Superelectrophilic carbocations: Preparation and reactions of a substrate with six ionizable groups

Article abstract of DOI:10.3762/bjoc.15.153

A substrate has been prepared having two triarylmethanol centers and four pyridine-type substituent groups. Upon ionization in the Br?nsted superacid CF3SO3H, the substrate undergoes two types of reactions. In the presence of only the superacid, the highl

Full text of DOI:10.3762/bjoc.15.153

Superelectrophilic carbocations: preparation and reactions of
a substrate with six ionizable groups
Sean H. Kennedy, Makafui Gasonoo and Douglas A. Klumpp*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1515–1520.
Department of Chemistry and Biochemistry, Northern Illinois
University, DeKalb, IL 60178, USA
doi:10.3762/bjoc.15.153
Received: 08 March 2019
Accepted: 21 June 2019
Published: 09 July 2019
Email:
Douglas A. Klumpp* - dklumpp@niu.edu
*
Corresponding author
This article is part of the thematic issue "Reactive intermediates –
carbocations".
Keywords:
cation; Friedel–Crafts; heterocycle; superacid; superelectrophile
Guest Editor: S. R. Hare
©
2019 Kennedy et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A substrate has been prepared having two triarylmethanol centers and four pyridine-type substituent groups. Upon ionization in the
Brønsted superacid CF3SO3H, the substrate undergoes two types of reactions. In the presence of only the superacid, the highly
ionized intermediate(s) provide a double cyclization product having two pyrido[1,2-a]indole rings. With added benzene, an aryl-
ation product is obtained. A mechanism is proposed involving tetra-, penta-, or hexacationic species.
Introduction
During the 1970s and 80s, Olah and co-workers described the Numerous studies from our group and others have shown that
novel chemistry of highly-charged organic cationic species. relatively stable cationic centers – such as ammonium, phos-
This work lead to the concept of superelectrophilic reactivity phonium, and pyridinium groups – may also be part of super-
[
1-5]. Examples of superelectrophiles include the nitronium electrophilic systems [10]. Recently, we described the chem-
dication (1) and the acetylium dication (2, Scheme 1). Both of istry of tri-, tetra-, and pentacationic electrophiles based on the
these species have been proposed as superelectrophilic interme- triarylmethyl cation scaffold (3–5, Scheme 1) [11,12]. These
diates in the reactions of nitronium (NO2+) and acetylium systems utilized pyridyl rings to produce increasing amounts of
(
CH3CO+) salts in superacids. In sufficiently acidic media, positive charge adjacent to the carbocation center. Both theoret-
cationic electrophiles such as the nitronium ion may undergo ical calculations and experimental results indicated that the
protonation, leading to the nitronium dication (1), and a greatly carbocation center undergoes a high degree of delocalization
enhanced electrophilic reactivity. In superacidic solutions, into the neighboring phenyl group. Both the trication 3 and the
nitronium salts have been shown to react with deactivated tetracation 4 were directly observed from FSO3H–SbF5 solu-
arenes and saturated hydrocarbons (including methane) [6-9]. tion using low temperature NMR. Experimental observations
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Scheme 1: Superelectrophilic species.
also revealed an exceptionally high acidity of the pyridinium compound 9 is treated with only superacid, the bis(pyrido[1,2-
N–H bonds. Here, we describe the preparation and chemistry of a]indole) 11 is formed as the major product. Likewise, the tri-,
a substrate with six ionizable groups – four pyridyl rings and tetra-, and pentacationic systems 3–5 provide the pyrido[1,2-
two carbinol centers.
a]indole ring system. Interestingly, there was no evidence of the
cyclization product 11 (NMR analysis) when compound 9
reacts with superacid in the presence of benzene – product 10 is
Results and Discussion
The desired substrate was prepared in four steps from 2,6-dibro- formed as the major product.
mopyridine (Scheme 2). Utilizing 2-lithio-6-bromopyridne,
product 6 is formed in modest yield by reaction with benzalde- These products may be explained by mechanisms involving
hyde. A nickel-catalyzed procedure gives the dipyridyl interme- highly ionized intermediates. It is proposed that compound 9
diate 7 [13]. This is easily oxidized to the diketone 8 and reac- initially reacts in excess superacid to give the tetracationic
tion of this substance with 2-lithiopyridine gives the precursor species 12 (Scheme 4). Protonation of the hydroxy groups leads
9
. The diol 9 is a substrate with six ionizable groups.
to immediate ionization and formation of the carbocation
centers. For related conversions, computational and experimen-
Upon ionization in superacidic CF3SO3H (triflic acid), com- tal data indicated that the protonated hydroxy groups (oxonium
pound 9 undergoes two types of reactions. When the substrate is ions) are not persistent intermediates, but rather cleavage of the
ionized in the presence of benzene and CF3SO3H, the arylation carbon–oxygen bond is almost instantaneous [12]. It is assumed
product 10 is formed as the major product (Scheme 3). Presum- that ionization to the carbocations occurs in a stepwise process,
ably, compound 10 is formed as a mixture of meso and dl first providing pentacation 13 then the hexacation 14. The prod-
stereoisomers. Similar reaction products were observed in our uct forming steps occur through either 13 or 14. For the aryl-
studies of tri-, tetra-, and pentacationic systems [11,12]. This ation product 10, charge delocalization at the carbocation leads
product, 10, is the result of charge migration involving the to nucleophilic attack at the para-position of the phenyl group.
carbocation center and the phenyl group (vide infra). When This SEAr step is followed by protonation at the methine posi-
Scheme 2: Synthesis of diol substrate 9.
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Scheme 3: Isolated yields of products from diol 9.
Scheme 4: Proposed mechanisms leading to products 10 and 11.
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tion and deprotonation of the para-carbon to complete the aryl- Our proposed mechanism of cyclization involves deprotonation
ation step. For the cyclization product 11, theoretical calcula- of an N–H bond at the pyridinium ring. Although pyridinium
tions indicate that cyclization requires deprotonation at the pyri- deprotonation is not generally expected in a Brønsted superacid,
dinium ring [11]. Thus, either the tetracation 15 or the pentaca- it can occur in these systems because of the large amount of
tion 16 is the likely precursor to the pyrido[1,2-a]indole ring cationic charge on these structures. In comparing the chemistry
system. The conversion to product 11 also involves a stepwise of compounds 9 and 18, compound 9 can lead to the hexaca-
process – initially forming compound 17 then a second cycliza- tionic intermediate 14 while compound 18 can lead to the
tion gives the final product 11.
pentacationic intermediate 5. Examination of these two struc-
tures suggests that the phenyl groups have a profound effect on
As noted above, no cyclization product 11 was observed when stabilizing the ions. Thus, the hexacationic system 14 is stabi-
the chemistry was done in the presence of benzene. Only prod- lized by two phenyl groups, while the pentacationic system 5
uct 10 was obtained. This observation is in stark contrast to our has one stabilizing phenyl group (Scheme 6). The ratio of
earlier results involving both the tetracation 4 and pentacation charges is 2:1 (pyridinium/benzylic carbocation) for the hexaca-
5
. When these highly charged ions are generated in CF3SO3H tion 14, while the ratio of charges is 4:1 (pyridinium/benzylic
and C6H6, significant quantities of the cyclization products are carbocation) for the pentacation 5. Similarly, we previously re-
formed with the respective arylation products. For example, ported good chemoselectivity for trication 3 – no cyclization
alcohol 18 provides a mixture of products 19 and 20 in a 32:68 product observed in the presence of benzene – but poor chemo-
ratio, presumably through the pentacation 5 (Scheme 5). Even selectivity for the tetracation 4. The ratio of charges in these
with the use of the stronger Brønsted acid, CF3SO3H–SbF5, sig- systems are consistent: a charge ratio of 2:1 shows good chemo-
nificant quantities of the cyclization product 20 are observed. selectivity (trication 3), while a charge ratio of 3:1 shows poor
This raises an obvious question: why does substrate 9 provide chemoselectivity (tetracation 4). As we previously reported, a
exclusively the arylated product 10 in the presence of benzene, reaction of tetracation 4 with benzene in CF3SO3H leads to a
while substrate 18 leads to a significant proportion of cycliza- mixture of arylated product (52%) and cyclization product
tion product 20?
(48%). Thus, we observed clean arylation chemistry when the
Scheme 5: Products and relative yields from the reaction of alcohol 18 with CF3SO3H and C6H6 [12].
Scheme 6: Comparison of superelectrophilic carbocations (3–5 and 14) and their chemistry.
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carbocation sites are flanked by not more than two pyridinium benzylic-type resonance. Thus, molecular structures having a
groups. This also means that increasing the number of adjacent very large overall charge may be viable if stabilizing groups are
pyridinium groups destabilizes the system as a whole and leads incorporated into the structure.
to greater N–H deprotonation. Tetracation 4 and pentacation 5
tend to undergo N–H deprotonation more readily, and conse- Experimental
quently, this leads to rapid cyclization reactions.
General. All reactions were performed using oven-dried glass-
ware under an argon atmosphere. Trifluoromethanesulfonic acid
Regarding the site of deprotonation, hexacation 14 could poten- (triflic acid) was freshly distilled prior to use. All commercially
tially undergo N–H deprotonation at the inside pyridinium ring available compounds and solvents were used as received. 1H
(
16) or the outside pyridinium ring (21, Scheme 7). While and 13C NMR were done using either 300 MHz or 500 MHz
inside deprotonation should give the observed cyclization prod- spectrometer; chemical shifts were made in reference to NMR
uct 11, outside deprotonation would give an entirely different solvent signals. Mass spectra were obtained from a commercial
product, one having the pyrido[1,2-a]indole ring at the end of analytical laboratory. The synthesis of compound 9 is detailed
the structure. Compound 11 is the only major product observed in Supporting Information File 1.
from the superacid-promoted reaction of diol 9. This suggests
outside deprotonation – and formation of ion 21 – does not Preparation of 6,6'-bis([1,1'-biphenyl]-4-yl(pyridin-2-
occur.
yl)methyl)-2,2'-bipyridine (10): In a pressure tube at 25 °C,
compound 9 (52.2 mg, 0.10 mmol) was dissolved in benzene
The preference for inside deprotonation may be understood to (1 mL, 11.2 mmol), stirred for 5 min before triflic acid (1 mL,
be a consequence of charge–charge repulsive effects. In the case 11 mmol) was slowly added and the tube was then tightly
of 21, the five cationic charges are on neighboring positions, closed. Following 24 h of stirring at 60–70 °C, the reaction was
while in the case of 16, the five cationic charges are separated cooled to room temperature, poured on about 10 g of ice and
into groups of three and two charges. The increased stability of then neutralized with 10 M NaOH solution. The resulting
the separated cationic charge is evident in the DFT calculated aqueous solution was then partitioned between chloroform and
energies of the ions. At the B3LYP 6-311G (d,p) level, ion 16 is distilled water in a separatory funnel. The aqueous fraction was
calculated to be 32.7 kcal·mol−1 more stable than ion 21 [8]. subjected to two further extractions after which the organic
Thus, highly charged organic ions may benefit by having fractions were combined, washed with brine, dried over an-
groups of charges separated into smaller clusters rather than hydrous sodium sulfate and filtered. The solvent was removed
having all of the charges grouped together.
by rotary evaporation and the product purified by column chro-
matography (Rf 0.21, hexane/ethyl acetate 1:1). Compound 10
was isolated in 52% yield as oil. 1H NMR (300 MHz, CDCl3) δ
Conclusion
We have prepared a substrate with six ionizable sites. Reaction 5.85 (s, 1H), 7.17–7.21 (m, 1H), 7.30–7.51 (m, 9H), 7.53–7.60
of the substrate in superacidic CF3SO3H leads to cyclization or (m, 4H), 7.64–7.70 (m, 1H), 8.61 (d, J = 4.02 Hz, 1H);
arylation products, depending on the presence or absence of 13C NMR (75 MHz, CDCl3) δ 60.7, 121.9, 123.1, 124.3, 126.1,
benzene. A mechanism is proposed involving tetra-, penta-, and 127.1, 127.28, 127.33, 128.8, 129.6, 136.8, 138.8, 139.9, 140.2,
hexacationic reactive intermediates. Most notably, this system 140.7, 141.4, 149.3, 161.1, 163.4; low-resolution ESIMS m/z:
shows remarkably good chemoselectivity in its reaction with 643 [M + 1], 553, 477, 475, 401, 324, 323; high-resolution
benzene (only arylation product is observed). This is attributed CIMS m/z: [M + 1] calcd for C46H35N4, 643.2862; found,
to the presence of two carbocationic sites stabilized by 643.2856.
Scheme 7: DFT calculated relative energies of pentacations 16 and 21 [14].
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5
6
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Preparation of 10,10'-di(pyridin-2-yl)-6,6'-bipyrido[1,2-
a]indole, (11): In a pressure tube at 25 °C, compound 9
(
1
200.1 mg, 0.481 mmol) was dissolved in triflic acid (1 mL,
1 mmol) and the tube was then tightly closed. Following 24 h
of stirring at 60–70 °C, the reaction was cooled to room temper-
ature, poured on about 10 g of ice and then neutralized with
7. Olah, G. A.; Lin, H. C. Synthesis 1974, 444–445.
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8
9
1
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Olah, G. A.; Orlinkov, A.; Oxyzoglou, A. B.; Prakash, G. K. S.
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Olah, G. A.; Wang, Q.; Orlinkov, A.; Ramaiah, P. J. Org. Chem. 1993,
1
0 M NaOH solution. The resulting aqueous solution was then
partitioned between chloroform and distilled water in a separa-
tory funnel. The aqueous fraction was subjected to two further
extractions after which the organic fractions were combined,
washed with brine, dried over anhydrous sodium sulfate and
filtered. The solvent was removed by rotary evaporation and the
product purified by column chromatography (Rf 0.30, hexane/
ethyl acetate 1:1). The product 11 was isolated in 45% yield as
brown oil. 1H NMR (300 MHz, CDCl3) δ 6.81–6.88 (m, 2H),
58, 5017–5018. doi:10.1021/jo00070a049
0.Klumpp, D. A. Activation of Electrophilic Sites by Adjacent Cationic
Groups. In Recent Developments in Carbocation and Onium Ion
Chemistry; Laali, K., Ed.; ACS Symposium Series 395; American
Chemical Society: Washington, DC, 2007; pp 144–159.
doi:10.1021/bk-2007-0965.ch008
11.Naredla, R. R.; Zheng, C.; Nilsson Lill, S. O.; Klumpp, D. A.
J. Am. Chem. Soc. 2011, 133, 13169–13175. doi:10.1021/ja2046364
7
7
.19 (t, J = 4.65 Hz, 1H), 7.35–7.40 (m, 1H), 7.51 (t, J =
.50 Hz, 1H), 7.75– 7.82 (m, 2H), 8.24–8.29 (m, 2H), 8.81 (d,
12.Gasonoo, M.; Naredla, R. R.; Nilsson Lill, S. O.; Klumpp, D. A.
J. Org. Chem. 2016, 81, 11758–11765. doi:10.1021/acs.joc.6b02220
1
1
3.Newkome, G. R.; Joo, Y. J.; Evans, D. W.; Pappalardo, S.;
Fronczek, F. R. J. Org. Chem. 1988, 53, 786–790.
doi:10.1021/jo00239a018
J = 2.55 Hz, 1H), 9.15 (d, J = 8.79 Hz, 1H); 13C NMR
75 MHz, CDCl3) δ 107.2, 116.0, 116.1, 116.7, 118.1, 119.2,
(
1
1
3
20.20, 120.28, 123.3, 123.6, 124.2, 128.3, 131.9, 136.4, 138.1,
49.7, 154.4; low-resolution ESIMS m/z: 487 [M + 1], 397,
53, 320, 319, 279, 244; high-resolution CIMS m/z: [M + 1],
4.Gaussian 09, Revision E.01; Gaussian, Inc.: Wallingford, CT, 2009.
calcd for C34H23N4, 487.1923; found, 487.1917.
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Experimental procedures, compounds characterization, and
NMR spectra; computational methods and results.
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Acknowledgements
This work was supported by the National Science Foundation
The definitive version of this article is the electronic one
which can be found at:
(
1300878). We gratefully acknowledge this support.
doi:10.3762/bjoc.15.153
ORCID® iDs
Douglas A. Klumpp - https://orcid.org/0000-0001-5271-699X
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