Hammett correlation of nornicotine analogues in the aqueous aldol reaction: Implications for green organocatalysis

Article abstract of DOI:10.1021/jo050161r

(Chemical Equation Presented) A series of meta- and para-substituted 2-arylpyrrolidines were synthesized and examined for their ability to catalyze an aqueous aldol reaction under buffered conditions. Kinetic analysis of arylpyrrolidine-catalyzed reactions displayed a linear Hammett correlation with ρ = 1.14 (R² = 0.996), indicating that the reaction is accelerated by electron-withdrawing aryl rings. These results show promise for the development of a synthetically viable aqueous organocatalyst.

Full text of DOI:10.1021/jo050161r

amine intermediates to catalyze aqueous aldol reactions
under physiological conditions (Scheme 1).5 The unprec-
edented ability of a xenobiotic secondary metabolite to
catalyze carbon-carbon bond formation led us to further
investigate the role of nornicotine in aqueous aldol
catalysis. In addition to the biological implications of this
reaction, an understanding of the basis of rate enhance-
ment could expand the impact of organocatalysis,6 and
provide the impetus for the discovery of a synthetically
relevant green organocatalyst.
Hammett Correlation of Nornicotine
Analogues in the Aqueous Aldol Reaction:
Implications for Green Organocatalysis
Claude J. Rogers, Tobin J. Dickerson,
Andrew P. Brogan, and Kim D. Janda*
Department of Chemistry and The Skaggs Institute for
Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
kdjanda@scripps.edu
Initial computational studies into the nornicotine-
catalyzed aqueous aldol reaction validated the proposed
enamine-based mechanism;7 however, it offered no par-
ticular insight into the structural basis for enhanced
catalysis relative to the related organocatalysts proline8
and pyrrolidine. In our first report of this reaction, it was
observed that altering the position of the pyridyl nitrogen
had little effect on catalysis. Replacing the pyridyl ring
with a phenyl substituent, however, reduced activity by
40%, while the use of pyrrolidine led to an 80% reduction
in activity. These results caused us to speculate as to the
relationship of the rate of the reaction on the electronic
nature of the aryl ring. We now report our experimental
findings into the stereoelectronic nature of arylpyrroli-
dine-based aqueous aldol catalysis, and its potential for
the design of “green” organocatalysts.
Received January 25, 2005
To test the electronic dependence of the nornicotine-
catalyzed aqueous aldol reaction, we synthesized a
variety of 2-arylpyrrolidines with Hammett values in the
range -0.83 e σx e 0.71. Compounds with electron-
donating or mildly electron-withdrawing substituents
were synthesized according to a lithium-catalyzed anionic
5-endo-dig cyclization method developed by Yus et al.
(Scheme 2).9 In this route, the appropriate arylaldehyde
was treated with 3-chloropropylamine in the presence of
triethylamine and magnesium sulfate.10 The resulting
N-arylmethylene-3-chloropropylamines were then re-
acted with lithium metal in the presence of catalytic
(20 mol %) di-tert-butylbiphenyl (DTBB) providing 2-aryl-
pyrrolidines 1b-5b in high yields (85-95% over two
steps).
A series of meta- and para-substituted 2-arylpyrrolidines
were synthesized and examined for their ability to catalyze
an aqueous aldol reaction under buffered conditions. Kinetic
analysis of arylpyrrolidine-catalyzed reactions displayed a
linear Hammett correlation with F ) 1.14 (R2 ) 0.996),
indicating that the reaction is accelerated by electron-
withdrawing aryl rings. These results show promise for the
development of a synthetically viable aqueous organo-
catalyst.
The use of tobacco products is the leading cause of
death in the United States, and is known to contribute
to a wide variety of pathologies, including certain types
of cancer.1 In light of the serious health consequences and
addictive nature of nicotine, we have recently initiated
a research program aimed at studying the chemical
reactivity of nicotine metabolites. Nornicotine, a minor
nicotine metabolite with an extended half-life,2 has been
demonstrated by our laboratory to perform iminium-
based chemistry in water; for example, we have shown
the aberrant glycation of proteins in vivo,3 as well as the
fortuitous glycation of the amyloid â-peptide.4 Through
a related mechanism, nornicotine can also utilize en-
In their report, Yus et al. primarily considered this
method on substrates with electron-donating groups.9
Unfortunately, lithium-catalyzed cyclization failed for
substrates with substituents more electron withdrawing
(4) Dickerson, T. J.; Janda, K. D. Proc. Natl. Acad. Sci. U.S.A. 2003,
100, 8182-8187.
(5) Dickerson, T. J.; Janda, K. D. J. Am. Chem. Soc. 2002, 124,
3220-3221.
(6) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-
5175.
(1) (a) Nelson, D. E.; Kirkendall, R. S.; Lawton, R. L.; Chrisom, J.
H.; Merritt, R. K.; Arday, D. A.; Giovino, G. A. Morbid. Mortal. Wkly.
Rep. 1994, 43, 1-8. (b) Reducing the Health Consequences of Smoking.
25 Years of Progress. A Report of the Surgeon General; U.S. Department
of Health and Human Services; Public Health Services: Rockville, MD,
1989.
(2) Kisaki, T.; Tamaki, E. Arch. Biochem. Biophys. 1961, 92, 351-
355.
(3) Dickerson, T. J.; Janda, K. D. Proc. Natl. Acad. Sci. U.S.A. 2002,
99, 15084-15088.
(7) Dickerson, T. J.; Lovell, T.; Meijler, M. M.; Noodleman, L.; Janda,
K. D. J. Org. Chem. 2004, 69, 6603-6609.
(8) (a) List, B. Synlett 2001, 11, 1675-1686. (b) List, B. Acc. Chem.
Res. 2004, 37, 548-557. (c) Notz, W.; Tanaka, F.; Barbas, C. F., III
Acc. Chem. Res. 2004, 37, 580-591.
(9) Yus, M.; Soler, T.; Foubelo, F. J. Org. Chem. 2001, 66, 6207-
6208.
(10) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002,
124, 13400-13401.
10.1021/jo050161r CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/31/2005
J. Org. Chem. 2005, 70, 3705-3708
3705

SCHEME 1. Nornicotine Catalyzed Aldol Reaction
(Ar ) 3-pyridyl)
determined under pseudo-first-order conditions with use
of acetone as the donor and 4-nitrobenzaldehyde as the
acceptor (Table 1). Using the Hammett eq 1,16 we found
kx
log
) Fσx
(1)
( )
kH
that the relationship between the log of the relative rate
constant17 and σx was linear over the entire domain of
tested compounds (F ) 1.14, R2 ) 0.996) with the
exception of 4-Me2N (σ ) -0.81), which did not have
activity over the uncatalyzed aldol reaction (Figure 1).
Indeed, according to the Hammett equation derived from
our data, the substituent on an arylpyrrolidine must have
a Hammett value g-0.70 before any catalytic activity is
observed. These results show that the mere presence of
a 2-aryl ring is not enough for rate enhancement, but
that the appearance of aldol catalysis is critically de-
pendent on the electronic nature of the ring. For example,
the observed rate constant of pyrrolidine5 is close to that
of 4-MeO analogue 2b.
The positive slope of the Hammett plot validates earlier
observations of the aqueous aldol reaction, that is, that
an electron-withdrawing aryl ring improves catalysis. To
our knowledge, prior to this report no pyrrolidine-based
catalyst has exhibited aqueous catalytic activity signifi-
cantly greater than that of nornicotine.18 We found that
substituents with Hammett values greater than σx g 0.39
have improved catalysis relative to nornicotine. In fact,
3-NO2 analogue 10b has a rate approximately double that
of nornicotine and represents the most efficient pyrroli-
dine-based aqueous aldol catalyst reported to date.
A possible explanation for the improved rates of
arylpyrrolidines substituted with electron-withdrawing
groups is that these substituents lower the pKa of the
pyrrolidine nitrogen, effectively increasing the concentra-
tion of available catalyst. In this context, nornicotine is
an effective aqueous aldol catalyst relative to pyrrolidine
or proline because the 3-pyridyl ring is sufficiently
electron withdrawing to perturb the pKa of the pyrroli-
dine nitrogen. Similarly, 1b does not catalyze aldol
formation because the 4-Me2N phenyl ring is sufficiently
electron donating to make the pyrrolidine nitrogen
predominantly protonated at pH 8.0, leaving only trace
amounts of active free amine catalyst. One may speculate
that eventually the electron-withdrawing nature of the
aryl ring could become too strong, and as such, the rate
of aldol catalysis would be expected to no longer increase
linearly with σx.
SCHEME 2. Synthesis of 2-Arylpyrrolidines,
Route Aa
a Reagents and conditions: (a) 3-chloropropylamine‚HCl, Et3N,
MgSO4, CH2Cl2. (b) Li wire, DTBB, THF, -78 °C.
than 3-methoxy (σ3-MeO > 0.12). When exposed to a
solution of lithium di-tert-butylbiphenylide, these sub-
strates formed stabilized aryl radicals, which reacted to
form a variety of side products with no pyrrolidine
detectable by GC analysis. To synthesize the full range
of electron-withdrawing 2-arylpyrrolidines, several other
routes were attempted, all of which proceeded through
myosmine analogues, that were reduced with sodium
borohydride to afford the desired 2-arylpyrrolidine (Scheme
3).
The 4-bromo and 4-chlorophenyl analogues, 6a and 7a,
were readily synthesized from commercially available
chlorobutyrophenones by displacement of the alkyl chlo-
ride with NaN3. The crude azide was then smoothly
reduced with PPh3 to afford the desired myosmine
analogue.11 While this route provided the pyrrolidine
product in good yield (∼75% over three steps), com-
mercially available chlorobutyrophenones were limited
to 4-substituted ortho/para directing groups. For meta
halide-containing members, Weinreb amides were re-
acted with protected Grignard reagent 11 at 0 °C for
12 h, followed by treatment with 10% HCl in EtOH to
induce concomitant deprotection of the amine and imine
formation in modest yields (50-65%).12,13 Stronger elec-
tron-withdrawing groups, such as nitro or trifluorometh-
yl, could not be synthesized with this route due to facile
dialkylation, even at lower temperatures (-78 °C).
Consequently, these compounds were synthesized from
the corresponding ethyl esters, which were treated with
1-vinyl-2-pyrrolidinone and sodium hydride in refluxing
THF, followed by acidification in refluxing HCl.14 Al-
though yields for this route were poor (∼30%),13 suitable
quantities of pure myosmine analogue could be obtained
after distillation.
In summary, these results show promise for the
development of improved aldol catalysts in aqueous
media. The field of green chemistry has received much
attention in recent years as a method to develop envi-
With the desired compounds in hand, the kobs for the
nornicotine analogues in the aqueous aldol reaction were
(11) De Kimpe, N.; Tehrani, K. A.; Stevens, C.; De Cooman, P.
Tetrahedron 1997, 53, 3693-3706.
(16) (a) Topsom, R. D. Prog. Phys. Org. Chem. 1976, 12, 1. (b) Uger,
S. H.; Hansch, C. Prog. Phys. Org. Chem. 1976, 12, 91. (c) Levitt, L.
S.; Widing, H. F. Prog. Phys. Org. Chem. 1976, 12, 119.
(12) Basha, F. Z.; DeBernardis, J. F. Tetrahedron Lett. 1984, 25,
5271-5274.
(13) Yields refer to the isolated yield of 2-arylpyrrolidine and were
not optimized.
(17) The relative rate refers to the rate constant of the 2-arylpyr-
rolidine-catalyzed reaction divided by the rate constant of the 2-phenyl-
pyrrolidine (3b)-catalyzed reaction.
(14) Maryanoff, B. E.; McComsey, D. F.; Gardocki, J. F.; Shank. R.
P.; Costanzo, M. J.; Nortey, S. O.; Schneider, C. R.; Setler, P. E. J.
Med. Chem. 1987, 30, 1433-1454.
(18) (a) Reymond, J.-L.; Chen, Y. J. Org. Chem. 1995, 60, 6970-
6979. (b) Co´rdova, A.; Notz, W.; Barbas, C. F., III Chem. Commun.
2002, 24, 3024-3025. (c) Peng, Y.-Y.; Ding, Q.-P.; Li, Z.; Wang, P. G.;
Cheng, J.-P. Tetrahedron Lett. 2003, 44, 3871-3875. (d) Hartikka, A.;
Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831-1834.
(15) (a) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-
195. (b) Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.;
Lein, E. J. J. Med. Chem. 1973, 16, 1207-1216.
3706 J. Org. Chem., Vol. 70, No. 9, 2005

SCHEME 3. Synthesis of 2-Arylpyrrolidines, Routes B, C, and Da
a Reagents and conditions: Route B: (a) (i) NaN3, NaI, DMSO, 55 °C, (ii) PPh3, hexane. Route C: (b) (i) 1-vinyl-2-pyrrolidinone, NaH,
THF, (ii) 4.6 M HCl. Route D: (c) (i) 11, THF, 0 °C, (ii) 10% HCl/EtOH. (d) NaBH4, 20% AcOH/MeOH, -45 °C.
TABLE 1. kobs for 2-Arylpyrrolidine-Catalyzed Aqueous
General Procedure for Li/DTBB-Catalyzed Cycliz-
ations. Lithium wire (20 equiv) was prepared by scraping its
surface under kerosene oil, cutting it into small pieces, and
placing the oil-covered pieces into a flask. The oil was removed
by washing the pieces with dry hexanes followed by THF under
a stream of Ar. To the prepared lithium wire was slowly added
di-tert-butylbiphenyl (0.2 equiv) as a concentrated solution in
THF. The resulting green suspension was diluted with THF, the
mixture was cooled to -78 °C, and the appropriate N-aryl-
methylene-3-chloropropyl-1-amine (1 equiv) was added as a
solution in THF, quenching the green color. After the green color
reappeared (ca. 2 h), the reaction was quenched by the slow
addition of water (20 mL), and the mixture was allowed to warm
to room temperature. The solution was acidified with 2 N HCl
and washed twice with Et2O. The aqueous layer was then
brought to pH 12-13 with 4 M NaOH, and the product was
extracted with ethyl acetate. The combined organic layers were
dried over Na2SO4, and concentrated in vacuo to afford 2-arylpyr-
rolidine, which was purified by bulb-to-bulb distillation.
General Procedure for Synthesis of Myosmine Ana-
logues from 4-Chlorobutyrophenones (Route B). A flask
containing the appropriate 4-chlorobutyrophenone (38 mmol),
NaN3 (3.73 g, 57 mmol), and NaI (0.19 g, 1.3 mmol) in DMSO
was warmed to 55 °C. After 15 h, the solution was poured into
water and extracted with Et2O. The combined organic layers
were washed with brine, dried (MgSO4), and concentrated in
vacuo. Triphenylphosphine (9.69 g, 37 mmol) was added to a
suspension of the resulting crude azide (35 mmol) in hexanes.
The resulting mixture was stirred for 14 h at room temperature
before being filtered. The solids were washed with cold Et2O and
the filtrate was evaporated. The residue was dissolved in Et2O:
hexane (1:1) and filtered. The filtrate was evaporated, affording
the crude myosmine analogue.
Aldol Reactions
c
yield
kobs
b
compd
substituent
4-Me2N
4-MeO
H
4-F
3-MeO
4-Cl
4-Br
3-Br
4-CF3
route (%)a
σx
(10-3 min-1
)
1b
2b
3b
4b
5b
6b
7b
8b
9b
A
A
A
A
A
B
B
D
C
C
91 -0.83
94 -0.27
0.7 ( 0.1
3.1 ( 0.2
4.6 ( 0.1
4.8 ( 0.1
6.3 ( 0.1
8.4 ( 0.2
9.1 ( 0.1
88
85
97
76
79
63
34
32
0.00
0.06
0.12
0.23
0.23
0.39 12.5 ( 0.4
0.54 18.0 ( 0.9
0.71 23.8 ( 1.7
10.1d
10b 3-NO2
nornicotine
pyrrolidine
uncatalyzed reaction
2.4d
0.7 ( 0.1
a Unoptimized isolated yield of 2-arylpyrrolidine. b Hammett
values, σx, taken from ref 15. c Initial rates were measured in 10%
DMSO/200 mM phosphate buffer (pH 8.0) at 37 °C with 240 mM
acetone, 2.4 mM catalyst, and initiated by the addition of 1-8 mM
aldehyde. The reaction was followed by monitoring the generation
of aldol addition product by reverse-phase HPLC. Values for kobs
were calculated by using linear regression analysis. d Values from
ref 5.
ronmentally benign chemical processes.19 Our data pro-
vide a clearer picture into the nature of aqueous pyrro-
lidine-based organocatalysts and suggest that with suitable
design, synthetically useful catalysts are attainable.
Experimental Section
General Procedure for Synthesis of Myosmine Ana-
logues from Aryl Esters (Route C). To a solution of NaH (0.86
g, 36 mmol) in THF was added 1-vinylpyrrolidinone (31 mmol,
3.3 mL) and aryl ethyl ester (26 mmol) as a solution in THF.
After being stirred at ambient temperature for 15 min, the
resulting mixture was warmed to reflux for 1 h. The flask was
then cooled to room temperature and treated with 4.6 M HCl.
The THF was evaporated, and the solution was treated with
another portion of 4.6 M HCl. The flask was then warmed to
reflux for 15 h. After heating, the solution was cooled in an ice
bath, and the reaction was basified by 50% NaOH. After
extraction with Et2O, the combined organic layers were washed
with H2O and brine, dried (MgSO4), and concentrated in vacuo.
General Procedure for N-Arylmethylene-3-chloropro-
pyl-1-amines. Triethylamine (2.2 mmol, 0.31 mL) was added
to a mixture of 3-chloropropylamine hydrochloride (0.29 g,
2.2 mmol) and MgSO4 (0.48 g, 4.0 mmol) in 10 mL of CH2Cl2.
After stirring at room temperature for 1 h, the appropriate
aldehyde (0.2 mmol) was added and the suspension was allowed
to continue to stir at ambient temperature, or heated to reflux
for 12 h. Upon completion, the MgSO4 was filtered and washed
with CH2Cl2. The filtrate was washed sequentially with satu-
rated aqueous NaHCO3 and brine, dried (Na2SO4), and concen-
trated in vacuo. Compounds were used without any further
purification.
General Procedure for Synthesis of Myosmine Ana-
logues from Weinreb Amides (Route D). To a flask contain-
ing Mg (0.17 g, 6.8 mmol) was added a few small crystals of
iodine. The flask was sealed and warmed with a heat-gun until
(19) (a) Kirchhoff, M. M. Environ. Sci. Technol. 2003, 37, 5349-
5353. (b) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford: New York, 1998.
J. Org. Chem, Vol. 70, No. 9, 2005 3707

FIGURE 1. Hammett correlation of the log of relative rate for aldol catalysis versus Hammett value, σx (taken from ref 15),
where kH ) kobs for 3b, and kx ) kobs for the tested compound.
the iodine vaporized. After the Mg metal was stirred in the vapor
for 30 min, the flask was purged with argon. After the iodine
was removed, a small amount of THF was added, followed by
the dropwise addition of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-
1-aza-2,5-disilacyclopentane (6.2 mmol, 1.53 mL). During the
addition, the flask was warmed with a heat-gun at such a rate
to maintain reflux. Once the suspension was able to maintain
its own reflux, additional THF was slowly added. After being
stirred for 1 h, the solution was cannulated into a chilled flask
(0 °C) containing Weinreb amide (0.5 g, 2.1 mmol) and THF.
Upon completion, the mixture was allowed to warm to room
temperature. After 18 h, the reaction was quenched by the
addition of 10% HCl in EtOH (20 mL) and stirred an additional
3 h. The solution was then brought to pH 12-13 with 4 M NaOH
and washed with EtOAc. The organic fractions were dried
(Na2SO4) and concentrated to afford crude myosmine analogue.
General Procedure for the Synthesis of Pyrrolidines
from Myosmine Analogues. NaBH4 (2 equiv) was added to a
solution of myosmine analogue in 20% AcOH/MeOH at -41 °C.
After being stirred for 1 h the solution was allowed to warm to
room temperature. Once the reaction was deemed complete by
TLC or GC analysis, the unreacted NaBH4 was quenched by the
addition of 2 N HCl. The solution was then diluted with H2O
and ether. The phases were separated, and the aqueous layer
was washed with an additional portion of ether. The aqueous
layer was basified with 4 M NaOH (pH 12-13) and washed with
ethyl acetate. The combined organic extracts were washed with
brine, and then dried over Na2SO4. Evaporation, followed by
bulb-to-bulb distillation afforded pure 2-arylpyrrolidine.
Initial Rate Kinetics. Initial rates and rate constants for
2-arylpyrrolidine catalyzed aldol condensation of 4-nitrobenzal-
dehyde and acetone were determined by monitoring the forma-
tion of 4-hydroxy-4-(4-nitrophenyl)butan-2-one by analytical
reverse-phase HPLC. Reactions were conducted at 37 °C with
2.4 mM freshly distilled arylpyrrolidine, 240 mM acetone, and
8.0 mM 4-nitrobenzaldehyde in 10% DMSO/200 mM phosphate,
pH 7.4. All reactions were performed in a total volume of
500 µL. To monitor the progress of the reaction, 10-µL aliquots
of the above solution were removed at various times during the
reaction and diluted to a total volume of 500 µL with phosphate
buffer. Then, 20 µL of these samples was injected onto an
analytical RP-C18 HPLC, and the amount of 4-hydroxy-4-
(4-nitrophenyl)butan-2-one (retention time ) 6.2 min) was
determined by interpolation of the peak height and area values
relative to standard curves. Pseudo-first-order rate constants
were measured by varying 4-nitrobenzaldehyde concentrations
(1-8 mM) in the above reaction.
Acknowledgment. This work was supported by The
Scripps Research Institute and The Skaggs Institute for
Chemical Biology.
Supporting Information Available: 1H and 13C NMR
spectra data for 2-arylpyrrolidines 1b-10b. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO050161R
3708 J. Org. Chem., Vol. 70, No. 9, 2005