Cyclic guanidine organic catalysts: What is magic about triazabicyclodecene?

Article abstract of DOI:10.1021/jo902369g

(Chemical Equation Presented) The bicyclic guanidine 1,5,7- triazabicyclo[4.4.0]dec-5-ene (TBD) is an effective organocatalyst for the formation of amides from esters and primary amines. Mechanistic and kinetic investigations support a nucleophilic mechanism where TBD reacts reversibly with esters to generate an acyl-TBD intermediate that acylates amines to generate the amides. Comparative investigations of the analogous bicyclic guanidine 1,4,6-triazabicyclo[3.3.0]oct-4-ene (TBO) reveal it to be a much less active acylation catalyst than TBD. Theoretical and mechanistic studies imply that the higher reactivity of TBD is a consequence of both its higher basicity and nucleophilicity than TBO as well as the high reactivity of the acyl-TBD intermediate, which is sterically prevented from adopting a planar amide structure.

Full text of DOI:10.1021/jo902369g

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Cyclic Guanidine Organic Catalysts: What Is Magic About
Triazabicyclodecene?
Matthew K. Kiesewetter,† Marc D. Scholten,† Nicole Kirn,† Ryan L. Weber,†
James L. Hedrick,*,‡ and Robert M. Waymouth*,†
†Department of Chemistry, Stanford University, Stanford, California 94305, and
‡IBM Almaden Research Center, 650 Harry Road, San Jose, California 95120
waymouth@stanford.edu
Received November 4, 2009
The bicyclic guanidine 1,5,7- triazabicyclo[4.4.0]dec-5-ene (TBD) is an effective organocatalyst for
the formation of amides from esters and primary amines. Mechanistic and kinetic investigations
support a nucleophilic mechanism where TBD reacts reversibly with esters to generate an acyl-TBD
intermediate that acylates amines to generate the amides. Comparative investigations of the
analogous bicyclic guanidine 1,4,6-triazabicyclo[3.3.0]oct-4-ene (TBO) reveal it to be a much less
active acylation catalyst than TBD. Theoretical and mechanistic studies imply that the higher
reactivity of TBD is a consequence of both its higher basicity and nucleophilicity than TBO as well as
the high reactivity of the acyl-TBD intermediate, which is sterically prevented from adopting a planar
amide structure.
Introduction
it is clear that organocatalytic reactions have evolved to
provide a powerful addition to the armamentarium of
methods for chemical synthesis.5-8 Organocatalysis has also
proven a powerful strategy for polymer synthesis.11 We have
investigated a variety of nucleophilic and basic organic
molecules as catalysts for transesterification12,13 and ring-
opening polymerization reactions (Figure 1).11 The highly
basic and nucleophilic N-heterocyclic carbenes are potent
organocatalysts for the ring-opening polymerization of lac-
tones, generating polyesters of defined molecular weights in
seconds at room temperature.11,14 Mechanistic and theoreti-
cal studies indicate that N-heterocyclic carbenes bind readily
Almost a century after its beginnings,1-4 the field of
organocatalysis has undergone a resurgence with the devel-
opment of new classes of highly enantioselective organocata-
lysts.5-8 Notwithstanding the extraordinary pace of devel-
opments in transition metal and organometallic catalysis,9,10
(1) Bredig, G.; Fiske, P. S. Biochem. Z. 1912, 46, 7–23.
(2) Langenbeck, W. Die Organische Katalysatoren und ihre Beziehungen
zu den Fermenten, 2nd ed.; Springer: Berlin, Germany, 1949.
(3) Eder, U.; Sauer, G.; Weichert, R. Angew. Chem., Int. Ed. 1971, 10,
496–497.
(4) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
(5) For a recent overview see “Organocatalysis” special issue: List, B., Ed.
Chem. Rev., 2007, 107, 5413-5883.
(6) Bertelsen, S.; Jorgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178–2189.
(7) Barbas, C. F. Angew. Chem., Int. Ed. 2008, 47, 42–47.
(8) MacMillan, D. W. C. Nature 2008, 455, 304–308.
(9) Cornils, B.; Herrmann, W. A., Eds. Applied Homogeneous Catalysis
with Organometallic Compounds; VCH: Weinheim, Germany, 2002; Vol. 1,
p 2.
(11) Kamber, N. E.; Jeong, W.; Waymouth, R. M.; Pratt, R. C.;
Lohmeijer, B. G. G.; Hedrick, J. L. Chem. Rev. 2007, 107, 5813–5840.
(12) Nyce, G. W.; Lamboy, J. A.; Connor, E. F.; Waymouth, R. M.;
Hedrick, J. L. Org. Lett. 2002, 4, 3587–3590.
(13) Grasa, G.; Kissling, R. M.; Nolan, S. P. Org. Lett. 2002, 4, 3583–
3586.
(10) Thomas, J. M.; Raja, R.; Lewis, D. W. Angew. Chem., Int. Ed. 2005,
44, 6456–6482.
(14) Jeong, W.; Shin, E. J.; Culkin, D. A.; Hedrick, J. L.; Waymouth, R.
M. J. Am. Chem. Soc. 2009, 131, 4884–4891.
9490 J. Org. Chem. 2009, 74, 9490–9496
Published on Web 11/23/2009
DOI: 10.1021/jo902369g
r
2009 American Chemical Society

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(P2-t-Bu)26 are all effective catalysts for the ring-opening
polymerization of lactones and cyclic carbonates27-32 (Figure1).
TBD is among the most active ring-opening polymeriza-
tion catalysts that we have investigated to date. The ring-
opening polymerization of lactide with 0.1% TBD in THF
exhibits a turnover frequency of 80 s-1 at room tempera-
ture,23,25 which is comparable to those of the most active
metal catalysts reported for ROP of lactide.33-35 These
polymerizations are also remarkably well-controlled, yield-
ing polylactide with well-defined molecular weights and
narrow polydispersities (Figure 2).
FIGURE 1. Nucleophilic and basic organic catalysts for ring-open-
ing polymerization.
TBD is a more active catalyst than MTBD or DBU for
lactide polymerization and catalyzes the ring-opening poly-
merization of δ-valerolactone and ε-caprolactone under
conditions where MTBD and DBU are inactive.23,25 TBD
(TBDHþ, pKa = 26), MTBD (MTBDHþ, pKa = 25), and
DBU (DBUHþ, pKa = 24) have comparable basicities in
THF36 to those calculated for the N-aryl-substituted N-
heterocyclic carbenes (pKa 27-28).37-39 The large differ-
ences in activity observed for TBD, MTBD, and DBU imply
that thermodynamic basicity is not the sole criterion for
predicting catalytic activity.
Guanidines and amidines are effective catalysts for a
variety of organic reactions.22,40-44 These commercially
available, easily handled bases have been reported as trans-
esterification catalysts.27,45-48 In water, guanidines and
amidines are readily protonated,36 and their biological acti-
vity49-51 and much of their reaction chemistry is assumed to
proceed via guanidinium or amidinium intermediates.42-44,51,52
However, several studies have shown that guanidines and
amidines can act as nucleophiles.22,53,54
to alcohols,15,16 activating the alcohol for nucleophilic
attack and stabilizing the resulting tetrahedral intermedi-
ates.16,17 In the absence of alcohols, the N-heterocyclic
carbenes react directly with lactones and mediate the zwit-
terionic ring-opening polymerization of esters by a nucleo-
philic mechanism.14,18 This mechanistic duality is common
to many acylation reactions catalyzed by amines and nitro-
gen heterocycles.19,20
In addition to the N-heterocyclic carbenes, we have also
surveyed a variety of other potent neutral organic bases as
catalysts for ring-opening polymerization reactions. Guani-
dines such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD),21,22
N-methyl-TBD (MTBD), and 1,4,6-triazabicyclo[3.3.0]oct-
4-ene (TBO),21 amidines such as 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU),23-25 and phosphazenes such as
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-
1,3,2-diazaphosphorine (BEMP) and 1-tert-butyl-2,2,4,4,4-
pentakis(dimethylamino)-2Λ5,4Λ5- catenadi(phosphazene)
We had previously shown that TBD can be acylated by
vinyl acetate, implicating that TBD can actas a nucleophile.23
Subsequent reaction of acyl-TBD with benzyl alcohol
(15) Cowan, J. A.; Clyburne, J. A. C.; Davidson, M. G.; Harris, R. L. W.;
Howard, J. A. K.; Kupper, P.; Leech, M. A.; Richards, S. P. Angew. Chem.,
Int. Ed. 2002, 41, 1432–1434.
(16) Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453–2456.
(17) Lai, C. L.; Lee, H. M.; Hu, C. H. Tetrahedron Lett. 2005, 46, 6265–
6270.
(18) Culkin, D. A.; Jeong, W. H.; Csihony, S.; Gomez, E. D.; Balsara, N.
R.; Hedrick, J. L.; Waymouth, R. M. Angew. Chem., Int. Ed. 2007, 46, 2627–
2630.
(19) Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43, 5436–
5441.
(32) Jing, F.; Hillmyer, M. A. J. Am. Chem. Soc. 2008, 130, 13826–13827.
(33) Chamberlain, B. M.; Cheng, M.; Moore, D. R.; Ovitt, T. M.;
Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2001, 123, 3229–3238.
(34) Williams, C. K.; Breyfogle, L. E.; Choi, S. K.; Nam, W.; Young, V.
G.; Hillmyer, M. A.; Tolman, W. B. J. Am. Chem. Soc. 2003, 125, 11350–
11359.
(20) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H. Y.;
Houk, K. N. Acc. Chem. Res. 2004, 37, 558–569.
(35) Chisholm, M. H.; Gallucci, J.; Phomphrai, K. Chem. Commun. 2003,
48–49.
(21) In this work, we use the von Baeyer nomenclature for the bicyclic
guanidines. The IUPAC name for TBD is 1,3,4,6,7,8-hexahydroimidazo[1,2-
a]pyrimidine (H-hpp) and for TBO the IUPAC name is 2,3,5,6-tetrahydro-
1H-imidazo[1,2-a]imidazole (H-tbo). See ref 22 for comparisons of the von
Baeyer and IUPAC nomenclature.
€
€
€
(36) Kaljurand, I.; Kutt, A.; Soovali, L.; Rodima, T.; Maemets, V.; Leito,
I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019–1028.
(37) Amyes, T. L.; Diver, S. T.; Richard, J. P.; Rivas, F. M.; Toth, K.
J. Am. Chem. Soc. 2004, 126, 4366–4374.
(22) Coles, M. P. Chem. Commun. 2009, 3659–3676.
(23) Pratt, R. C.; Lohmeijer, B. G. G.; Long, D. A.; Waymouth, R. M.;
Hedrick, J. L. J. Am. Chem. Soc. 2006, 128, 4556.
(38) Kim, Y. J.; Streitwieser, A. J. Am. Chem. Soc. 2002, 124, 5757–5761.
(39) Magill, A. M.; Cavell, K. J.; Yates, B. F. J. Am. Chem. Soc. 2004, 126,
8717–8724.
(24) Chuma, A.; Horn, H. W.; Swope, W. C.; Pratt, R. C.; Zhang, L.;
Lohmeijer, B. G. G.; Wade, C. G.; Waymouth, R. M.; Hedrick, J. L.; Rice, J.
E. J. Am. Chem. Soc. 2008, 130, 6749–6754.
(25) Lohmeijer, B. G. G.; Pratt, R. C.; Leibfarth, F.; Logan, J. W.; Long,
D. A.; Dove, A. P.; Nederberg, F.; Choi, J.; Wade, C.; Waymouth, R. M.;
Hedrick, J. L. Macromolecules 2006, 39, 8574–8583.
(26) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.; Dam-
bacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J.; Fritz, H.;
Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Ji, G. Z.; Peters, E.
M.; Peters, K.; vonSchnering, H. G.; Walz, L. Liebigs Ann. 1996, 1055–1081.
(27) Le Perchec, P.; Baudry, R.; Alvarez, F. U.S. Patent 6,646,103 B1,
2003.
(40) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157–160.
(41) Simoni, D.; Rossi, M.; Rondanin, R.; Mazzali, A.; Baruchello, R.;
Malagutti, C.; Roberti, M.; Invidiata, F. P. Org. Lett. 2000, 2, 3765–3768.
(42) Ishikawa, T.; Kumamoto, T. Synthesis (Stuttgart) 2006, 737–752.
(43) Leow, D.; Tan, C. H. Chem.;Asian J. 2009, 4, 488–507.
(44) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228–9229.
(45) Green, M. J. Eur. Patent Appl. 110629, 1986.
(46) Gelbard, G.; Vielfaure-Joly, F. Tetrahedron Lett. 1998, 39, 2743–
2746.
(47) Kantam, M. L.; Sreekanth, P. Catal. Lett. 2001, 77, 241–243.
(48) Schuchardt, U.; Vargas, R. M.; Gelbard, G. J. J. Mol. Catal. A:
Chem. 1995, 99, 65–70.
(28) Zhang, L.; Nederberg, F.; Pratt, R. C.; Waymouth, R. M.; Hedrick,
J. L.; Wade, C. G. Macromolecules 2007, 40, 4154–4158.
(29) Zhang, L.; Nederberg, F.; Messman, J. M.; Pratt, R. C.; Hedrick, J.
L.; Wade, C. G. J. Am. Chem. Soc. 2007, 129, 12610–12611.
(30) Nederberg, F.; Trang, V.; Pratt, R. C.; Mason, A. F.; Frank, C. W.;
Waymouth, R. M.; Hedrick, J. L. Biomacromolecules 2007, 8, 3294–3297.
(31) Nederberg, F.; Lohmeijer, B. G. G.; Leibfarth, F.; Pratt, R. C.; Choi,
J.; Dove, A. P.; Waymouth, R. M.; Hedrick, J. L. Biomacromolecules 2007, 8,
153–160.
(49) Berlinck, R. G. S.; Burtoloso, A. C. B.; Kossuga, M. H. Nat. Prod.
Rep. 2008, 25, 919–954.
(50) O’Brien, P. J.; Lassila, J. K.; Fenn, T. D.; Zalatan, J. G.; Herschlag,
D. Biochemistry 2008, 47, 7663–7672.
(51) Perreault, D. M.; Cabell, L. A.; Anslyn, E. V. Biorg. Med. Chem.
1997, 5, 1209–1220.
(52) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743.
(53) Ghosh, N. Synlett 2004, 3, 574–575.
(54) Baidya, M.; Mayr, H. Chem. Commun. 2008, 1792–1794.
J. Org. Chem. Vol. 74, No. 24, 2009 9491

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FIGURE 2. Ring-opening polymerization of lactide with TBD is even faster than that with NHC0s.
FIGURE 3. Model studies demonstrating the acylating ability of
TBD.
FIGURE 4. Hydrogen-bonding mechanism suggested by theoreti-
yielded the ester, leading us to propose a nucleophilic
mechanism as a potential pathway for ring-opening by
TBD (Figure 3).23,25 Subsequent theoretical studies24,55 in-
dicated that a nucleophilic mechanism was feasible, but had
a considerably higher barrier than a hydrogen bond
mediated mechanism (Figure 4) for transesterification reac-
tions.
The implication that TBD can act as a bifunctional
nucleophilic catalyst suggests that it may be able to acylate
other nucleophiles. The acylation of amines is of particular
interest as the formation of amides from esters is an exceed-
ingly useful reaction typically carried out under forcing
conditions with highly basic catalysts.56-67 Maggi had pre-
viously demonstrated that TBD catalyzes the formation of
ureas from carbonates and primary amines,68,69 and while
cal studies.24,55
this work was ongoing, Mioskowski reported the aminolyis
of esters with amines to form amides under solvent-free
conditions.70
In this article, we report kinetic studies on the acylation of
amines by esters which strongly implicate a nucleophilic
mechanism for the conversion of esters to amides in the
presence of TBD. Studies of the analogous bicyclic guanidine
1,4,6-triazabicyclo[3.3.0]oct-4-ene (TBO)21 revealed it to be
a much slower catalyst; mechanistic and theoretical studies
provide useful insights on the stereoelectronic properties of
TBD that contribute to its remarkable ability to catalyze
acylation reactions.
Results and Discussion
(55) Simon, L.; Goodman, J. M. J. Org. Chem. 2007, 72, 9656–9662.
(56) Waghoo, G.; Jayaram, R. V.; Joshi, M. V. Synth. Commun. 1999, 29,
513–515.
(57) Huang, P.; Zheng, X.; Deng, X. Tetrahedron Lett. 2001, 42, 9039–
9041.
(58) Smith, L. A.; Wang, W.; Burnell-Curty, C. Synlett 1993, 850–852.
(59) Houghton, R. P.; Williams, C. S. Tetrahedron Lett. 1967, 40, 3929–
3931.
(60) Lui, W.; Xu, D. D.; Repic, O.; Blacklock, T. J. Tetrahedron Lett.
2001, 42, 2439–2441.
(61) Riviere-Baudet, M.; Morere, A.; Dias, M. Tetrahedron Lett. 1992,
33, 6453–6456.
(62) Sim, T. B.; Yoon, N. M. Synlett 1994, 10, 827–829.
(63) Han, C.; Lee, J. P.; Lobkovsky, E.; Porco, J. A. J. Am. Chem. Soc.
2005, 127, 10039–10044.
(64) Sidler, D. R.; Lovelace, T. C.; McNamara, J. M.; Reider, P. J. J. Org.
Chem. 1994, 59, 1231–1233.
(65) Feo, R. J. D.; Strickler, P. D. J. Org. Chem. 1963, 28, 2915–2917.
(66) Wang, J.; Rosingana, M.; Discordia, R. P.; Soundararajan, N.;
Polniaszek, R. Synlett 2001, 9, 1485–1488.
The amidation of vinyl acetate with 4 equiv of n-butyla-
mine with 10 mol % of TBD in toluene solution at 25 °C
affords n-butylacetamide quantitatively in 6 min (Figure 5).
While vinyl esters are known to acylate primary amines in the
absence of a catalyst,71,72 these reactions are significantly
slower than that observed in the presence of TBD (6 min vs.
24 h). In the presence of 4 equiv of n-butylamine, benzyl
acetate converted cleanly (99% conversion, 94.9% isolated
yield) to n-butylacetamide in 5 h at 80 °C in toluene in the
presence of 10 mol % of TBD. Under solvent-free conditions
reported by Mioskowski,70 neat benzyl acetate reacts with
1.3 equiv of butylamine in the presence of 22 mol % of
TBD to give n-butylacetamide in 89% isolated yield after 2 h.
(67) Stephenson, N. A.; Zhu, J.; Gellman, S. H.; Stahl, S. S. J. Am. Chem.
Soc. 2009, 131, 10003–10008.
(70) Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C. Tetrahedron
Lett. 2007, 48, 3863–3866.
(68) Carloni, S.; De Vos, D. E.; Jacobs, P. A.; Maggi, R.; Sartori, G.;
Sartorio, R. J. Catal. 2002, 205, 199–204.
(71) Kabouche, Z.; Bruneau, C.; Dixneuf, P. H. Tetrahedron Lett. 1991,
32, 5359–5362.
(69) Ballini, R.; Fiorini, D.; Maggi, R.; Righi, P.; Sartori, G.; Sartorio, R.
Green Chem. 2003, 5, 396–398.
(72) Kita, Y.; Maeda, H.; Omori, K.; Okuno, T.; Tamura, Y. J. Chem.
Soc., Perkin Trans. 1 1993, 2999–3005.
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FIGURE 5. Catalytic amidation of esters.
No special care is needed in the purification of solvents:
reactions in reagent grade toluene, THF, DMSO, or CH2Cl2
proceeded in quantitative yield, albeit with slightly slower
rates than those in dry toluene. The conversion of benzyl
acetate to n-butylacetamide did not proceed at an appreci-
able rate when N-methylTBD (MTBD) or triethylamine was
substituted for TBD.
FIGURE 6. Proposed mechanism for formation of n-butylaceta-
mide from benzyl acetate and butylamine.
The amidation of (S)-ethyl lactate is considerably faster
than benzyl acetate, generating a 71% yield of n-butyl
lactamide within 30 min at 80 °C. Analysis of the Mosher
ester of n-butyl lactamide reveals it to be of high diastereo-
meric purity (only one isomer observed by 19F NMR) and
derived from (S)-n-butyl lactamide, indicating that the ami-
dation of ethyl lactate proceeds with retention of configura-
tion with minimal epimerization. In contrast, amidation of
the more acidic and sterically demanding (S)-2-(6-methox-
ynaphthalen-2-yl)propionic acid methyl ester was consider-
ably slower (20 days, 64% yield) and yielded racemic n-butyl
2-napthyl propranamide. In the latter case, due to the much
slower rate, TBD-catalyzed epimerization of either the ester
or amide can compete with amidation. Thus, while we had
anticipated that the basic nature of TBD might lead to the
racemization of acidic esters, it is clear that the extent of
racemization depends sensitively on the nature of the ester.
Screening experiments (see the Supporting Information)
To this end, kinetic investigations of the reaction of benzyl
1
acetate with n-butylamine were studied by H NMR in the
presence of TBD. In toluene-d8 at 298 K under pseudo-first-
order conditions, the rate of disappearance of benzyl acetate
is first order in benzyl acetate, first order in TBD, first order
in amine, and inverse first order in benzyl alcohol, yielding a
rate law described by eq 1,
d½Esterꢀ
½Esterꢀ½RNH2ꢀ½TBDꢀ
½ROHꢀ
-
¼ kobs
ð1Þ
dt
where [Ester], [RNH2], [TBD], and [ROH] equal the con-
centrations of benzyl acetate, n-butylamine, TBD, and ben-
zyl alcohol, respectively; and kobs = 1.9 ( 0.1 ꢁ 10-3 M-1
s-1. This rate law can be accommodated by the mechanism
shown in Figure 6 involving the reversible formation of an
acyl-TBD intermediate, followed by irreversible trapping of
acyl-TBD with butylamine to generate n-butylacetamide and
TBD.
1
by H NMR revealed that catalytic formation of amides
from branched and secondary amines or from branched
esters exhibited much slower rates at 25 °C in solution
([Ester]o = 0.23 M) than those of benzyl acetate and ethyl
lactate. However, under solvent-free conditions, the catalytic
amidation of methyl phenylacetate yields the amides in 94%
yield after 12 h at 75 °C.70
Kinetics and Mechanism. Theoretical studies implicate that
a hydrogen-bonded mechanism has a lower barrier than a
nucleophilic acylation mechanism for transesterification
reactions (Figure 4).24,55 For amine nucleophiles, an H-
bonded mechanism analogous to Figure 4 is less likely and
motivated us to investigate the chemical and kinetic compe-
tence of a nucleophilic mechanism for amine acylation.
Application of the steady-state assumption to the mechan-
ism described in Figure 6 yields the rate law in eq 2:
d½Esterꢀ k1k2½Esterꢀ½RNH2ꢀ½TBDꢀ
-
¼
ð2Þ
dt
k-1½ROHꢀ þ k2½RNH2ꢀ
This rate equation would be consistent with the experi-
mental rate law under conditions where k-1[ROH] . k2-
[RNH2], for which:
k1k2
kobs
k-1
J. Org. Chem. Vol. 74, No. 24, 2009 9493
¼
ð3Þ