3-Pyridinecarboxaldehyde: A Model System for Superelectrophilic Activation and the Observation of a Diprotonated Electrophile

Article abstract of DOI:10.1021/jo9824908

3-Pyridinecarboxaldehyde (7) has been studied as a model system for superelectrophilic activation. When compound 7 is compared with benzaldehyde (3) in acid-catalyzed condensation reactions with arenes, 7 is more reactive than 3. Compound 7 reacts with ch

Full text of DOI:10.1021/jo9824908

J . Org. Chem. 1999, 64, 7309-7311
7309
3-P yr id in eca r boxa ld eh yd e: A Mod el System for Su p er electr op h ilic
Activa tion a n d th e Obser va tion of a Dip r oton a ted Electr op h ile
Douglas A. Klumpp* and Siufu Lau
Department of Chemistry, California State Polytechnic University, 3801 West Temple Avenue,
Pomona, California 91768
Received December 30, 1998
3-Pyridinecarboxaldehyde (7) has been studied as a model system for superelectrophilic activation.
When compound 7 is compared with benzaldehyde (3) in acid-catalyzed condensation reactions
with arenes, 7 is more reactive than 3. Compound 7 reacts with chlorobenzene, o-dichlorobenzene,
or nitrobenzene in CF3SO3H (triflic acid, TfOH) to give diaryl-3-pyridylmethanes, while 3 does not
react with these deactivated arenes in TfOH. Moreover, 7 reacts with benzene in solutions as weakly
acidic as Ho ) -9, while 3 requires acidity in the range of Ho ) -11.5 to -14 to reach a comparable
level of electrophilic reactivity. Compound 7 was studied in acidic solution by 13C NMR, and the
diprotonated, dicationic species was observed at -60 °C in a solution of FSO3H-SbF5.
In tr od u ction
and the superelectrophilic intermediate (5) is sufficiently
electrophilic to react with C6H6.
The concept of superelectrophilic activation was first
proposed by Olah, and since then, the study of super-
electrophilic intermediates has been a very active area
of research.1 Superelectrophilic intermediates are typi-
cally generated when a cationic electrophile is protonated
or coordinated by a Lewis acid to produce a dicationic
species. For example, Shudo and Ohwada recently stud-
ied the cyclization of 1 in superacidic triflic acid (CF3-
SO3H, TfOH) and proposed the formation of superelec-
trophile 2, which leads to the condensation product (eq
1).2 In other recent studies, it was reported that benzal-
It was reported some time ago that 3-pyridinecarbox-
aldehyde (7) condenses with C6H6 in H2SO4 to give 8 (eq
3).5 In contrast, benzaldehyde does not react with C6H6
in H2SO4 even though the carbonyl group is extensively
protonated.6 These results suggest that carboxonium ions
can show enhanced electrophilic activity if an adjacent
base-site is available for protonation. If compounds such
as 7 can form dicationic electrophiles in strongly acidic
media, then they may be suitable models for superelec-
trophilic intermediates. We have studied the electrophilic
activation of 7, and we report a comparison of 7 with
benzaldehyde in hydroxyalkylation reactions, the direct
observation of a dicationic species by low-temperature
NMR, and the condensations of 7 with deactivated arenes
in TfOH.
dehyde condenses with C6H6 in TfOH (eq 2).3 This
hydroxyalkylation reaction4 was proposed to occur through
diprotonated benzaldehyde, and theoretical analysis sug-
gests that the second protonation occurs on the phenyl
ring (5).3a Thus, the carboxonium ion (4) is protonated
Resu lts a n d Discu ssion
To compare the electrophilic reactivities of the two
aldehydes, benzaldehyde (3) and 7 were reacted with
C6H6 in solutions of TfOH and CF3CO2H (TFA) in ratios
having varying acidity (Table 1).1g,7 Aldehyde 3 is found
to condense slowly with C6H6 in 100% TfOH (Ho ) -14)
and even more slowly in solutions of Ho ) -12.5 and
-11.5, whereas 7 condenses with C6H6 in solutions as
weakly acidic as Ho ) -9. These results are consistent
with the formation of diprotonated intermediates preced-
ing the electrophilic attack on C6H6. Benzaldehyde
requires the more highly acidic media because the second
(1) (a) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 2, 767.
(b) Prakash, G. K. S.; Schleyer, P. v. R., Eds. Stable Carbocation
Chemistry; Wiley: New York, NY, 1997. (c) Olah, G. A.; Wang, Q.;
Neyer, G. Synthesis 1994, 276. (d) Yamazaki, T.; Saito, S.-i.; Ohwada,
T.; Shudo, K. Tetrahedron Lett. 1995, 36, 5749. (e) Berkessel, A.;
Thauer, R. K. Angew. Chem., Int. Ed. Engl. 1995, 34, 4, 2247. (f) Olah,
G. A.; Klumpp, D. A.; Neyer, G.; Wang, Q. Synthesis 1996, 321. (g)
Klumpp, D. A.; Baek, D. N.; Prakash, G. K. S.; Olah, G. A. J . Org.
Chem. 1997, 62, 6667. (h) Klumpp, D. A.; Yeung, K. Y.; Prakash, G.
K. S.; Olah, G. A. J . Org. Chem. 1998, 63, 4481. (i) Klumpp, D. A.;
Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A. Synlett 1998, 918.
(2) Saito, S.; Sato, Y.; Ohwada, T.; Shudo, K. J . Am. Chem. Soc.
1994, 116, 2312.
(5) U.S. Patent 3,042,678, 1962; Chem. Abstr. 1965, 63, 14825.
(6) (a) Yates, K.; Stewart, R. Can. J . Chem. 1959, 37, 664. (b)
Stewart, R.; Yates, K. J . Am. Chem. Soc. 1958, 80, 6355. (c) Olah, G.
A.; Prakash, G. K. S.; Sommer, J . Superacids; Wiley: New York, 1985.
(7) Saito, S.; Saito, S.-i.; Ohwada, T.; Shudo, K. Chem. Pharm. Bull.
1991, 39, 2718.
(3) (a) Olah, G. A.; Rasul, G.; York, C. T.; Prakash, G. K. S. J . Am.
Chem. Soc. 1995, 117, 11211. (b) Saito, S.; Ohwada, T.; Shudo, K. J .
Am. Chem. Soc. 1995, 117, 11081.
(4) Olah, G. A. Friedel-Crafts and Related Reactions; Wiley: New
York, 1964; Vol. 2, pp 597-640.
10.1021/jo9824908 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/10/1999

7310 J . Org. Chem., Vol. 64, No. 20, 1999
Klumpp and Lau
Ta ble 1. Resu lts fr om th e Con d en sa tion Rea ction of
Ben zen e w ith Ald eh yd es in Solu tion s of Va r yin g Acid ity
ratiob
aldehyde
acid, w/w TfOH/TFA
aldehyde/product
3, X:CH
100% TfOH (Ho ) -14.1)
78% (Ho ) -12.5)
43.5% (Ho ) -11.5)
22.1% (Ho ) -10.5)
5% (Ho ) -9)
100% TFA (Ho ) -2.7)
100% TfOH (Ho ) -14.1)
78% (Ho ) -12.5)
29:71
83:17
87:13
100:0
100:0
100:0
0:100
0:100
0:100
0:100
3:97
7, X:N
43.5% (Ho ) -11.5)
22.1% (Ho ) -10.5)
5% (Ho ) -9)
100% TFA (Ho ) -2.7)
100:0
F igu r e 1. 13C NMR spectrum of 10a ,b in FSO3H-SbF5-SO2-
ClF at -60 °C (asterisk denotes acetone-d6 peaks).
a
b
TfOH, CF3SO3H; TFA, CF3CO2H. Product ratio determined
by 1H NMR integration.
Sch em e 1
carbons at 207 and 208 ppm; ring carbons C-2, C-4, and
C-6 at 144 to 155 ppm; and ring carbons C-3 and C-5 at
125 and 129 ppm.10 Ring carbons C-2, C-4, and C-6 show
distinct absorptions for the isomeric structures 10a and
10b, whereas carbons C-3 and C-5 are magnetically
equivalent for 10a and 10b. Benzaldehyde was studied
under similar conditions, and the isomeric ions (4) were
observed with carboxonium resonances appearing at 203
and 205 ppm.3a However, the diprotonated ion(s) from
benzaldehyde could not be observed by NMR. Superelec-
trophilic dications (such as 5) are difficult to observe
directly because they are typically formed in very low
concentrations.
Ta ble 2. 13C NMR Da ta fr om 3-P yr id in eca r boxa ld eh yd e
(7) in Acid ic Solu tion
acid system (Ho)
13C NMR data,a δ (ppm)
To evaluate its reactivity as an electrophile, compound
7 was reacted with a series of deactivated aromatic
compounds in TfOH.11 Compound 7 reacts with chlo-
robenzene in TfOH to give product 11 in 62% isolated
yield (along with other regioisomers), while under the
same reaction conditions benzaldehyde does not react at
all. Reaction of 7 and o-dichlorobenzene in TfOH gives
12 in 87% yield. Despite a significant deactivation of
nitrobenzene toward Friedel-Crafts-type reactions, 7
reacts with nitrobenzene in TfOH to give a 10% yield of
13. The remaining product balance is unreacted starting
material. These data indicate that 7 generates very
strong electrophilic intermediates in superacidic solution
and that 7 is far more reactive than benzaldehyde as a
protolytically generated electrophile.
CF3CO2H (-2.7)
CF3SO3H (-14.1)
FSO3H (-15.1)
184.0 (c), 142.0, 140.2, 138.1, 129.2, 123.4
193.3 (c), 147.1, 144.9, 142.3, 131.3, 127.5
201.0 (c), 149.7, 148.5, 146.1, 130.5, 129.5
SbF5-FSO3H (<-18) 208.6 (c), 155.8, 149.8, 144.6, 129.0, 125.2
207.1 (c), 151.4, 150.5, 148.6, 129.0, 125.2
a
Experiments with CF3CO2H or CF3SO3H were done at 25 °C;
experiments with FSO3H or SbF5-FSO3H were done at -70 °C
with SO2ClF diluent. (c) Indicates carbonyl signal.
protonation occurs at a weak base site, while 7 requires
less acidic media because the ring nitrogen is first
protonated (9) and then protonation of the carbonyl
oxygen gives the reactive dication 10 (Scheme 1).
Compound 7 was also studied in acidic solutions by 13
C
NMR spectroscopy (Table 2). With increasingly acidic
media, the carbonyl resonance shifts progressively to an
apparent maximum value in SbF5-FSO3H. These results
indicate a growing positive charge on the carbonyl group
as the acidity of the medium increases.8 The 13C NMR
in SbF5-FSO3H shows peaks from two structures (Figure
1). On the basis of previous studies of the protonation of
aldehydes,3a,9 the 13C NMR data suggest the formation
of the isomeric dications 10a and 10b. The 13C NMR
spectrum shows three groups of peaks: carboxonium
We propose that 7 is more reactive than benzaldehyde
because 7 more readily forms the dicationic intermedi-
ates. The dicationic intermediates are necessary for the
electrophilic reactions with the deactivated arenes, par-
ticularly nitrobenzene. Dications 10a ,b are formed by
protonation of a relatively strong base-site (the pyridyl
(8) Schleyer, P. v. R.; Lenoir, D.; Mison, P.; Liang, G.; Prakash, G.
K. S.; Olah, G. A. J . Am. Chem. Soc. 1980, 102, 683.
(9) (a) Olah, G. A.; White, A. M.; O’Brien, D. H. Chem. Rev. 1970,
70, 561. (b) Olah, G. A.; O’Brien, D. H.; Calin, M. J . Am. Chem. Soc.
1967, 89, 3582. (c) Brookhart, M.; Levy, G. C.; Winstein, S. J . Am.
Chem. Soc. 1967, 89, 1735.

Model System for Superelectrophilic Activation
J . Org. Chem., Vol. 64, No. 20, 1999 7311
High-resolution mass spectrum analyses were done by the
Southern California Mass Spectrometry Laboratory, Univer-
sity of California, Riverside.
ring) and a weak base-site (the carbonyl). However, to
form a dication from benzaldehyde, protonation must
occur at the weakly basic carbonyl group and then
subsequently at an even weaker base-site (either the
phenyl ring or at the carboxonium ion). It suggests that
adjacent base-sites may have an important influence on
the reactivity of the carbonyl group.12 This effect was
shown recently in the superacid-induced condensations
of piperidones (14) and arenes.13 Piperidones condense
with arenes in TfOH (eq 4), while under similar condi-
tions, cyclohexanone does not react with benzene. Pro-
P r oced u r e for Va r ia ble Acid ity Rea ction s. Under an
atmosphere of N2, 0.050 mL of the aldehyde was combined with
1 mL of C6H6, and 4 mL (ca. 100 equiv) of the premixed acid
solution was then added. The mixture was stirred for 20 h and
then poured over ice. For benzaldehyde, the solution was
extracted twice with 25 mL of CHCl3; for 7, the solution was
first neutralized with NaOH, and then the solution was
extracted with CHCl3. The organic extracts were then washed
with H2O and brine and dried with MgSO4. CHCl3 was then
removed by distillation, and the product(s) were analyzed by
NMR.
P r oced u r es for t h e P r ep a r a t ion Dia r yl-3-p yr id yl-
m eth a n es. Meth od A. A 0.2 mL portion of 3-pyridinecarbox-
aldehyde (7) was dissolved in 1.0 mL of an aromatic compound
(C6H6, C6H5Cl, or C6H4Cl2), and 2 mL of TfOH was added. The
reaction progress may be monitored by TLC (4:1 hexanes/
ether). After 12 h, the mixture was poured over ice, the solution
was neutralized with NaOH, and the products were extracted
into CHCl3. The organic extracts were then washed with H2O
and brine and dried with MgSO4. Concentration in vacuo
provided the crude products, which were then purified by
recrystallization or column chromatography. Meth od B. For
reaction with C6H5NO2, method A was modified as follows: 0.2
mL of 7 was dissolved in 1.0 mL of C6H5NO2, and 4 mL of
TfOH was added. The solution was stirred at 130 °C for 48 h.
The reaction was worked up as above, and the products were
purified by column chromatography.
tonation of a base-site adjacent to a carbonyl group may
cause electrostatic and/or inductive effects,14 and upon
protonation of the carbonyl group, highly electrophilic
intermediates are formed. In accord with Olah’s concept
of superelectrophilic activation, the chemistry of 3-py-
ridinecarboxaldehyde (7) further demonstrates the reac-
tivities of dicationic electrophiles.15
Bis(4-ch lor op h en yl)-3-p yr id ylm eth a n e (11): 1H NMR
(CDCl3) δ 5.52 (s, 1H), 7.03 (d, J ) 8.4 Hz, 4H), 7.25-7.40 (m,
6H), 8.43 (s, 1H), 8.54 (d, J ) 2.4 Hz, 1H), 8.51 (d, J ) 3.3 Hz,
1H); 13C NMR (CDCl3) δ 53.0, 123.4, 128.8, 130.4, 132.9, 136.6,
140.6, 148.1, 150.5; HRMS C18H13Cl2N calcd 313.0425, found
313.0413.
Exp er im en ta l Section
Gen er a l Meth od s. 3-Pyridinecarboxaldehyde was pur-
chased from Aldrich and used as received. Triflic acid was
purchased from 3M Co., and trifluoroacetic acid was purchased
from Aldrich; both acids were distilled under a dry, inert
atmosphere prior to their use. Benzene, chlorobenzene, o-
dichlorobenzene, and nitrobenzene were reagent-grade chemi-
cals that were dried prior to their use. Column chromatogra-
phy was done according to standard methods using Merck
5840-grade silica gel and reagent-grade solvents. Low-tem-
perature NMR experiments were done according to published
procedures.16 Triple-distilled FSO3H was used as received
(Aldrich); SbF5 was distilled prior to use. NMR experiments
Bis(3,4-dich lor oph en yl)-3-pyr idylm eth an e (12): 1H NMR
(CDCl3) δ 5.42 (s, 1H), 6.87 (dd, J ) 9.0, 2.1 Hz, 2H), 7.12 (d,
J ) 2.1 Hz, 2H), 7.22-7.34 (m, 2H), 7.36 (d, J ) 8.1 Hz, 2H),
8.36 (d, J ) 2.4 Hz, 1H), 8.51 (dd, J ) 4.8 Hz, 1.8 Hz, 1H); 13
C
NMR (CDCl3) δ 52.6, 123.6, 128.4, 130.7, 130.9, 131.5, 133.0,
136.4, 137.0, 141.7, 148.6, 150.3; HRMS C18H11Cl4N calcd
380.9646, found 380.9632.
Bis(3-n it r op h en yl)-3-p yr id ylm et h a n e (13): 1H NMR
(CDCl3) δ 5.74 (s, 1H), 7.22-7.28 (m, 4H), 7.35-7.53 (m, 3H),
7.92 (s, 2H), 8.10 (d, J ) 8.1 Hz, 1H), 8.38 (s, 1H), 8.50 (d, J
) 4.8 Hz, 1H); 13C NMR (CDCl3) δ 53.4, 122.5, 123.7, 123.8,
124.1, 130.0, 135.0, 136.4, 143.3, 148.6, 148.9, 150.3; HRMS
were done on
a Varian 300 MHz instrument; HETCOR
experiments were done on a Bruker 500 MHz instrument.
(10) Peak assignments were assigned based on the HETCOR NMR
spectrum of 7 in TfOD and TfOH (see the Supporting Information).
(11) (a) March, J . Advanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992; Chapter 9. (b) Gore, P. H. In Friedel-Crafts and Related
Reactions; Olah, G. A., Ed.; Interscience: New York, 1964; Vol. 3,
Chapter 31. (c) Taylor, R. Electrophilic Aromatic Substitution, Wiley:
New York, 1990; Chapter 2.
(12) (a) Conroy, J . L.; Sanders, T. C.; Seto, C. T. J . Am. Chem. Soc.
1997, 119, 4285. (b) Yang, D.; Yip, Y.-C.; J iao, G.-S.; Wong, M.-K. J .
Org. Chem. 1998, 63, 8952.
C
18H13N3O4 calcd 335.0906, found 335.0909.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (SO6GM53933-0251). We
also thank the Loker Hydrocarbon Research Institute
at the University of Southern California and G. K.
Surya Prakash for assistance with the low-temperature
NMR experiments and Allan Kershaw for assistance
with HETCOR experiments.
(13) Klumpp, D. A.; Garza, M.; J ones, A.; Mendoza, S. J . Org. Chem.,
in press.
(14) (a) Bowden, K.; Grubbs, E. J . Chem. Soc. Rev. 1996, 25, 171.
(b) Chen, C.-T.; Siegel, J . S. J . Am. Chem. Soc. 1994, 116, 5959.
(15) Similar results have been obtained for 2- and 4-pyridinecar-
boxaldehydes. These results will be reported in due course.
(16) Head, N. J .; Olah, G. A.; Prakash, G. K. S. J . Am. Chem. Soc.
1995, 117, 11205.
1
Su p p or tin g In for m a tion Ava ila ble: 13C, H, and HET-
COR NMR spectra of 7 in acidic solutions. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O9824908