Mechanism of the solvent-free reactions between indole derivatives and 4-nitrobenzaldehyde studied by solid-state NMR and DFT calculations

Article abstract of DOI:10.1039/c2ce25754h

In an effort to determine the details of the solid-state reaction mechanism of the Friedel-Crafts hydroxyalkylation between indole derivatives (indole, 1^A, and N-methylindole, 1^B) and an aromatic aldehyde (4-nitrobenzaldehyde), a series of solid-state NMR experiments have been performed. The reaction proceeds through a melted phase. By means of the DE pulse sequence the hydroxylic intermediate species (1H-indol-3-yl)(4- nitrophenyl)methanol (3^A) and (1-methyl-1H-indol-3-yl)(4-nitrophenyl) methanol (3^B) in the melt could be observed and characterized, providing evidence for elucidating the reaction mechanism. To support the experimental results, DFT calculations have been carried out showing that the first step of the reaction involving indole and nitrobenzaldehyde to give the intermediate 3^A is energetically favored by 24.7 kJ mol^-1, whereas the final product 3,3′-((4-nitrophenyl)methylene)bis(3a,7a- dihydro-1H-indole) (5^A) is 54.8 kJ mol^-1 lower in energy than the reactants. The calculated and experimental chemical shifts are also in good agreement providing further support to the proposed mechanism. This journal is

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PAPER
Mechanism of the solvent-free reactions between indole derivatives and
4-nitrobenzaldehyde studied by solid-state NMR and DFT calculations{
Michele R. Chierotti, Katia Gaglioti, Roberto Gobetto,* Margherita Barbero and Carlo Nervi
Received 15th May 2012, Accepted 27th June 2012
DOI: 10.1039/c2ce25754h
In an effort to determine the details of the solid-state reaction mechanism of the Friedel–Crafts
hydroxyalkylation between indole derivatives (indole, 1A, and N-methylindole, 1B) and an aromatic
aldehyde (4-nitrobenzaldehyde), a series of solid-state NMR experiments have been performed. The
reaction proceeds through a melted phase. By means of the DE pulse sequence the hydroxylic
intermediate species (1H-indol-3-yl)(4-nitrophenyl)methanol (3A) and (1-methyl-1H-indol-3-yl)(4-
nitrophenyl)methanol (3B) in the melt could be observed and characterized, providing evidence for
elucidating the reaction mechanism. To support the experimental results, DFT calculations have been
carried out showing that the first step of the reaction involving indole and nitrobenzaldehyde to give
the intermediate 3A is energetically favored by 24.7 kJ mol21, whereas the final product 3,39-((4-
nitrophenyl)methylene)bis(3a,7a-dihydro-1H-indole) (5A) is 54.8 kJ mol21 lower in energy than the
reactants. The calculated and experimental chemical shifts are also in good agreement providing
further support to the proposed mechanism.
stages.12 In studies of reacting solid-state systems, information is
Introduction
often required about phases or compounds present, their
Solvent-free organic syntheses are gathering increasing interest
from the viewpoint of green chemistry.1 In recent years, under
Despite recent progresses of preparative mechanochemistry,
structure or mechanisms of their formation or decomposition.
the impetus of crystal engineering,2 solvent-free processes have
understanding of physical and chemical events that take place in
begun to be investigated for the preparation of crystalline
solids during mechanical processing remains limited. Indeed, the
materials,3 molecular cocrystals,4 coordination networks5 and
absence of solvent usually requires that other means (co-grinding
salts.6 Such solvent-free systems have been recently reviewed7
or kneading) have to be used to bring molecules into contact
and variously termed as solid–solid8 or solid-state reactions.9
and to activate the formation of specific interactions. As a
However, Scott and co-workers have highlighted that often
consequence, crystals tend to shatter into microcrystalline
solvent-free reactions actually proceed through formation of
particles as the reaction proceeds, diminishing the usefulness of
eutectic phases between reactants or between reagents and
X-ray diffraction (XRD) methods for the characterization that
requires solid-state spectroscopic techniques.13 Among these,
product(s), i.e. through formation of a liquid or melted phase
containing an intimate mixture of macroscopic solid reactant
solid-state NMR (SS NMR) spectroscopy plays an important
particles. In this way molecules of the solid particles are
role since it relies on the local nuclear environment rather than
sufficiently mobile for frequent molecular collisions to occur.10
the long-range order providing information on reaction progress
Thus, these reactions should be classified as liquid–liquid or
and product formation.
liquid–solid systems reacting without added solvents as also
In this work we show how SS NMR is able to follow solvent-
confirmed by other authors,11 though each case has to be
free reactions discriminating the mechanism through detection of
carefully evaluated and confirmed.
intermediate species and characterization of solid powdered
Concerning solid–solid reactivity, there has been great interest
products. Here we report an exploration of the solvent-free
in finding mechanistic aspects in the context of intra- and inter-
Friedel–Crafts hydroxyalkylation reaction between indoles
(indole, 1A, and N-methylindole, 1B) and an activated aromatic
crystal reactions. The crystal packing determines the extent of
molecular loosening required for the reactants to reorient
aldehyde (4-nitrobenzaldehyde, 2) that we were able to follow by
sufficiently to undergo molecular changes. In this context
a series of SS NMR experiments.
Kaupp has put forward a general mechanism involving three
This electrophilic aromatic substitution reaction gives rise to
bis(indolyl)methanes and it has been carried out in the presence
of a wide number of Brønsted or Lewis acid as catalysts.14
Department of Chemistry, University of Torino, Via P. Giuria 7, I-10125
Torino, Italy
{ Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ce25754h
Recently, we reported a new practical synthesis of a number
of triaryl-, bis(indolyl)- and tris(indolyl)methanes under
6732 | CrystEngComm, 2012, 14, 6732–6737
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solvent-free reaction conditions, at room temperature or under
heating and in the presence of a strong Brønsted acid in
catalytic amounts.15 Following this procedure the product
yields range from 73–100% (19 examples). Furthermore,
starting from the strongly activated 4-nitrobenzaldehyde and
indoles, the reaction reached completion in the absence of any
catalyst, only by heating the reaction mixture for 1 or 2 h
(3 examples; 70, 86 and 100% yields). To the best of our
knowledge, Friedel–Crafts hydroxyalkylation reactions with-
out catalyst have been reported only by us and Patil, in neat
conditions and under heating, and by Li in glycerol at 90 uC,
where the role of the protic solvent in promoting aldehyde
activation through hydrogen bonding was considered
plausible explanation.15
a
Therefore, according to the literature, it would appear that the
reaction does not proceed in a solvent in the absence of a catalyst
at room temperature. Carrying out the reaction in a non-protic
solvent would require a catalyst. Interested in the reaction
mechanism, we decided to investigate further the reaction under
solvent-free reaction conditions and in the absence of any
catalyst.
Scheme 1
high-c (1H: 100%, 26.7 6 107 rad T21 s21) to a diluted low-c
(13C: 1.1%, 6.7 6 107 rad T21 s21) nucleus.
Solid powdered 1A and 2 liquefy almost immediately upon
contacting each other without intervention of grinding. Similar
behaviors have been already reported for other cases.17 The
liquefaction is rapid and complete (10 min) and yields an orange
liquid phase (Fig. 1). The reaction takes about 24 h to complete
with the precipitation of a yellow solid product, characterized as
5A (Scheme 1).
Results and discussion
The reaction between 1A and 2 proceeds through the formation
of an eutectic phase melted at temperatures below 30 uC. In this
case we relied on the SS NMR ability of characterizing both
melted and solid phases through different pulse sequences: direct
excitation coupled with high power decoupling (DE) and cross
polarization (CP), respectively, both under magic angle spinning
(MAS) conditions. These, in turn, allowed us to observe
intermediate species present in the melt and to characterize the
solid product.
Evolution of the melted phase has been followed over time by
DE NMR spectra (Fig. 2 selected spectra, see ESI for the
complete series of spectra{). In order to fully understand the
reaction mechanism the reagents have been mixed either in 2 : 1
or 1 : 1 1A : 2 ratios. The main discussion will be focus on the
reaction with the 2 : 1 ratio, shown in Fig. 2, since also the 1 : 1
ratio leads to the di-substituted product 5A together with
unreacted 2. This is in agreement with the high reactivity of the
carbocation species supposed to be an intermediate (see below).
The t = 0 DE spectrum (the accumulation takes about 30 min)
(Fig. 2a) is characterized by very narrow (solution-like)
resonances directly related to the reactant peaks. The assign-
ment of the melted phase, based on reagent spectra (Fig. 3,
Table 1), is reported in Table 2 (for atom labeling we refer to
Scheme 1). At t = 2 h, new small signals are observed indicating
the formation of intermediate species in the melt (Fig. 2b). It is
worth noting the decrease of the aldehydic peak at 191.0 ppm
(note that chemical shifts of the melt slightly differ from those
of solid reagents) with the concomitant appearance of three
resonances at 39.7, 68.9 and 78.7 ppm. All signals are associated
with CH atoms as confirmed by the 13C DE spectrum acquired
without decoupling (Fig. 2e) which shows doublet signals for all
Indeed, a melt is very similar to the solution phase where the
molecular tumbling provides efficient relaxation mechanisms
able to drastically reduce relaxation delays (T1) and to average
the heteronuclear dipolar interactions. This allows the direct
acquisition of heteronuclei such as 13C in reasonable times
through DE experiments. This technique has been used for
studied melted phases reported in the literature such as molten
salts.16
For solid molecules, the lack of mobility leads to 13C T1 of
hours and to strong heteronuclear dipolar interactions. In this
case, the CPMAS pulse sequence, expressly built for rigid solids,
is very efficient since relies on the shorter T1 of protons whose
magnetization is transferred to heteronuclei (for instance 13C)
through the heteronuclear dipolar interaction. This allows either
a higher scan number to be acquired in the time frame or a signal
intensity gain since we transfer magnetization from an abundant
Fig. 1 (a) Powdered samples: 1A (right) and 2 (left); (b) powdered 1A and 2 mixed at room temperature; (c) immediately after reagent contact, an
orange liquid phase forms at the contact surface; (d) after merely mixing with a glass rod the entire mass becomes a homogeneous liquid melted phase;
(e) the solid, yellow final product 5A.
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Fig. 3 13C (100.64 MHz) CPMAS (a, c–e) and DE (b) experiments of
pure (a) indole (1A), (b) N-methylindole (1B), (c) 4-nitrobenzladehyde (2),
(d) final product 5A and (e) final product 5B recorded with a spinning
speed of 12 kHz at RT. Asterisks denote spinning sidebands.
Afterwards, no significant changes are observed in the
spectrum (Fig. 2d, t = 13 h) but an increasing of linewidths
and noise level are in agreement with reagent consumption and
product precipitation. This is confirmed by the disappearance of
the aldehydic peak (191.0 ppm) and of all peaks associated to
intermediate species and to the final product.
Fig. 2 13C (100.64 MHz) DE (a–d), DE without proton decoupling (e)
and CPMAS (f) spectra of the reaction between 1A and 2 at: (a) t = 0,
spectrum of reagents in the melted phase; (b) t = 2 h, signals of 3A, of a
hydrogen-bonded intermediate and of 5A starting to appear; (c) t = 7 h,
the signals of 3A, of a hydrogen-bonded intermediate and of the product
forming; (d) t = 13 h, noisy spectrum due to product precipitation and
reagent consumption; (e) t = 7 h; (f) solid yellow product 5A. All spectra
were recorded with a spinning speed of 12 kHz at RT.
At the end of the reaction (after 24 h) by switching to CPMAS
techniques, the spectrum of the solid product 5A was acquired
(Fig. 2f). The signal assignment of 5A (Table 1) has been
performed with the help of the non-quaternary suppression
(NQS) technique which shows only quaternary carbon atoms. It
1
these resonances due to H–13C scalar couplings (126, 144 and
154 Hz, respectively). The former is attributed to C7 of the final
product 5A, the second to C7 of the hydroxylic intermediate 3A
(Scheme 1), while the latter to an unknown intermediate species
(see below).
Table 1 13C chemical shift assignments for pure solid compounds 1A, 2,
5A and 5B, and pure liquid 1B
After 7 h, (Fig. 2c with inset) all the cited signals increase their
intensity and it is easier to distinguish three sets of resonances
with similar behaviours: 1) signals at 68.9 (C7 = CH), 150.9 (C4
= Cq) and 146.2 (C1 = Cq); 2) signals at 39.7 (C7 = CH), 152.0
(C4 = Cq) and 145.5 (C1 = Cq) and 3) signals at 78.7 CH, 146.9
Cq, 146.0 (sh) Cq. The first two sets are attributed to 3A and 5A,
respectively (see Scheme 1). The third set (78.7 CH, 146.9 Cq,
146.0 (sh) Cq) is associated to an unknown intermediate species
probably characterized by the presence of a strong hydrogen
bond on the OH group able to shift the signal from 68.9 to
78.7 ppm. Likely, this interaction also involves the NH group of
another indole molecule. We believe that the formation of this
Atoma 1A
1B
2
5A solid
5B solid
C1
C2
C3
C4
C5
C6
C7
C8
—
—
—
—
—
—
—
—
—
—
—
—
—
—
150.1 144.8/142.7
124.6 123.3–110.9
133.8 136.1/131.2
140.1 154.7/151.9
127.4 136.1
146.2
128.1
128.7sh
153.4
131.8
128.1
38.8
124.6 123.3–110.9
188.3 39.7/38.9
101.6 101.1
123.6 121.4
111.7 109.6
118.3 119.6
120.6 121.4
120.6 121.4
127.0 129.1
135.1 137.0
—
—
—
—
—
—
—
—
—
119.4sh/117.6/116.0/113.7 114.7/114.4
C9
123.3–110.9
123.3–110.9
123.3–110.9
123.3–110.9
123.3–110.9
127.6/126.5/125.8
131.2
106.5–123.1
106.5–123.1
106.5–123.1
106.5–123.1
106.5–123.1
127.0/126.6
137.1/136.0
29.6/29.2
C10
C11
C12
C13
C14
C15
C16
a
…
O–H N contact, possible only with the lack of N-substituents,
promotes and catalyzes the reaction. This is confirmed by the
longer time required for the reaction carried out with the
N-methyl analogue 1B.
—
31.7
—
For atom labeling we refer to Scheme 1.
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Table 2 Experimental and calculated (only for the indole reaction) 13C chemical shifts with assignment of compounds 1A, 1B, 2, 5A and 5B in the melta
Atom
1A exp
1A calc
1B exp
2A exp
2A calc
2B exp
3A exp
3A calc
3B exp
5A exp
5A calc
5B exp
C1
C2
C3
C4
C5
C6
C7
C8
—
—
—
—
—
—
—
101.8
121.5
111.2
122.8
119.5
120.4
135.5
135.5
—
—
—
—
—
—
—
—
108.9
127.8
114.8
127.9
125.8
126.6
135.9
143.0
—
—
—
—
—
—
—
—
100.4
121.0
108.9
122.4
118.9
120.4
136.2
136.2
31.2
149.6
124.5
129.1
138.7
127.6
124.5
191.0
—
—
—
—
—
158.7
130.9
139.8
146.4
133.9
131.2
195.6
—
—
—
—
—
149.3
128.6/128.3
146.1
—
—
150.9
—
—
68.9
—
—
—
—
—
—
—
—
—
155.4
130.4
133.0
160.4
133.2
129.4
73.5
130.5
129.2
115.8
129.5
127.3
122.8
133.8
142.9
—
146.3
126.5
126.5
151.5
128.7
126.5
68.6
125.8
121.6
109.2
119.1/116.9
119.1/116.9
119.1/116.9
126.8
145.5
—
—
152
—
—
39.7
—
—
—
—
—
—
—
—
—
154.7
145.7
—
—
152.1
—
—
39.8
122.3sh
121.4
109.2
130.9 (130.7)
135.2 (136.3)
162.7
136.3 (135.2)
130.7 (130.9)
43.5
128.6 (125.5)
129.2 (130.6)
115.1 (115.0)
128.9 (128.3)
126.0 (126.2)
125.4 (125.1)
134.6 (134.4)
143.6 (143.8)
—
138.5
128.6/128.3
189.7
—
—
—
—
—
—
—
—
C9
C10
C11
C12
C13
C14
C15
C16
a
119.2/116.2
—
—
—
—
—
—
—
—
127.8
137.2
—
136.9
31.3
—
Only signals whose assignment is certain are reported.
also highlights the presence of two independent molecules in the
unit cell as easily observed from the splitting of the signals
related to atoms C1 (144.8/142.7 ppm), C4 (154.7/151.9 ppm), C7
(39.7/38.9 ppm) and C15 (136.8/136.1 ppm).
any time. Thus, we can conclude that the presence of a methyl
group hampers the formation of the hydrogen-bonded inter-
mediate able to catalyze and accelerate the reaction. At t = 9, 11
and 13h the absence of the hydrogen-bonded intermediate and of
It is worth noting that a) the reagent mixture is a melt and thus
observable by DE only; b) the product forms quite suddenly but
remains in the melt for hours allowing its direct acquisition by
DE experiments. Later (after about 13 h), it precipitates as a
yellow powdered solid observable only by CPMAS techniques; c)
the intermediate species 3A is a melted phase rather than solid.
This has also been confirmed by following the reaction by
CPMAS experiments which do not show any signal until the
formation of an adequate amount of 5A (see below). However, 3A
is clearly observed by DE experiments; d) the reaction proceeds
through 3A which loses a water molecule leading to the
carbocation species 4A which immediately converts to 5A.
Owing to long NMR acquisition time (about 15 min for reliable
signal-to-noise ratio), it was not possible to observe 4 which is
known to be a very reactive species.18
By following the reaction by CPMAS, after 13 h it was
possible to observe the product spectrum. No signals were found
by applying 13C CPMAS techniques acquired in the initial 7–8 h.
Indeed, one has to consider the low NMR sensitivity, the
acquisition time required (about 1–2
h needed for each
spectrum), and, most importantly, that 3A and 4A are in the
melt, and thus not detectable by CPMAS.
Similar analysis has been performed for the reaction between
the N-methyl analogue, 1B, which is liquid at RT, and 2. As in
the previous case, after a few minutes a homogeneous liquid
phase is formed without grinding. The reaction takes longer
(about 48 h) to complete and at the end a yellow solid product,
characterized as 5B, is recovered. Selected NMR spectra are
reported in Fig. 4 together with the DE spectrum acquired
without decoupling (t = 13 h) and the CPMAS spectrum of 5B
(all the spectra are reported in the ESI{).
The following considerations can be drawn: a) the reaction
proceeds through the intermediates 3B and 4B. The former is
highlighted by the signal at 68.6 ppm, while the latter again is not
observable. b) The product, 5B, appears in the melt (representa-
tive resonance at 39.8 ppm) and precipitates at the end of the
reaction. However, c) no signal around 78 ppm is observed at
Fig. 4 13C (100.64 MHz) DE (a–d), DE without decoupling (e) and
CPMAS (f) spectra of the reaction between 1B and 2 at: (a) t = 0,
spectrum of reagents in the melted phase; (b) t = 9 h, signals of 3B appear;
(c) t = 11 h, the signals of 3B grow while signals of 5B start appearing; (d)
t = 13 h, the signals of 3B start decreasing; (e) t = 13 h; (f) solid yellow
product 5B. All spectra were recorded with a spinning speed of 12 kHz
and at RT.
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5B allows the complete discrimination and assignments of 3B as
reported in Table 2.
SS NMR spectroscopy
All SS NMR spectra were recorded on a Bruker Avance II 400
1
Rather long acquisition times prevent an accurate kinetic
study, so to support the proposed reaction mechanism, DFT
calculations in the gas phase at the B3LYP/6-311++G(d,p) level
have been performed. DFT shows that the overall reaction
depicted in Scheme 1 is thermodynamically favored. The first
step of the reaction involving indole and nitrobenzaldehyde (1A
and 2, Scheme 1) to give the intermediate 3A is energetically
favored by 24.7 kJ mol21, whereas the final product 5A is
54.8 kJ mol21 lower in energy than the reactants. The structure
of the intermediate 3A has been optimized, its absolute NMR
shieldings computed and the corresponding chemical shifts
compared with the SS NMR experimental data (Table 2). The
two computed optical isomers of 3A have the same energy
(minimal differences are due to local minima). During DFT
calculations we do not take in account the interactions in the
melted phase. Nevertheless the calculated and experimental
chemical shifts summarized in Table 2 are in good agreement,
and the general trend of the chemical shifts is reasonably well
reproduced by the calculations. In particular, the computed
resonances of C7 atoms of 3A and 5A, 73.5 and 43.5 ppm, fit
well with the observed experimental data of 68.9 and 39.8,
respectively, which lie in a region of chemical shifts free of other
resonances. From Table 2 one can note that the optimized
molecular geometry of 5A is not symmetric, inducing different
values of the chemical shifts (shown in parentheses) for the two
indole atoms that should be magnetically equivalent due to the
free rotation around the C–C bonds. The small discrepancies
observed between calculated and experimental chemical shifts
can be explained by the neglect of the dynamics and the weak
interactions in the melted phase, which induces slightly different
local energy minima.
instrument operating at 400.23 and 100.65 MHz for H and 13C
nuclei, respectively.
For monitoring the evolution of intermediate species in the
melt, 1 : 1 mixtures of reagents were put inside 4 mm rotors in a
disposable Kel-F insert sealed with glue. Direct excitation (DE)
1
experiments were acquired with a H 90u pulse of 5 ms, recycle
delays of 5 s and 350 transients. When applied, the two pulse
phase modulation (TPPM) decoupling scheme was used with a
frequency field of 75 kHz.
Solid reagent and product samples were packed in cylindrical
4 mm (o.d.) zirconia rotors with sample volume of 80 mL and
spun at 12 kHz at RT. 13C CPMAS spectra were recorded using
a standard ramp cross-polarisation pulse sequence with contact
times of 2–4 ms (13C), a 1H 90u pulse of 2.90 ms, recycle delays of
40–50 s and 198–1051 transients. Non-quaternary suppression
(NQS) experiments were performed with dephasing times of
45 ms and 180u 13C refocusing pulse of 8 ms.
Carbon chemical shift scale was externally referenced via the
resonance of glycine (13C CH2 signal at 43.86 ppm relative to
tetramethylsilane).
Computational details
Calculations were performed with the Gaussian 09 package19
employing the density functional theory (DFT) method with
Becke’s three parameter hybrid functional and Lee–Yang–Parr’s
gradient-corrected correlation functional (B3LYP), with
6-311++G(d,p) as basis set. The geometries of the compounds
were optimized in the gas phase and the nature of all stationary
points was confirmed by a normal-mode analysis. Thermal
correction based on harmonic vibrational frequencies and Gibbs
free energy calculations were performed at 298.15 K and 1 atm.
DFT calculations herein performed does not take into account
the interactions in the melted state, which is beyond the scope of
the present work, but the results appear to be reasonably in
agreement with the experimental data. These geometries were
employed to compute the absolute magnetic shielding s,
performed at the B3LYP/6-311++G(d,p) level using the GIAO
Conclusions
We have characterized the mechanism of the solid-state Friedel–
Crafts hydroxyalkylation reaction between indole derivatives
(indole, 1A, and N-methylindole, 1B) and the aromatic 4-nitro-
benzaldehyde with unprecedented detail. A combination of solid-
state NMR spectroscopy analysis supported by DFT calcula-
tions allowed us to detail a reaction mechanism in which the
intermediate species 3A and 3B were observed and characterized
in the melt. A new hydrogen-bonded intermediate species,
responsible for the higher reaction rate starting from 1A, has
been detected. The lack of a substituent in the nitrogen position
in the indole moiety seems to be the reason for the formation of a
hydrogen bond with the hydroxyl intermediate 3. Furthermore,
the CPMAS technique allowed the characterization of solid
products that, due to solvent-free methods, are rarely obtained
as single crystals suitable for the X-ray analysis. In conclusion we
have demonstrated that SS NMR techniques represent an
excellent opportunity for studying solvent-free reactions which
proceed either through melt or solid phases.
method of Gaussian 09, and the s values were converted into 13
C
chemical shifts d relative to the magnetic shielding of TMS, taken
as reference, computed at the same level (s = 2184.0724).
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