Loras CollegeMatthew Busta

Erin Dahlke Ph.D.

The Effect of Substituent Groups on the Energetics of Phenyl Shifts

Flavonoid Background Flavonoid backbone (left)

shows the general structure of all flavonoids, with over 8000 unique compounds known 1

Variations seen in oxidation of C ring and position of B ring (e.g. Isoflavone and Flavanol) as well as other groups attached to the backbone

4

A C

B

2

3

Backbone

Isoflavone

Flavanol

(1)Pietta, P. Flavonoids as Antioxidants. J. Nat. Prod. 2000, 63, 1035-1042.

Obtained by humans via consumption of plants and their derivatives

Consumption has been linked to health benefits such as antiallergenic, antioxidant, antimutagenic, and anticancer among others

Concentrations and types of flavonoids vary in plants, as do their effect in humans

Many of their effects have been linked to free radical scavenging ability and signaling ability2,3

(2)Lu, J.; Papp, L. V.; Fang, J.; Rodriguez-Nieto, S.; Zhivotovsky, B.; Holmgren, A. Inhibition of Mammalian Thioredoxin Reductase by Some Flavonoids: Implications for Myricetin and Quercetin Anticancer Activity. Cancer Research 2006, 66, 4410 -4418. (3) Nair, H. K.; Rao, K. V. K.; Aalinkeel, R.; Mahajan, S.; Chawda, R.; Schwartz, S. A. Inhibition of Prostate Cancer Cell Colony Formation by the Flavonoid Quercetin Correlates with Modulation of Specific Regulatory Genes. Clin Diagn Lab Immunol 2004, 11, 63-69.

Flavonoid Metabolism4

Metabolized by P450’s (left) Multiple P450’s can

metabolize a given flavonoid, with some more active than others

Ingested flavonoids may be converted to more biologically active derivatives

(4) Kagawa, H.; Takahashi, T.; Ohta, S.; Harigaya, Y. Xenobiotica34 (2004): 797-810.

R = H Flav anoneR = OCH3 4'-Methoxyflav anone

3

2

4'

-H2O

R = H Flav oneR = OCH3 4'-Methoxyflavone

4'

.

R = H 2,3-trans-FlavanonolR = OCH3 2,3-trans-4'-Methoxyflav anonol

2

4'

3.

Isoflav one

-H2O

O

OC ·H

H H

HO

O

O H O

O

C ·H

OH

Mechanism proposed by Kagawa et al. for the metabolism of flavanone

This project looks at phenyl shift step in mechanism

R = H Flav anoneR = OCH3 4'-Methoxyflav anone

3

2

4'

-H2O

R = H Flav oneR = OCH3 4'-Methoxyflavone

4'

.

R = H 2,3-trans-FlavanonolR = OCH3 2,3-trans-4'-Methoxyflav anonol

2

4'

3.

Isoflav one

-H2O

O

OC ·H

H H

HO

O

O H O

O

C ·H

OH

Breinholt et al. suggest that metabolites may have different activities than parent flavonoid4

Understanding mechanism will allow for more targeted and effective use of flavonoids

Kagawa et al. found that when R=H the phenyl shift occurs, but not when R=OCH3

Why does methoxy group inhibit phenyl shift?

Previous work proposed that keto-enol tautomerization plays a role in phenyl shift

Has shown that enol form is much more stable for all substituents than the keto form after phenyl shift

Current Status Product and reactant structures of

Kagawa mechanism have been optimized

Not all intermediate and transition state structures have been optimized When attempted, guess structure

optimizes to reactant or product structure

This project looks at substituent effect on phenyl shift to allow for a better guess to be made

Methods Two systems used to model

radical phenyl shift Biphenyl radical Vinyl radical

DFT calculations done using Gaussian 03 with computational methods BLYP, B3LYP-DZ, and B3LYP-TZ

Biphenyl Radical with CN group

Vinyl Radical with CN group

Para substituted with CH3, Cl, CN, H, NO2, OCH3 and OH Chosen because of electron donating

and electron withdrawing effects

Each of these substituents have inductive and resonance effects affecting the overall molecule

Results

Figure 1. Correlation of change of free energy during phenyl shift to substituent group using B3LYP-TZ.

Figure 2. Angle at site of phenyl shift using B3LYP-TZ.

Conclusions Figure 1 shows good correlation between

change in free energy and para Hammett parameters Will attempt to use other Hammett

Parameters to find a better correlation as well as possibly get insight on inductive and resonant effects

Figure 2 shows angle in intermediate state is not the 60° used in original guesses to obtain optimized structures

Figure 2 also shows that substituent plays a role in the angle created by the phenyl shift at the transition state

Acknowledgements Bernard and Arlene Gillis Loras College Midwest Undergraduate Computational Chemistry

Consortium (MU3C)