1
1.1
−0.200
−0.198
−0.097
−0.091
0.565
1.2
a
b
BP = Boltzmann population. Data obtained from uncomplexed NO+ cation (i.e., NOBF4).
in compound 5. This can be explained for the H-25 proton by
the proximity of the double bond (in compound 4) or the
aldehyde group (in compound 5), whereas for the second (H-
28) we have to invoke the presence of an ortho polar group,
such as OH, but more reasonably NO or NO2, in C-3.
Accordingly, two of the eight quaternary aromatic carbons are
shifted in the 13C NMR spectra upfield (δ = 116.5 ppm) and
downfield (δ = 131.8 ppm) with respect to the parent
resorc[4]arene 1 and were attributed to C-1 and C-3,
respectively. The presence of a NO2 group attached to an
aromatic ring was confirmed by the two typical absorption
bands caused by symmetrical and asymmetrical stretching
vibrations of the NO double bond at 1330−1299 and 1500−
1465 cm−1, respectively, found in the Fourier transform infrared
spectra of compounds 4 and 5.
The structures 4 and 5 (Chart 2) were assigned to the two
products. The above results suggested that at least two events
may be responsible for the macrocycle ring-opening: (i) an
aromatic protodealkylation reaction, frequently observed for
alkyl-substituted aromatic compounds in the presence of strong
Lewis acids,20,21 and (ii) an ipso electrophilic aromatic
substitution (SEAr) by NO+.22
In summary, isolation of compounds 4 and 5 from
resorc[4]arene 1 showed that, depending on the concentration,
NO+ cation could behave, at the same time, as reactant and
catalyst. The former behavior is demonstrated by the presence,
in both the two products, of the nitro group (the end oxidation
product of the nitroso substituent) in one of the four aromatic
rings. The second performance is suggested by the fact that
compounds 4 and 5 could be obtained only when [NO+]/[1]
molar ratios were ≥1, whereas only complexation phenomena
could take place for molar ratios ≤1. Thus, we may suppose an
ipso electrophilic attack by a second unit of NO+ on the
resorcinol dimethyl ether ring, catalyzed by an already hosted
NO+ cation (vide infra).
several experiments followed by classical molecular modeling
calculations.
Molecular Modeling Studies on Resorc[4]arene 1. The
starting points of our theoretical calculations were the 1b−NO+
and 1c−NO+ geometries obtained from previous studies on 1−
NO+ complexes under conditions of host excess18 (see Figure
3). Under conditions of guest excess, we may suppose that a
second NO+ unit further interacts, preferably in the nitro-
sonium cation-free regions, either in the upper or in the lower
rim of already formed 1x−NO+ complexes (with x = b or c).
According to that, three-body adducts have been modeled,
−
considering also the presence of the counterion (BF4 ), by
adding a new NO+ cation inside the cone cavity of the 1c−NO+
two-body adduct, obtaining two different geometries, namely
1a−(NO+)2 and 1b−(NO+)2 (Figure 3). Afterward, the two
geometries were first fully optimized by ab initio Hartree−Fock
(HF) calculations and next refined by the density functional
theory (DFT) method at the B3LYP/6-31G(d) level of theory.
Geometry 1b−(NO+)2 proved to be more stable than 1a−
(NO+)2 by 8.5 kcal mol−1 at 298 K (see Table 2); therefore,
calculation of Boltzmann populations in the gas phase suggests
that the amount of complex 1a−(NO+)2 is negligible at 298 K.
In both of the three-body complexes, the nitrogen of the cation
accommodated inside the cone cavity (namely, NO+up) is
pointing toward a flattened aromatic ring, with its van der Waals
sphere almost in contact with those of both the aromatic
carbons bound to the methine bridges (namely Cipso atoms, see
Figure 4), the distance N−Cipso being 3.62 Å in 1a−(NO+)2
and 3.79 Å in 1b−(NO+)2. The same holds for the van der
Waals sphere of the carbon atom which is ortho to the couple
of Cipso atoms (namely Cortho, see Figure 4), the distance N−
Cortho being 3.50 Å in 1a−(NO+)2 and 3.67 Å in 1b−(NO+)2.
However, only in 1b−(NO+)2 geometry the second NO+ unit
placed in the lower rim of the resorcarene (NO+down) and
pointing its nitrogen atom toward the center of a flattened
aromatic ring displays this atom at a very short distance from
the Cipso and the Cortho carbon atoms, even shorter than that
Because both polar and radical processes involving the NO+
cation as the reactive species have been reported in the
literature,21 we checked the nature of our transformation by
adding hydroquinone and benzophenone separately to the
resorcarene/NO+ mixtures. No relevant changes were detected
when the reaction was carried out in the presence of such
radical scavengers. To explore the feasibility of the mechanism
leading to compounds 4 and 5 from resorc[4]arene 1, we set up
found for NO+ (see Figure 4). N−Cipso and N−Cortho
up
distances of 4.91 Å and 4.90 Å were, in fact, measured for
1a−(NO+)2, respectively, while for 1b−(NO+)2, they were 2.55
Å and 2.47 Å. The tight atomic contacts measured for both of
the NO+ units in 1b−(NO+)2 geometry strongly suggests, by
entropic factors, that either the NO+ cation inside the cone
cavity or that located outside the macrocycle and leaning
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Clearly, in both of the geometries, the Cipso aromatic carbons,
bound to the methine bridge and belonging to the flattened
aromatic ring placed between the couple of NO+ cations, are
favored to behave as the nucleophile. In fact, they are
characterized, at the same time, by all the following three
necessary conditions: (i) a tight contact with the nitrogen atom
of NO+, (ii) an appropriate negative atomic charge, and (iii) a
good expansion of their orbital lobes within the HOMO.
Indeed, although in both of the adduct geometries the Cortho
atoms have a negative charge greater than that of the Cipso
atoms, only on the first type of carbon is the relative expansion
of the HOMO orbital lobes lacking (see Figure 5).
The data collected (see Table 2) confirmed a potential good
propensity of both the three-body 1a−(NO+)2 and 1b−(NO+)2
adducts to undergo the electrophilic substitution by the NO+
cation. However, although 1a−(NO+)2 displays the most useful
LUMO−HOMO gap and QN−QCipso charge difference, we
can assume that 1b−(NO+)2 is the only populated geometry
capable of undergoing an electrophilic attack by the NO+up unit,
as judged by both the LUMO−HOMO energy gap (1.3 eV by
NO+up against 2.8 eV by NO+down) and the QN−QCipso charge
difference (0.658 by NO+up against 0.442 by NO+down). Figure 5
shows satisfactory lobe expansion for the calculated HOMO−
LUMO orbitals of 1b−(NO+)2, which provide evidence of a
Cipso−nucleophile/NO+up−electrophile interaction.
Figure 4. Calculated proximity of the nitrogen atom of NO+ cation
units with Cipso and Cortho carbon atoms of resorc[4]arene 1 in three-
body 1a−(NO+)2 and 1b−(NO+)2 adducts.
against one aromatic ring may easily trigger a classical
electrophilic aromatic substitution (SEAr) on the resorcinol
dimethyl ether ring.
To give a quantitative support to the picture, we evaluated
the charge and frontier orbital properties of the aromatic donor
(HOMO) and the nitrosonium acceptor (LUMO). Therefore,
for both the 1a−(NO+)2 and 1b−(NO+)2 species we
calculated: (i) the atomic charges on the Cipso (namely, QCipso
)
The same kind of calculation was repeated for the two-body
1b−NO+ and 1c−NO+ adducts18 (the first being more stable
by 6.4 kcal mol−1; see Table 2), as well as for the parent
uncomplexed resorc[4]arene 1. By inspection of the data
obtained, it may be argued that, starting from the free
resorcarene 1, complexation of each further NO+ unit leads
to a progressive increment of the QN−QCipso charge difference
and Cortho (namely, QCortho) aromatic carbons belonging to the
flattened ring tightly close to NO+, as well as the atomic charges
on the nitrogen atom of the closer NO+ cation (QN), and (ii)
the energy of the HOMO (or next HOMO) and LUMO (or
next LUMO) frontier orbitals involved in the cited contact (see
Table 2), as well as the lobe expansion of such orbitals (Figure
5).
Figure 5. Lobe expansion calculated for the HOMO (mesh style) and LUMO (solid style) molecular orbitals of the two-body (1b−NO+ and 1c−
NO+) and three-body (1a−(NO+)2 and 1b−(NO+)2) adducts.
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Scheme 1. Plausible Chemical Evolution of Resorc[4]arene 1 Complexed as Three-Body 1b−(NO+)2 Adduct to Compound 4
after an Ipso-SEAr by NO+
Scheme 2. Chemical Evolution of Olefin 4 to Aldehyde 5 after Addition of Water to the Reaction Mixture
(from 0.292 to 0.649 electrons for the two-body adducts and to
0.661 electrons for the three-body adducts) and a decrease of
the LUMO−HOMO energy gap (from 2.4 to 1.4 eV for the
two-body adducts and to 1.3 eV for the three-body adducts),
thus suggesting a potential increase in reactivity for the
resulting complexes toward a Cipso substitution.
Plausible Mechanistic Evolution of Resorc[4]arene 1
into Compounds 4 and 5. On the basis of the above-
reported theoretical studies, the three-body 1b−(NO+)2
geometry proved to be the prereactive supramolecular species.
Thus, we may assume an ipso electrophilic attack on the
resorcinol ring by NO+ (see Scheme 1), catalyzed by the
up
second NO+ unit located outside the macrocycle and leaning
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Figure 6. Kinetic pathway of the interaction between resorc[4]arene 2 and NO+ monitored by UV spectroscopy at 339 and 563 nm. Plot A: growth
of the spectral bands in the HEB zone; plot B: spectral evolution of the absorption bands in the LEB zone (registration window: from 0 to 408 min);
plot C: spectral evolution of the absorption bands in the LEB zone (registration window: beyond 408 min).
against one aromatic ring (namely, NO+down). Displacement of
the methine carbon from the Wheland intermediate, which
leads to the ring-opening of macrocycle, yields a benzylic
carbocation on the other side of the ruptured bond. Removal of
the adjacent proton by a base provides alkene intermediate 4′,
which evolves to the final olefin 4 by spontaneous oxidation of
NO to NO2. Such an event happens even for temporary
exposure to the air, as already shown for p-nitro-substituted
phenols obtained from the corresponding p-nitroso compounds
in the presence of oxygen.23 Such a base-catalyzed mechanism
was supported by the evidence that when the reaction was
performed in the presence of 2,6-di-tert-butyl-4-methylpyridine
(DBMP), it gave compound 4 in higher yield.
Taking into account the large excess of NOBF4 used in the
reaction and the well-known reactivity between nitrosonium
cation and olefins,24−26 a further progress of the reaction may
be hypothesized (see Scheme 2), starting from olefin precursor
4 and leading to aldehyde 5 after addition of water, according
to at least two possible mechanisms, namely a and b. With
regard to mechanism a, the formation of intermediate 5′ as a
precursor of the final aldehyde 5 finds a reasonable theoretical
backing, because it was shown by high-level ab initio
calculations that the four-membered cycle of the structure is
more stable than the equivalent opened fragment.27
Supporting Information) indeed showed that mechanism b is
the more likely pathway to aldehyde 5.
A dedicated experiment on a simplified olefinic model
compound treated with a 3-fold excess of NOBF4 was devised
(vide infra), which confirmed the supposed conversion of the
olefinic double bond into the aldehyde group, with formation of
the corresponding oxime. Moreover, these findings agreed with
the above-mentioned process 2 monitored at λ = 313 nm (see
Table 1), which belongs to the typical UV absorption range of
carbonyl groups.
Kinetic Studies on Resorc[4]arene 2. The kinetic
pathway for the formation of 2−NO+ complexes was
monitored under pseudo-first-order conditions, recording in
the 250−800 nm UV−visible wavelength range spectra of
chloroform solutions containing a guest-to-host molar ratio of
10. By inspection of the overlapped UV−visible absorption
profiles already shown in Figure 1 (bottom), it clearly results in
a progressive and intense growth of two bands centered at 284
and 339 nm, in contrast with the visible zone, where all the
bands show a very weak absorption (Figure 6, plot A). In fact,
in the wavelength range from 500 to 600 nm, only electronic
transitions seriously hampered by the high noise level may be
observed and appeared only by a strong magnification of the
spectra. Nevertheless, the existence of an isosbestic point
centered at 480 nm (Figure 6, plot B) accounts for an
interconversion process occurring between two species.
As already observed for resorc[4]arene 1, also in this case the
large excess of NO+ cation used could account for the
formation of isomeric complexes with stoichiometry greater
than 1:1. However, comparison of the spectral changes
observed over the time in the HEB and LEB zones for 1−
NO+ and 2−NO+ complexes clearly showed a quite different
Mechanism b represents a more classic type of evolution, in
which water attacks the benzylic carbocation (or its resonance
structure consisting of a three-membered cycle, in analogy to
bromonium) to afford intermediate 5″, followed by a retro-
aldol-like fragmentation. In both cases, however, the same final
products would be formed, namely aldehyde 5 and the oxime
derivative of 2-bromoethanal. DFT calculations (see the
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evolution rate of the corresponding processes (Figure 2S of the
Supporting Information), as a result of the replacement of the
bromine atom in resorc[4]arene 1 with the ester carbonyl
group in host 2. In particular, when the host was 2, the
differential absorbance change in the HEB region with respect
to those in the LEB zone was much faster than when the host
was 1. This behavior seems to suggest that when the host is 1,
the spectral transformations are governed by a NO+ cation
guest located in the upper rim of the resorcarene host, whereas
the opposite position of the guest (i.e., NO+ in the lower rim) is
responsible for the observed modifications when the host is 2.
Nonlinear curve fitting of the spectral changes collected as a
function of time in the HEB zone (λmax = 339 nm; see Table 1)
led to the identification of two consecutive and reversible
processes (Figure 6, profile a), both following first-order
kinetics but featuring very different rates, the second one being
much slower (k1 = 1.5 × 10−6 s−1) than the first one (k1 = 9.2 ×
10−4 s−1). Equivalent findings were obtained by kinetic analysis
performed at λ = 563 nm (Figure 6, profile b). However, in this
case, the rate constant for the first process (k1 = 2.2 × 10−4 s−1)
was found 4-fold lower than that registered in the HEB zone.
Finally, as found for resorc[4]arene 1, a drastic change in the
trend was detected when the absorbance reached a minimum
(portion corresponding to plot B in profile b), coincident with
the step of the process responsible for the isosbestic point at λ
= 480 nm. Thus, we can assume that, also in this case, process 1
leads to the formation of a prereactive supramolecular species
able to undergo the chemical evolution described by the linear
kinetic profile of process 2.
Chart 3. Structures of Compounds 6 and 7 Obtained from
Resorc[4]arene 2
−
counterion (BF4 ) to keep the supermolecules neutral. Two
different geometries, namely 2a−(NO+)2 and 2b−(NO+)2,
were obtained by insertion of NO+ cation either upon the
flattened ring overhanging the other NO+ unit or at the top side
of the other flattened ring. Afterward, the two geometries were
fully optimized as described above (see Figure 7). The
Resorc[4]arene 2 was subjected to the same experiments
with NOBF4 as those performed for resorc[4]arene 1, featuring
changes in the reaction time and in the [2]/[NO+] molar ratio.
Periodic monitoring of the reaction mixtures was carried out by
both NMR and HPLC techniques, before and after the
quenching of the chloroform solutions with water. When
bleached solutions from [2]/[NO+] mixtures in a 1:3 molar
ratio were examined by NP-HPLC (Figure 3S of the
Supporting Information), besides the parent resorc[4]arene 2
(peak A), a major peak (B, 70%) was present, whereas a second
product (peak C) was reduced to trace levels. Compounds 6
and 7 (corresponding to peaks B and C, respectively) were first
isolated by preparative TLC, checked for purity by NP-HPLC
(85−90%), and then fully characterized by NMR and ESI-
HRMS (see the Supporting Information).
Not surprisingly, resorc[4]arene 2, which differs from
resorc[4]arene 1 only in the nature of the side chains, gave
rise to the same kind of products in the reaction with
nitrosonium cation, although with different yields. In other
words, the same typology of structures was assigned to the two
products 6 and 7 recovered from the reaction (see Chart 3),
i.e., 6 is a trans-olefin (two coupled protons at δ = 6.38 and 7.86
were detected, J = 16 Hz) and 7 contains an aldehyde group
(singlet at δ = 10.25). To shed light on the possible mechanistic
evolution of resorc[4]arene 2 to compounds 6 and 7, we set up
several experiments followed by classical molecular modeling
calculations.
Figure 7. Structures obtained by DFT calculations for resorc[4]arene
2 and its two-body (2b−NO+ and 2c−NO+) and three-body (2a−
(NO+)2 and (2b−(NO+)2) adducts with NO+ cation (the counterion
−
BF4 was added to keep neutral the supermolecules).
corresponding data (i.e., energies of the HOMO (or next-
HOMO) and LUMO (or next-LUMO) molecular orbitals as
well as the atom charge located on the Cipso and Cortho aromatic
carbons and on the nitrogen atom of the NO+ units) are
collected in Table 2. Geometry 2a−(NO+)2 (0.0 kcal mol−1,
Boltzmann population in the gas phase 69.9% at 298 K) proved
to be more stable than 2b−(NO+)2 by 0.5 kcal mol−1
(Boltzmann population in the gas phase 30.1% at 298 K). As
already found for resorc[4]arene 1, the Cortho aromatic carbons
do not possess at the same time all the features necessary to
behave as the nucleophile toward the tightly close NO+ unit. As
depicted in Figure 8, in fact, lobe expansion, that in the HOMO
orbital should depart from the Cortho atom, is missing.
Comparison of QN−QCipso charge differences for the two
2a−(NO+)2 and 2b−(NO+)2 geometries clearly shows that the
2a−(NO+)2 adduct is the most favored to behave as the
nucleophile toward the NO+
unit, for both energetic
Molecular Modeling Studies on Resorc[4]arene 2.
Three-body adducts of resorc[4]arene 2 with NO+ were
similarly built starting from 2b−NO+ and 2c−NO+ geometries
obtained from previous studies on 2−NO+ complexes under
conditions of host excess.18 The adducts were modeled by
adding a second NO+ cation inside the cone cavity of the 2c−
NO+ two-body adduct, considering also the presence of the
down
(greater Boltzmann population at 298 K) and electrostatic
(greater QN−QCipso difference) factors (see Table 2). Notably,
in this case, the LUMO−HOMO energy gap and the QN−
QCipso charge differences provide evidence of a greater
reactivity of the NO+
unit with respect to the NO+
.
down
up
Moreover, also for resorcarene 2, complexation of each further
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in the α position, with respect to the bromoethyl function in
compound 4. According to these considerations, we treated
olefin 6 with a 3-fold excess of NOBF4 salt in chloroform for 24
h (see Experimental Section for conditions): after quenching
with water, we isolated aldehyde 7 (30% yield), while partly
recovering the starting material. The formation of aldehyde 7 as
main product from olefin 6 also revealed the stability of the
Ar−CH−Ar system in a linear arrangement toward NO+ and
thus the peculiarity of the reaction of tetracyclic resorcarenes 1
and 2 with excess added NOBF4 salt. In particular, the results
provide strong evidence of the key catalytic role of NO+ in
promoting the Cipso aromatic substitution only when engaged
in a convenient supramolecular arrangement with the
resorcarene host.
CONCLUDING REMARKS
■
We investigated the interaction of resorc[4]arenes 1 and 2 in
the cone conformation with NOBF4 in chloroform solution.
Under conditions of host-to-guest excess, we have already
shown that the kinetic trend of the complexation is connected
to the side-chain functionality of the host. Now, further
experiments with guest-to-host excess revealed the formation of
specific nitration products according to a postulated SEAr
mechanism. The main products 4 and 6 (from 1 and 2,
respectively) are derived from the rupture of one of the
methine bridges that leads to the loss of the C4v symmetry of
the host conformation, via an ipso-substitution of a quaternary
aromatic carbon. Although such reactivity is independent of the
nature of the side chains, the overall yields of the reaction were
somehow dependent on the substitution, the final oxidation
products (aldehydes 5 and 7 from 4 and 6, respectively) being
preferentially formed in the case of the bromoethyl side chain
(i.e., from olefin 4).
Figure 8. Lobe expansion calculated for the HOMO (mesh style) and
LUMO (solid style) molecular orbitals of the two-body (2b−NO+ and
2c−NO+) and three-body (2a−(NO+)2 and 2b−(NO+)2) adducts.
NO+ unit leads to a progressive increment of the QN−QCipso
charge difference and a decrease in the LUMO−HOMO
energy gap. In other words, progressive encapsulation of NO+
units improves the nucleophilicity of the Cipso carbon atoms
and enables the macrocycle to undergo the electrophilic
substitution. Such findings easily justify the lack of electrophilic
reactivity that we observed18 when [NO+]/[2] molar ratios
were ≤1.
Rationale for the Ipso Electrophilic Attack by NO+ on
Resorc[4]arene 2. On the basis of the above-reported
theoretical studies, we can imagine the chemical evolution of
resorc[4]arene 2 to compound 6 as the sum of two events: the
first one allows the fast allocation of one NO+ unit beside a
flattened aromatic ring (i.e., NO+down) and corresponds to
process 1 of Figure 6; the second one results from the
electrophilic attack on a Cipso carbon atom by the same
As shown by molecular modeling and frontier orbital
calculations, 1b−(NO+)2 and 2a−(NO+)2 three-body adducts
are the prereactive supramolecular species capable of under-
going an electrophilic attack by the NO+ cation: in the first
case, it involves the NO+ unit, while for host 2 it is the
up
NO+down unit to perform the attack. Such charge-transfer three-
body adducts are an interesting example of supramolecular
control of a reaction outcome.17a,29 In particular, as critical
precursors to an ipso-aromatic substitution, they provide strong
evidence of the key catalytic role of NO+ in promoting the
reaction only when it is engaged in a convenient supra-
molecular arrangement with the resorcarene host. Such findings
easily justify the lack of electrophilic reactivity previously
observed under conditions of host excess.
NO+
unit, triggered by the quite fast insertion of a second
NO+dcowantion into the cone cavity (i.e., NO+up) and corresponds
to process 2, monitored at both 339 and 563 nm. Most likely,
such transformation takes place from the three-body 2a−
(NO+)2 prereactive species, whose formation is suggested by
the isosbestic point detected at 480 nm (Figure 6, plot B).
Notably, process 2 also describes the chemical evolution of
olefin 6 to aldehyde 7 (see Chart 3), according to the same
mechanism depicted in Scheme 2 for resorc[4]arene 1. To
confirm the mechanism of such conversion, already envisioned
for resorc[4]arene 1 (vide supra), (E)-2,4-dimethoxycinnamic
acid ethyl ester28 was chosen as a simplified olefinic model and
treated with a 3-fold excess of NOBF4 salt (see Experimental
Section for conditions). As expected, 2,4-dimethoxybenzalde-
hyde was recovered as main product (22% yield) after the
quenching with water.
EXPERIMENTAL SECTION
■
Calculation Procedures. All molecular modeling calculations
were performed by use of the computer program SPARTAN 08 v 1.2.0
(Wave Function Inc., Irvine, CA). Structures of the three-body 1a−
(NO+)2, 1b−(NO+)2, 2a−(NO+)2, and 2b−(NO+)2 adducts were
obtained by insertion of a new NO+ cation inside the cone cavity of
the already modeled two-body 1c−NO+ and 2c−NO+ adducts,18
respectively. As starting geometries of resorc[4]arenes 1 and 2 and of
two-body 1b−NO+, 2b−NO+, and 2c−NO+ adducts were again used
as the most relevant previously obtained.18 Within the two-body and
three-body adducts, the positive charge of each NO+ cation has been
Notably, the rate constant for the 4 → 5 conversion (1.2 ×
10−5 s−1, see Table 1) was 8-fold greater than that for the 6 → 7
reaction (1.5 × 10−6 s−1), thus accounting for the different
relative amount of aldehydes 5 (34%) and 7 (2%) recovered by
decomposition of intermediate olefins 4 and 6, respectively,
under the same reaction conditions. In fact, in the case of olefin
6, the availability of the double bond π electrons is reduced by
the presence of the electron-withdrawing ester carbonyl group
−
counterbalanced by addition of an equivalent number of BF4 units,
placed in close proximity. Afterward, all the structures were optimized
at the Hartree−Fock (HF) 3-21G level of theory and then redefined
by the DFT method, at the B3LYP/6-31G(d) level of theory. Natural
atomic charges, as well as energies of the HOMO (and next HOMO)
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and LUMO (and next LUMO) orbitals, were also calculated
accordingly. DFT calculations were also performed on uncomplexed
resorc[4]arenes 1 and 2 as well as on NOBF4.
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental methods and spectroscopic character-
ization of compounds 4−7. Cartesian coordinates of structures
optimized at the B3LYP/6-31G(d) level of theory. This
material is available free of charge via the Internet at http://
pubs.acs.org.
General Procedure for the Reaction of Resorc[4]arenes 1
and 2 with NOBF4 Salt. Resorc[4]arenes 1 and 2 used as hosts were
prepared as previously described.18 Stock solutions of NOBF4 salt
(Aldrich) and resorc[4]arenes 1 and 2 (1 × 10−2 M) were prepared in
freshly distilled HPLC grade chloroform under a nitrogen atmosphere
in an isolated glovebox at room temperature. The two solutions were
then mixed to reach [host]/[guest] molar ratios of 1:1, 1:2, and 1:3.
After 24 h, the intensely colored 1:3 reaction mixtures were quenched
with water several times, extracted with chloroform, and dried over
Na2SO4. The bleaching was always accompanied by the disappearance
of the dark blue or purple color and led to pale yellow solutions.
HPLC was used to monitor the reactions (see the Supporting
Information for chromatographic conditions) before and after
quenching with water to get quantitative information on covalent
nitration products 4−7, which were isolated and purified with
preparative TLC plates (eluent: chloroform for 4 and 5 and
dichloromethane−hexane−ethyl acetate, 7:1.5:1.5 for 6 and 7; 85−
90% purity, checked by analytical NP-HPLC (see the Supporting
Information for chromatographic conditions).
AUTHOR INFORMATION
■
Corresponding Author
*Phone: +39-06-49912784. Fax +39-06-49912780. E-mail:
ilaria.dacquarica@uniroma1.it (I.D.); marco.pierini@uniroma1.
it (M.P.).
Present Address
‡Institut de Recerca Biomed
̀
ica (IRB-PCB), Barcelona, Spain.
Notes
The authors declare no competing financial interest.
Compound 4. Pale yellow oil, 91.9 mg, 0.086 mmol (44% yield).
ACKNOWLEDGMENTS
1H and 13C NMR signals are given in the Supporting Information.
■
We acknowledge financial support from Center for Life
NanoScience@LaSapienza, Istituto Italiano di Tecnologia
(IIT), Roma, Italy (Funds 2011−2015) and Sapienza
Anal. Calcd for C44H51Br4NO10: C, 49.23; H, 4.79; Br, 29.77; N, 1.30.
Found C, 49.08; H, 4.77; Br, 29.69; N, 1.29. FT-IR (KBr): 2921, 2851,
1731, 1613, 1509, 1465, 1299 cm−1.
Compound 5. Pale yellow oil, 65.0 mg, 0.066 mmol (34% yield).
1H and 13C NMR signals are given in the Supporting Information. ESI-
HRMS (positive): C42H48Br3NO11Na requires 1002.06752 (mono-
isotopic), m/z found 1002.06810 ([M + Na]+). FT-IR (KBr): 2924,
2855, 1728, 1615, 1508, 1468, 1299 cm−1.
̀
Universita di Roma, Italy (Funds for Selected Research Topics
2011−2013). We gratefully acknowledge Dr. Deborah Quaglio
for her technical assistance.
REFERENCES
■
Compound 6. Pale yellow oil, 174.0 mg, 0.176 mmol (83% yield).
1H and 13C NMR signals are given in the Supporting Information. ESI-
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1H NMR (CDCl3, 400 MHz): δ (ppm) 10.26 (s, 1H, CHO), 7.78 (d, J
= 8.67 Hz, 1H), 6.58 (dd, J = 8.7, 2.1 Hz, 1H), 6.47 (d, J = 2.1 Hz,
1H), 3.88 (s, 3H, OCH3), 3.85 (s, 3H, OCH3). 13C NMR (CDCl3, 75
MHz): δ (ppm) 188.3 (CHO), 166.2 (Ar−C4), 163.7 (Ar-C2), 130.7
(Ar-CH), 119.1 (Ar-C1), 105.8 (Ar-CH), 98.0 (Ar-CH), 55.6 (2 ×
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was purified by silica gel column chromatography (dichloromethane−
hexane−ethyl acetate, 7:1.5:1.5) to yield compound 7 as the main
product (27.9 mg, 0.030 mmol, 30% yield).
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