IS KETENE AN INTERMEDIATE IN THE ADDITION OF IMINES TO AZLACTONE TO FORM BETA-LACTAM?

CAROLINE KORDESDR. JOSEPH SCANLONDR. PATRICK WILLOUGHBYRIPON COLLEGE

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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 

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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

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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

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BETA-LACTAM SYNTHESISo One common synthesis

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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

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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

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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

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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

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MÜNCHNONE PATHWAY

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o The mechanism found

SOLUTION PHASE RESULTS∆

E(k

cal/m

ol)

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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

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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

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DIRECT ADDITION PROPOSED PATHWAY

~H+

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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

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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

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PROTONATED DIRECT ADDITION PATHWAY

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PROTONATED DA SOLUTION PHASE RESULTS

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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

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ACYLIUM ION

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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

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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

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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

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FUTUREo Protonated Direct Addition Pathway

o M-Intermediate and 3rd Transition Stateo Substituent Effectso Find the ∆G for the münchnone pathway TS1

and TS2

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ACKNOWLEDGEMENTS•Dr. Joe•Dr. Willoughby•Ripon College Chem department•MU3C •NSF-MRI Grant #1039925•Ripon Center for Social Responsibility•Family & Friends

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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

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