Role of hydroxyl groups on the aromatic ring in the reactivity and selectivity of the reaction of β -phenylethylamines with non-enolizable aldehydes

Article abstract of DOI:10.1007/s11164-015-1987-4

The influence of hydroxyl groups on the β-phenylethylamine aromatic ring was studied during its reaction with non-enolizable aldehydes. Computational calculations established that the degree of hydroxylation generates differences in the activation pattern

Full text of DOI:10.1007/s11164-015-1987-4

Res Chem Intermed
DOI 10.1007/s11164-015-1987-4
Role of hydroxyl groups on the aromatic ring
in the reactivity and selectivity of the reaction
of b-phenylethylamines with non-enolizable aldehydes
1
Rodolfo Quevedo1 Christian Dıaz-Oviedo
Yovanny Quevedo-Acosta1
•
•
´
Received: 26 October 2014 / Accepted: 22 February 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract The influence of hydroxyl groups on the b-phenylethylamine aromatic
ring was studied during its reaction with non-enolizable aldehydes. Computational
calculations established that the degree of hydroxylation generates differences in the
activation patterns of the ring (different reaction pathways) and in the nucle-
ophilicity of the nitrogen atoms (different reaction yields). Cyclic aminals, ben-
zoxazinephanes, or tetrahydroisoquinolines were obtained in the reaction with
formaldehyde, and Schiff’s bases or tetrahydroisoquinolines were produced in the
reaction with other non-enolizable aldehydes. The product obtained depends on the
degree of hydroxylation of the ring of the starting phenylethylamine.
Keywords Dopamine Á Tyramine Á Phenethylamine Á Aldehyde Á Aromatic
Mannich reaction
Introduction
The Pictet–Spengler reaction involves the formation of an imine or iminium ion
from an aldehyde and a b-arylethylamine followed by cyclization through an
intramolecular aromatic electrophilic substitution in the presence of a catalyst [1–3].
Commonly, the amines used have benzene or indole rings as an aromatic nucleus,
forming 1,2,3,4-tetrahydroisoquinolines (THIQ) and 1,2,3,4-tetrahydro-b-carbolines
(THBC), respectively. Because the THIQs and the THBCs are nuclei with multiple
biological activities, the Pictet–Spengler reaction is considered to be of great
importance in the synthesis and biosynthesis of alkaloids and other nitrogenated
derivates [4–9].
&
Rodolfo Quevedo
arquevedop@unal.edu.co
1
´
Departamento de Quımica, Facultad de Ciencias, Universidad Nacional de Colombia,
Sede Bogota, Carrera 30 No. 45-03, Bogota, Colombia
´
´
123

R. Quevedo et al.
Dopamine (3,4-dihydroxyphenethylamine) is one of the most used phenylethy-
lamines in the Pictet–Spengler reaction because the high activation of the ring
favors its reaction with carbonyl compounds, even under physiological conditions.
Recently, the regioselective synthesis of 6,7-dihydroxylated THIQs from dopamine
and non-enolizable aldehydes was reported. When the reaction was performed with
3,4-dimethoxyphenethylamine (less activated ring than dopamine) and 3-nitroben-
zaldehyde, an intermediate Schiff base was obtained. This cyclization was only
possible under strong conditions (reflux in strong acid medium) [10].
The importance of the hydroxyl group on the C-3 of the phenylethylamine ring in the
reaction course became evident in a recent study of the reaction between 4-hydrox-
yphenylethylamines (tyramine and L-tyrosine esters) and formaldehyde. This reaction
did not produce the expected THIQs but instead led to the formation of benzox-
azinephane-type macrocyclic compounds (2 units of 3,4-dihydro-2H-1,3-benzoxazine
bonded by ethylene bridges) through a double Mannich-type aromatic reaction [11].
In this work, the effect of hydroxyl groups on the aromatic ring was studied in the
reaction course of b-phenylethylamines with non-enolizable aldehydes, selecting
the following as model amines: phenethylamine 1 (non-hydroxylated ring),
tyramine 2 (4-hydroxylated ring) and dopamine 3 (3,4-dihydroxylated ring).
Experimental
General
Ethanol was fractionally distilled at atmospheric pressure. Chloroform and methanol
˚
were dried over 5-A molecular sieves. All other chemicals were used as
commercially available (Alfa Aesar, Panreac). All reactions were conducted with
continuous magnetic stirring in oven-dried glassware. Reactions were monitored by
TLC until completion using silica gel-coated glass plates (Merck Kieselgel 60). The
plates were visualized under iodine vapors.
The nuclear magnetic resonance (NMR) 1H and 13C spectra were collected using a
Bruker Avance 400 spectrometer (400 MHz for 1H and 100 MHz for 13C) using the
residual signal of the solvent as a reference. All of the chemical shifts are reported as d
values (ppm). The melting points were determined in an electrothermal apparatus
(Mel-Temp) with open capillaries, and the reported results are not corrected. The
Fourier transform infrared spectroscopy (FT-IR) spectra were obtained using a
Nicolet iS10 spectrometer (Thermo Fisher Scientific) in 1 % KBr pellets.
Mass spectra were recorded on a Shimadzu LCMS-IT-TOF instrument using
electrospray ionization (ESI). Samples were dissolved in a 90:10:1 acetonitrile/
water/formic acid mixture and directly injected. The instrument was operated in
positive mode with the following parameters: CDL temperature, 200 °C; heating
block, 200 °C; nebulizer (N2) flow, 1.5 l/min; detector voltage, 1.69 kV; scan
range, m/z 100–500.
Ab initio calculations were performed with the Firefly QC package (version 8.0),
which is partially based on the GAMESS (US) code, with a level of theory DFT-
B3LYP and 6-31G(d,p) as basis.
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Role of hydroxyl groups on the aromatic ring
Reaction of phenethylamine 1 with formaldehyde
Formaldehyde 37 % (2.5 mmol) was added to a solution of 1 (300 mg, 2.5 mmol)
in methanol (5 ml) and then the mixture was stirred at room temperature for 60 h
and the solvent was evaporated under reduced pressure.
1,3,5-triphenethylhexahydro-1,3,5-triazine 4 Light-yellow viscous liquid. Yield:
96 %, bp = 130 °C, refractive index 20 °C: n = 1.6956, 1H NMR (400 MHz,
CDCl3): d 7.24 (15H, m), 3.44 (6H, br s), 2.73 (8H, m). 13C NMR (100 MHz,
CDCl3): d 140.3, 128.7, 128.3, 126.0, 74.4, 54.5, 34.5. FT-IR (KBr) cm-1: 3,027,
2,929, 1,674, 1,600. ESI-HRMS: m/z 399.2590 ([M].?, calc. 399.2669), 422.2440
([M ? Na]?, calc. 422.2567), 438.1825 ([M ? K]?, calc. 438.2306).
General procedure for the reaction of phenethylamine 1 with non-enolizable
aldehydes
The aldehyde (9 mol) was added to a solution of phenethylamine 1 (9 mol) in
methanol. The mixture was stirred at room for 48 h. The resulting solid was filtrated
and dried in an oven at 60 °C overnight to give the desired product.
N-(3-nitrobenzylidene)-2-phenylethanamine 8a Dark orange viscous liquid. Yield:
1
94 %, H NMR (400 MHz, CDCl3): d 8.52 (1H, t, J = 1.8 Hz), 8.25 (1H, dd,
J = 8.2 Hz and 2.3 Hz, 1.0 Hz), 8.19 (1H, s), 8.03 (1H, d, J = 7.7 Hz), 7.57 (1H, t,
J = 7.9), 7.32–7.17 (5H, m), 3.92 (2H, t, J = 7.3 Hz), 3.04 (2H, t, J = 7.3 Hz). 13
C
NMR (100 MHz, CDCl3): d 158.8, 148.6, 139.5, 137.8, 133.4, 129.6, 129.0, 128.4,
126.3, 125.0, 122.8, 63.0, 37.2. FT-IR (KBr) cm-1: 3,085, 3,027, 2,927, 2,849,
1,648, 1,615. ESI-HRMS: m/z 255.1091 ([M ? H]?, calc. 255.1089).
N-(4-hydroxy-3-methoxybenzylidene)-2-phenylethanamine
8b Purple
solid.
1
Yield: 98 %, mp = 110–113 °C. H NMR (400 MHz, CDCl3): d 8.04 (1H, s),
7.43 (1H, d, J = 1.8 Hz), 7.31–7.16 (5H, m), 7.03 (1H, dd, J = 8.1 Hz and 1.8 Hz),
6.89 (1H, d, 8.1 Hz), 3.88 (3H, s), 3.82 (2H, t, J = 7.6 Hz), 3.00 (2H, t,
J = 7.6 Hz). 13C NMR (100 MHz, CDCl3): d 161.7, 148.7, 147.3, 139.8, 129.0,
128.4, 126.1, 124.0, 114.2, 108.4, 62.8, 55.9, 50.6, 37.6. FT-IR (KBr) cm-1: 3027,
1644, 1591. ESI-HRMS: m/z 256.1665 ([M ? H]?, calc. 256.1293).
1,4-bis(N-phenethyliminomethyl)benzene 8c White solid. Yield 100 %,
1
mp = 123–125 °C. White solid. mp = 123–125 °C. H NMR (400 MHz, CDCl3):
d 8.17 (2H, s), 7.73 (4H, s), 7.32–7.16 (10H, m), 3.88 (2H, t, J = 7.5 Hz), 3.02 (2H,
t, J = 7.5 Hz). 13C NMR (100 MHz, CDCl3): d 160.9, 139.8, 138.0, 129.0, 128.4,
128.2, 126.1, 63.3, 37.5. FT-IR (KBr) cm-1: 3,027, 2,930, 2,836, 1,642. ESI-HRMS
(ESI): m/z 341.1896 ([M ? H]?, calc. 341.2012).
2-phenyl-N-((E)-3-phenylallylidene)ethanamine 8e Dark-red resinous solid. Yield
1
90 %. H NMR (400 MHz, CDCl3): d 8.17 (2H, s), 7.73 (4H, s), 7.32–7.16 (10H,
m), 3.88 (2H, t, J = 7.5 Hz), 3.02 (2H, t, J = 7.5 Hz). 13C NMR (100 MHz,
CDCl3): d 163.1, 141.6, 139.8, 135.7, 129.1, 128.9, 128.8, 128.4, 128.1, 127.2,
123

R. Quevedo et al.
126.1, 63.0, 37.5. FT-IR (KBr) cm-1: 3,027, 2,929, 2,855, 1,670, 1,601. ESI-
HRMS: m/z 236.1391 ([M ? H]?, calc. 236.1434).
General procedure for the reaction between tyramine 2 and non-enolizable
aldehydes
The aldehyde (9 mol) was added to a solution of 2 (9 mol) in ethanol 96 %. The
mixture was refluxed for 24 h; subsequently, the solvent was removed at reduced
pressure. The solid obtained was recrystallized from ethanol (96 %).
N-(3-nitrobenzylidene)-2-(4-hydroxyphenyl)ethanamine 9a Orange solid. Yield
60 %. Mp = 118–121 °C. 1H NMR (400 MHz, DMSO-d6): d 8.49 (1H, t,
J = 1.8 Hz), 8.37 (1H, s), 8.27 (1H, dd, J = 8.2 Hz and 2.3 Hz), 8.11 (1H, d,
J = 7.7 Hz), 7.72 (1H, t, J = 7.9 Hz), 7.02 (2H, d, J = 8.4 Hz), 6.65 (2H, d,
J = 8.4 Hz), 3.78 (2H, t, J = 7.3 Hz), 2.82 (2H, t, J = 7.3 Hz). 13C NMR
(100 MHz, DMSO-d6): d 159.4, 155.7, 148.3, 137.8, 134.2, 130.6, 129.9, 125.1,
122.0, 115.2, 62.4, 36.0. FT-IR (KBr) cm-1: 3,087, 2,911, 1,644, 1,612. ESI-
HRMS: m/z 271.1028 ([M ? H]?, calc. 271.1077).
N-(4-hydroxy-3-methoxybenzylidene)-2-(4-hydroxyphenyl)ethanamine 9b White
solid. Yield 87 %. mp = 139–141 °C. 1H NMR (400 MHz, DMSO-d6): d 9.19 (1H,
br s), 8.14 (1H, s), 7.64 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.4 Hz), 6.97 (2H, d,
J = 8.8 Hz), 6.65 (2H, d, J = 8.4 Hz), 3.78 (3H, s), 3.68 (2H, t, J = 7.4 Hz), 2.77
(2H, t, J = 7.4 Hz). 13C NMR (100 MHz, DMSO-d6): d 161.2, 160.3, 155.5, 130.1,
129.8, 129.5, 129.1, 115.1, 114.1, 62.5, 55.4, 36.3. FT-IR (KBr) cm-1: 3,012, 2,920,
2,678, 2,604, 1,649, 1,605. ESI-HRMS: m/z 272.1228 ([M ? H]?, calc. 272.1281).
1,4-bis(N-(2-(4-hydroxyphenyl)ethyl)iminomethyl)benzene 9c Light-brown solid.
Yield 94 %. mp = 168–169 °C. 1H NMR (400 MHz, DMSO-d6): d 9.21 (2H, br s),
8.25 (2H, s), 7.75 (4H, s), 7.02 (4H, d, J = 8.4 Hz), 6.65 (4H, d, J = 8.4 Hz), 3.75
(4H, t, J = 7.3 Hz), 2.80 (4H, t, J = 7.3 Hz). 13C NMR (100 MHz, DMSO-d6): d
160.7, 155.6, 137.9, 130.0, 129.8, 128.2, 115.1, 62.6, 36.1. FT-IR (KBr) cm-1
:
3,486, 3,200–2,500, 1,641. ESI-HRMS: m/z 373.1815 ([M ? H]?, calc. 373.1911).
2-(4-hydroxyphenyl)-N-((E)-3-phenylallylidene)ethanamine 9d Light-brown sol-
id. Yield 46 %. mp = 165–168 °C. 1H NMR (400 MHz, Pyridine-d5): d 11.33 (1H,
br s), 7.98 (1H, d, J = 8.7 Hz), 7.52 (2H, d, J = 7.1 Hz), 7.35–7.25 (5H, m),
7.21–7.15 (3H, m), 6.94 (1H, d, J = 16.1 Hz), 3.84 (2H, t, J = 7.3 Hz), 3.02 (2H, t,
J = 7.3 Hz). 13C NMR (100 MHz, Pyridine-d5): d 163.2, 157.7, 141.6, 136.8,
131.4, 130.9, 129.6, 129.54, 129.52, 128.0, 116.6, 64.3, 37.5. FT-IR (KBr) cm-1
:
3,200–2,200, 1,635, 1,610. ESI-HRMS: m/z 252.1331 ([M ? H]?, calc. 252.1383).
Procedure for the reaction between dopamine 3 and trans-cinnamaldehyde 7d
The aldehyde 7d (9 mol) was added to a solution of 3 (9 mol) in methanol. The
mixture was refluxed for 24 h; subsequently, the solvent was removed at reduced
pressure. The solid obtained was recrystallized from ethanol (96 %).
123

Role of hydroxyl groups on the aromatic ring
2-(3,4-dihydroxyphenyl)-N-((E)-3-phenylallylidene)ethanamine 11d Light-brown
solid. Yield 83 %. mp = 122–123 °C. 1H NMR (400 MHz, CD3OD): d 8.39 (1H, d,
J = 10.0 Hz), 7.88 (1H, d, J = 15.6 Hz), 7.77 (2H, d, J = 7.2 Hz), 7.59 (1H, t,
J = 6.8 Hz), 7.53 (2H, t, J = 7.6 Hz), 7.20 (1H, dd, J = 15.6 Hz and 10.0 Hz),
6.75 (1H, d, J = 8.0 Hz), 6.72 (1H, d, J = 2.0 Hz), 6.58 (1H, dd, J = 8.0 Hz and
2.0 Hz), 3.99 (2H, t, J = 6.8 Hz), 2.97 (2H, t, J = 6.8 Hz). 13C NMR (100 MHz,
CD3OD): d 159.2, 145.4, 144.3, 133.4, 133.1, 129.6, 129.2, 117.8, 115.7, 115.3,
53.6, 33. FT-IR (KBr) cm-1: 3,335–2,300, 1,663, 1,618. ESI-HRMS: m/z 268.1271
([M ? H]?, calc. 268.1332).
Results and discussion
Initially, geometry optimization computational calculations were performed in the
Firefly program version 8.0 [12], partially based in the GAMESS computational
quantum chemistry software (US), at a DFT-B3LYP/6-31G(d,p) theory level [13].
The combination of this ab initio method and this base set is appropriate for
structure prediction in similar molecules [14]. The analysis of frontier molecular
orbitals in the aromatic ring for the three model amines showed significant
differences (Fig. 1): in 1, the ring contributes little to the HOMO orbital, while in 2
and 3 (hydroxylated amines), the aromatic rings participate substantially in their
Fig. 1 HOMO of
a phenethylamine 1, b tyramine
2 and c dopamine 3 (DFT-
B3LYP/6-31G(d,p),
isovalue = 0.05)
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R. Quevedo et al.
respective HOMO orbitals by resonance effects of hydroxyl groups. In addition, the
HOMO of 2 and 3 reveal that in 2, the most activated positions are the ortho- to the
hydroxyl group (positions C-3 and C-5), while for 3, the most activated position is
C-6.
The electronic differences observed based on the analysis of the molecular
orbitals (Fig. 1) for compounds 1–3 correlated fully with the experimental
observations for the reaction with formaldehyde. The HOMO orbital of phenylethy-
lamine 1 shows the amine group as the site of greatest nucleophilicity; upon reaction
with formaldehyde, the 1,3,5-triphenylhexahydro-1,3,5-triazine 4 was obtained, the
product of reacting three moles of phenylethylamine with three moles of
formaldehyde [15]. The HOMO orbital of the phenylethylamine 2 shows the
carbons ortho to the phenolic hydroxyl (C-3 and C-5) as sites of greater
nucleophilicity; the reaction with formaldehyde at one of these carbons, through
a Mannich-type aromatic condensation, produces azacyclophane-type macrocyclic
[11]. The HOMO orbital of the phenylethylamine 3 shows carbon 6 as the position
of greatest activation, and against formaldehyde, it produces the respective
tetrahydroisoquinoline 6 through a Pictet–Spengler reaction (Scheme 1) [10].
Given the great differences observed for the reaction of phenylethylamines 1–3
with formaldehyde, it became necessary to explore their reactivity against other
non-enolizable aldehydes. Chosen for this study were an aldehyde with electron-
withdrawing substituents (3-nitrobenzaldehyde 7a), an aldehyde with electron-
donating substituents (vanillin 7b), a dialdehyde (terephthalaldehyde 7c) and an
a,b-unsaturated aldehyde (trans-cinnamaldehyde 7d).
It is known that dopamine 3 reacts with aromatic aldehydes to produce THIQs
through a Pictet–Spengler reaction, as occurred with formaldehyde [10]. In this
work, it was observed that when the reaction is performed with aldehydes 7a–c, the
respective THIQs 10a–c are obtained. This product does not occur when the
Scheme 1 Reaction of phenylethylamines 1–3 with formaldehyde
123

Role of hydroxyl groups on the aromatic ring
reaction is performed with trans-cinnamaldehyde 7d; in this case, it was only
possible to obtain with good yields the corresponding intermediate imine 11d
(Scheme 2). Even under strong experimental conditions (reflux in HCl 37 %) it was
not possible to obtain the respective THIQ. The formation of the respective THIQ is
not favored, most likely due to the conjugation of 11d, which decreases the carbon
electrophilicity and prevents the nucleophilic addition reaction.
The reaction of phenylethylamines 1 and 2 with the aldehydes under study
presented the same behavior, and in all cases it was only possible to obtain the
corresponding imines (8a–d and 9a–d) (Scheme 2). This behavior allows the
conclusion that the nucleophilicity of the aromatic rings in these two phenylethy-
lamines is low and does not favor the aromatic electrophilic substitution required for
the formation of THIQs. Likewise, the electrophilicity of the imines (8a–d and 9a–d) is
too low to generate aminals or benzoxazinic azacyclophanes through nucleophilic
addition reactions, as occurred in the reactions with formaldehyde.
As shown in Table 1, the yields obtained for 1 were higher than those for 2 and 3.
As mentioned above, the analysis of the HOMO orbitals of the three studied amines
showed differences in the contribution of the nitrogen atom (Fig. 1). In 1, the
nitrogen atom contributes mainly to the HOMO; the corresponding orbitals in the
hydroxylated amines 2 and 3 do not exhibit a contribution from the nitrogen. The
decreased contribution of the nitrogen atom to the HOMO orbital as the
hydroxylation degree of the ring increases can be related to a lower nucleophilicity
character of the amine and explains the decrease in the reaction yields with 2 and 3
compared to the reaction with 1.
N
R
NH2
R-CHO
7a-d
8a-d
1
N
R
NH2
R-CHO
7a-d
HO
HO
9a-d
2
HO
HO
HO
N
R
HO
HO
NH2
R-CHO
7a-d
or
NH
HO
R
3
10a-c
11d
a: R= 3-NO2-Ph-; b: R= 4-OH-3-OMe-Ph-; c: R= OHC-Ph-; d: R= Ph-CH=CH-
Scheme 2 Reaction of b-phenylethylamines 1–3 with aldehydes 7a–d
123

R. Quevedo et al.
Table 1 Reaction of b-phenylethylamines 1–3 with aldehydes 7a–d (products and yields)
R-CHO
Phenethylamine 1
(Yield %)
Tyramine 2
(Yield %)
Dopamine 3
(Yield %)
3-NO2-Ph- (7a)
3-OMe-4-OH-Ph- (7b)
(1,4)-C6H4- (7c)
(E)-Ph-CH=CH- (7d)
a
8a (98)
8b (91)
8c (100)
8d (90)
9a (60)
9b (80)
9c (94)
9d (46)
10a (90)a
10b (38)a
10c (35)a
11d (83)
Data taken from Quevedo et al. [10]
Fig. 2 HOMO of dopamine 3 (left) versus 3,4-dimethoxyphenethylamine (right) (DFT-B3LYP/6-
31G(d,p), isovalue = 0.05)
In an attempt to obtain the corresponding THIQs, the imines 8a and 11d were
subjected to reflux for long periods of time in methanol, using acetic acid as a
catalyst, to simulate the previously reported experimental conditions [10]. No
transformations were observed in any of the cases, and the starting amines were
always recovered. In imine 8a, the poor activation of the phenethylamine 1 ring
disfavors the aromatic electrophilic substitution required for the cyclization; in
imine 11d, the conjugation of the a,b-unsaturated imine imposes high energy
barriers for the nucleophilic addition, even with the high activation of the dopamine
ring. In an attempt to force the cyclization of a tyramine amine towards the THIQ,
imine 9a was treated with concentrated HCl (37 %) in reflux; even for strong
experimental conditions, as in this case, it was not possible to accomplish the
Pictet–Spengler cyclization. These results demonstrate that for the Pictet–Spengler
cyclization to occur, it is necessary for the carbon 3 of the phenylethylamine ring to
be strongly activating.
To determine if the hydroxyl group is responsible for decreased nucleophilicity
of the nitrogen in phenylethylamine, the geometry of 3,4-dimethoxyphenethylamine
(O-protected dopamine) was optimized. As observed in Fig. 2, the nitrogen atom of
the O-protected amine present a similar contribution to the values observed in 1.
The analysis of the HOMO orbitals allows the conclusion that the low
nucleophilicity of the nitrogen in 2 and 3 and the low yields obtained in the
reactions of these amines with non-enolizable aldehydes are due to the presence of
hydroxyl groups in the aromatic ring: hydroxyl groups that, by inductive effect,
decrease electronic density at the nitrogen and by resonance effects increase
123

Role of hydroxyl groups on the aromatic ring
electronic density on the aromatic ring. The analysis of the HOMO orbitals explains
the high yield (90 %) reported for the reaction of dimethoxyphenethylamine with
3-nitrobenzaldehyde [10].
Conclusions
In conclusion, in this work, differences were found in the reactivity of the b-
phenylethylamines (phenethylamine 1, tyramine 2, and dopamine 3) against
formaldehyde, generating a cyclic aminal, a benzoxazinephane, and a tetrahy-
droisoquinoline, respectively. The differences in reactivity were explained by
comparing the HOMO orbitals for the starting amines, observing changes in the ring
activity and in the nucleophilicity of the nitrogen. In the reaction with other less
reactive non-enolizable aldehydes, only the most activated amine in the ring
(dopamine) generated tetrahydroisoquinolines, while the other two formed Schiff
bases. The computational calculations demonstrated that a greater hydroxylation on
the ring corresponds to a lower nucleophilicity of the nitrogen due to inductive
effects; however, if the phenolic hydroxyls are protected, the inductive effect
decreases, and the nitrogen nucleophilicity increases.
Acknowledgments The authors wish to acknowledge the Universidad Nacional de Colombia for
´
´
funding this study (DIB Research Project No. 18615). C.D.-O. thanks the Vicerrectorıa Academica de la
Universidad Nacional de Colombia for their fellowship support. Y.Q.-A. thanks COLCIENCIAS for their
fellowship support.
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