Post on 12-Jul-2020
IS KETENE AN INTERMEDIATE IN THE ADDITION OF IMINES TO AZLACTONE TO FORM BETA-LACTAM?
CAROLINE KORDESDR. JOSEPH SCANLONDR. PATRICK WILLOUGHBYRIPON COLLEGE
1
BETA-LACTAMSo First synthesized in 1907 by Hermann Staudinger where he reacted
benzaldehyde with diphenylketene
https://en.wikipedia.org/wiki/Hermann_Staudinger
o β-Lactams make up one of the three largest groups of antibiotics.o Penicillin
2
BETA-LACTAMSo Penicillin was first observed by Alexander Fleming in 1928
o However, wasn’t introduced as an antibiotic until the 1940’s
o Antibiotics like pencillin work by penetrating and damaging the bacteria’s cell wall
o Resistance to β-lactam antibiotics happen when the bacteria produces β-lactamase that hydrolyzes the β-lactam which disables the antibiotic
3
https://en.wikipedia.org/wiki/Alexander_Fleming
KETENESoDiscovered by Herman Staudinger in 1905
oCommonly invoked as an intermediate in organic mechanisms
o The reactive species, carbonyl carbon is nucleophilic due to the carbon double bond oxygen
4
BETA-LACTAM SYNTHESISo One common synthesis
5
Azlactone Beta-LactamsImine
MUNCHNONE-KETENE MECHANISMo The generally accepted pathway is the münchnone Pathway
o azlactone münchnone ketene β-Lactam
oAlso known as the Staudinger ketene-Imine cycloaddition
o Rolf Huisgen in 1967 asserted that munchnone and ketene a part of the mechanism
o Ketene predicted to be a high energy intermediate compared to azlactone
6
Azlactoneβ-Lactams
KeteneMunchnone
DIRECT ADDITION MECHANISMo Another possible mechanism o A direct addition of the imine to the azlactone
instead of a ketene intermediate
oMay not involve high energy intermediates like ketene
7
Beta-LactamsImineAzlactone
PURPOSEo To determine the mechanism of this reaction of
azlactone with an imine to form β-lactam
o münchnone & ketene intermediates are much higher in energy than azlactones
o Overall, want to develop alternative methods for synthesizing β-lactam so new antibiotics can be found
8
Azlactone Beta-LactamImine
THEORETICAL METHODS o Guassian 09
oTheory: M05-2X Density FunctionaloBasis Set: 6-311+G(2d,p)
o SolvationoSingle point calculations with gas phase geometriesoImplicit solvation model: SMDoSolvent: Acetonitrile
oFind the potential energy diagrams for both pathwaysoCalculating ∆EoCalculating ∆G
9
MÜNCHNONE PATHWAY
10
o The mechanism found
SOLUTION PHASE RESULTS∆
E(k
cal/m
ol)
11
Azlactone
Münchnone
TS1 KeteneTS2
M-Intermediate
TS3
Product
-25.00
-20.00
-15.00
-10.00
-5.00
0.00
5.00
10.00
15.00
20.00
25.00
MÜNCHNONE PATHWAY CONCLUSIONSo 13 kcal/mol from azlactone to münchnone for the
solution phase is too high
o ketene is about 20 kcal/mol higher in energy than the azlactone
12
DIRECT ADDITION PATHWAYo The imine is added directly to the azlactone
o There may not be any high energy intermediates involved in the mechanism
azlactone imine DA-Intermediate A beta-lactam
13
DIRECT ADDITION PROPOSED PATHWAY
~H+
14
M-intermediate DA_Intermediate B
DIRECT ADDITION PATHWAY RESULT
o Higher Energy intermediateso The DA-Intermediate B is less likely than the keteneo DA-Intermediate A could not be located
o Direct Addition Pathway is unlikely
Reactants & Products Relative Energy (kcal/mol)
azlactone 0.00
DA Intermediate A -DA Intermediate B 62.17
M-Intermediate 9.56Products -17.15
15
HOWEVER, PROTONATIONo Protonation might make Direct Addition
pathway more likelyo Might be more reactive if the azlactone was
protonatedo The carbonyl carbon becomes more reactive
through resonance o The pKa of azlactone ~ 9 o If in the right conditions, azlactone could act
as a weak base
16
PROTONATED DIRECT ADDITION PATHWAY
17
PROTONATED DA SOLUTION PHASE RESULTS
18
Protonated Azlactone
PDA-complex solution
PTS1
PDA-Intermediate B
M-Intermediate
TS3
Product
-25.00
-20.00
-15.00
-10.00
-5.00
0.00
5.00
10.00
15.00
20.00
25.00
∆E
(kca
l/mol
)
PROTONATED DIRECT ADDITION CONCLUSIONS
oThe energy difference went down considerably from the azlactone to the Protonated DA-Intermediate B
oAt the moment, all intermediates are lower in energy then the protonated azlactone except the M-IntermediateoIf the azlactone is protonated the reaction could proceed without the ketene
19
ACYLIUM ION
20
o The protonated azlactone is in resonanceo Could lead to the acylium ion being formed
o Could the acylium ion play a part in the β-lactam formation?
ACYLIUM ION
21
o Way too high in energy for the Acylium Ion to form
o Unlikely to participate in mechanism
OTHER FACTORSo Substituents could help stabilize the ketene
22
Unsubstituted Relative Energy (kcal/mol)
Substituted Relative Energy (kcal/mol)
Azlactone 0 0
Münchnone 12.74 5.2
Ketene 19.71 *ketene-imine complex 22.1 4.03
M-Intermediate 2.76 2.96
Product -18.3 -19.75
*Calculation still running
CONCLUSIONSo It was found that the energy difference is too high at room
temperature to form ketene or münchnone from azlactone
o It is not more energetically favored if the imine was added directly to the azlactone
o A key intermediate could not be located for direct addition of the Imine to the azlactone
o It is found that if the azlactone is protonated, then the reaction proceeds without any high energy intermediates
23
FUTUREo Protonated Direct Addition Pathway
o M-Intermediate and 3rd Transition Stateo Substituent Effectso Find the ∆G for the münchnone pathway TS1
and TS2
24
ACKNOWLEDGEMENTS•Dr. Joe•Dr. Willoughby•Ripon College Chem department•MU3C •NSF-MRI Grant #1039925•Ripon Center for Social Responsibility•Family & Friends
25
REFERENCESCremonesi, G.; Dalla Croce, P.; La Rosa, C. HCA, 2005, 88, 1580–
1588Cremonesi, G., Dalla Croce, P.; La Rosa, C. Tetrahedron, 2004, 60,
93–97Dalla Croce, P.; Ferraccioli, R.; La Rosa, Concetta, Tetrahedron,
1995, 51, 9385-9392Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. Rev. 2007, 36,
1432-1440Khasanov, A. B.; Ramirez-Weinhouse, M. M.; Webb, T. R.;
Thiruvazhi, M. J. Org. Chem., 2004, 69 (17), 5766–5769Sharma, V.; Tepe, J. J.; Org. Lett., 2005, 7(22), 5091-5094Venturini, A.; Gonza, J. J. Org. Chem. 2002, 67 (25), 9089–9092
26