Polar Effects in Radical Reactions - Michigan State University · Polar Effects in Radical...

Polar Effects in Radical Reactions

Partha Nandi

HHH

Department of ChemistryMichigan State University

Objectives and Motivations

• Origin of polar effects in organic radical reactions

• Improve the ability to design experiments

• Find new ways to expand the scope of known reactionmechanisms to address reactivity-selectivity problems

Outline• The polar-effect in traditional organic reaction mechanisms.

Is a polar-effect anticipated for radical reactions?

• Factors responsible for polar-effect in radicals

(1) Geometry and Orbital interactions (2) Non-perfect synchronization of TS(3) Solvent polarity and viscosity (“cage effect”)

• Specific examples and illustrations

• Conclusions and remarks

Outline

• Polar-effects in traditional organic reaction mechanismsIs a polar-effect anticipated for radical reactions?

• Factors responsible for polar-effects in radicals

(1) Geometry and Orbital interaction effects(2) Non-perfect synchronization of TS(3) Solvent polarity and viscosity (“cage effect”)



Polar Effects in Stereo-type Organic Reaction Mechanisms?

I. SN1 Case II. SN2 case

R-X + Y(s)n

R (s)n

TS1TS2

R-Y + X(s)n

More polar solvent

Less polar solventR

R-X + Y(s)n

X RY

R-Y + X(s)n

More polar solvent

Less polar solvent

YX

Same notion works for E1 and E2 mechanism

“Theoretical and Physical Principles of Organic Reactivity”, Pross, A. John Wiley & Sons, Inc. 1996.

Summary of the Solvent Polarity Effect

Large DecreaseAnnihilationY–+ R–X--> Y– δ…R…X+δ

Small DecreaseDispersionY– + R–X--> Y– δ…R…X–δ

Small DecreaseDispersionR–X+δ−−> R+δ…X–δ

Large IncreaseSeparationY+ R–X-->Y+ δ…R…X–δ

Large IncreaseSeparationR–X-->R+δ…X–δ

Effect of polarity increase on reaction rate

Nature of Charge Type

Reaction Type


Outline• Polar-effects in traditional organic reaction mechanisms a

brief overview. Is polar-effect anticipated for radical reactions





Geometry and Orbital Polarization: Methyl Radical

H3 M.O C A.Os

2pz 2px 2py

MOs for Me

σ

π π

π∗ π∗

σ*

nb

(Not to scale)

E


Energy Changes on Pyramidalizations

• ESR coupling

• Computations

• MO picture

• Polarization proportionalto dipole moment

CF3

CHF2

CH3

CH2F

E

0 4 8 12

ω, degrees

C

ω=α−90

α

Zheng, X.; Phillips, D. L. J. Phys. Chem. A. 2000, 104, 1030.Cramer, C. J. J. Org. Chem., 1991, 56, 5229.

Rozum, I.; Tennyson, J. J. Phys. B. 2004, 37, 957.

MO for Pyramidalization

C XX X

SOMO - filled lone pairs repulsion

pyramidalization helps to stabilize the SOMO

by the interaction of p-σ∗

• Geometrical flexibility of radicals can be rationalized from MO.

• Vibrational polarizability

Vibrational Polarization & Pyramidalization

“Solvation of the Methyl radical and Its implication” Stratt, R. M.; Desjardins, S. G. J. Am. Chem. Soc. 1984, 106, 256.

Vibrational polarization turning onPyramidal inversion

E

Role of Substituents on SOMO

X typeNR2, ORCl, Me, I

Z typeCOR, CN, SOR,NO, NO2

C typeC=CH2Ph, etc

E

n or filled σ

"C" centeredSOMO

π

π∗π∗

orbital

“Orbital Interaction Theory in Organic Chemistry’” 2001, 2nd Ed, Rauk, A. Wiley & sons. Inc.,

Outline

•Polar-effects in traditional organic reaction mechanisms a brief overview. Is polar-effect anticipated for radical reactions?



•Specific examples and illustrations

•Conclusions and remarks

Hammond’s Postulate and Limitations• Hammond’s postulate - what does it tell us?

• Instant idea on nature of TS

• Fails to give an accurate location of TS

• Does not consider multiple degrees of freedomsalong the reaction coordinate

R

P

R'P'

E

RC

• Modern version and extension of Hammond’s postulate - “The Principle of Nonperfect Synchronization”

Bernasconi, C. F. Acc. Chem. Res. 1992, 25, 9.

Nonperfect Synchronization• ------- hypothetical resonance developments synchronous with charge transfer

• ____ actual situation where resonance development lags behind charge transfer

• Smaller degree of resonance stabilization of TS leads to a higher barrier

“The Principle of Nonperfect Synchronization: More than a qualitative concept?”Bernasconi, C. F. Acc. Chem. Res. 1992, 25, 9.

“Nonperfect Synchronization” & “Imperfect TS”

• Reaction potential energy surface is multi-dimensional

• Bond breaking and formation

• Solvation and desolvation

• Delocalization and localization of charge

• Unequal progress at the TS, termed as “Imperfect TS”

“The Principle of Nonperfect Synchronization: More than a qualitative concept ?” Bernasconi, C. F. Acc. Chem. Res. 1992, 25, 9.

Outline• Polar-effects in traditional organic reaction mechanisms a

brief overview. Is polar-effect anticipated for radical reactions?


(1) Geometry and Orbital interaction effects(2) Non-perfect Synchronization of TS(3) Viscosity (“cage effect”) and solvent polarity



Viscosity EffectsFate of diffusive cage pair

( R/R )cage

R-R

R-H + R-H

kdisp

kdim

R + Rkdiff

k-diff

kdisp/ kdim

for t-Buradical

η (cP)0

5

5.5

6.5

1 2 3

for 2-Propyl radical

•Variation of kdisp/kdim with viscosity

•Shape matters: t-Bu radical an ellipsoid, isopropyl “V” shaped

•Similar trend observed for polar radicalreactions

Shuch, H. H.; Fischer, H. Helv. Chim. Acta 1978, 61, 2463.Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.; Serravalle, M.; Giordano, C. J. Org. Chem. 1987, 52, 730.

Polar Solvent Decelerating the Rate

N

O

CH2

+ N

O

Solvent

TEMPO

9.5 + 0.7Acetonitrile6.23 + 3Tetrahydrofuran5.17 + 2Chlorobenzene4.18 + 1Benzene3.41 ± 2Cyclohexane2.

50 + 1.5n-pentane1.

kT X 10-7, M-1 s-1SolventEntry

Beckwith, A. L. J.; Bowry, V. W.; Ingold, K. U J. Am. Chem. Soc. 1992, 114, 4983.

Outline

• Polar-effects in traditional organic reaction mechanisms a brief overview. How do we think about radicals?


(1) Solvent polarity effects(2) Internal pressure and viscosity (“cage effect”)(3) Non-perfect synchronization of TS(4) Geometry and Orbital polarization



Early Examples of Polar Radical Reactions

+ Br2hv

CH2 H Brδ−δ+

Br

Kim, S. S.; Choi, S. Y.; Kang, C. H. J. Am. Chem. Soc. 1985, 107, 4234.

R CO

O O R C OO

OC(Me)3 R + CO2 + tBuOheat

Barlett, P. D.; Hiatt, R. R. J. Am. Chem. Soc. 1958, 80, 1398.

Specific Examples and Illustrations

(1) NO catalyzed oxidations

(2) MGM, ICM and MCM catalyzed isomerizations

(3) Silyl enol ether mediated 5-exo and 6-endo cyclizations,and general approach to 4-allyl oxyl radical cyclizations

Aerobic Oxidation of Benzyl Alcohols by NHPI or PINO

O2PhCH(OOH)OH

PhCH(OH)2PhCHO

N

O

O

O H-CHOHPh+ N

O

O

O H CHOHPh+– δ δ

N

O

O

O H-PhCHOH

PhCHOH PhCH(O)OH

-H2O

– OH

H atom abstraction

Minisci, F.; Punta, C.; Recupero, F.; Fontana, F.; Pedulli, G. F. J. Org. Chem. 2002, 67, 2671.Annunziatini, C.; Gerini, M. F.; Lanzalunga, O.; Lucarini, M. J. Org. Chem. 2004, 69, 3431.

Structural Modifications in PINO

N

O

O

O

R1

R2

R3

HO+

HON

O

O

OH

R1

R2

R3

+

PINO NHPI

-0.54HMeOMeO5

-0.60HHMeO4

-0.68HHH3

-0.69HHF2

-0.70HMeOCOH1

ρR3R2R1Entry

Annunziatini, C.; Gerini, M. F.; Lanzalunga, O.; Lucarini, M. J. Org. Chem. 2004, 69, 3431.

Electronic Perturbation & Implications

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

-0.9 -0.5 -0.1 0.3 0.7

p-OMe

p-Me

p-CN

m-NO2m-CN

m-Cl

m-OMe

p-Clm-Me

p-NO2

σ+

log(kx/kH)

OH

X

O

X

H

PINO

Hammet plot whereρ= – 0.69

Minisci, F.; Recupero, F.; Cecchetto, A.; Gambarotti, C.; Punta, C.; Faletti, R.; Paganelli, R.; Padulli, G. Eur. J. Org. Chem. 2004, 109.

Barrier Height for H Atom Abstraction

N

O

O

O H-CHOHPh+ N

O

O

O H CHOHPh+– δ δ

N

O

O

O H-PhCHOH

664949(O=CH)2NO

928683(O=CH)N(CH3) O

927978(O=CH)NHO

115109103H2NO

CCSD (T)-ccpVDZ/B3LYP/6-311++G

B3LYP/6-311++G

B3LYP/6-31G (kJ mol-1)

>NO radical

Hermans, I.; Vereecken, P. A.; Jacobs, A.; Peters, J. Chem. Commun., 2004, 1140.

Potential Energy Surface Topology

-40

-30

-20

-10

0

10

20

30

TS/Saddle point

Pre-reaction complex

Post reaction complex

>NO + CH3OOH

>NOH + CH3OO

Reaction Co-ordinateZPE corrected Energy( kJmol-1)

E

(O=CH)2NO

Hermans, I.; Vereecken, P. A.; Jacobs, A.; Peters, J. Chem. Commun., 2004, 1140.

MO Picture for H Atom Abstraction

B B H-A

H-A

B H A

Energy (Not to scale)B-H

B-H A

A

“The stability of alkyl radicals”, Tsang, W. J. Am. Chem. Soc., 1985, 107, 2872.“Kinetics and Thermochemistry of CH3, C2H5, i-C3H7, Study of equilibrium of R + HBr”Russel, J. J.; Seetula, J. A.; Gutman, D. J. Am. Chem. Soc., 1990, 112, 1347.

Enthalpy Effect

N

OH

N

O

OHN

O

O

OH

O-H Bond Dissociation Energy (kcal/mol)

79.2 88.169.6

Minisci, F.; Recupero, F.; Cecchetto, A.; Gambarotti, C.; Punta, C.; Faletti, R.;Paganelli, R.; Padulli, G. Eur. J. Org. Chem. 2004, 109-119.

Fundamental Steps of TEMPO CatalyzedOxidations

RN

RO

RN

RO R O O R O O

R H + O X R HOX+

NO

R

NOR

NO

2NO

NOH

+H

NOH

NO

O2

Mn(II), Co(II)

NO

OH

NOH

O + H +

Minisci, F.; Recupero, F.; Cecchetto, A.; Gambarotti, C.; Punta, C.; Faletti, R.; Paganelli, R.; Padulli, G.Eur. J. Org. Chem. 2004, 109-119.

Polar Non-radical Mechanism?

NO

+ HOH

B

NHO O

H B

-BH

NOH

+ O

NO

+ HOH

-H

NO O

H

NOH

+ O

Minisci, F.; Recupero, F.; Cecchetto, A.; Gambarotti, C.; Punta, C.; Faletti, R.; Paganelli, R.; Padulli, G.Eur. J. Org. Chem. 2004, 109-119.



(2) MGM, MCM and ICM catalyzed isomerization

(3) Silyl enol ether mediated 5-exo and 6-endo cyclizations, and general approach to 4-allyl-oxyl radical cyclizations.

Polar Radical Pathway of MGM

HOOC

COOHHOOC

COOH

MGM orMethyleneglutarate-mutase

3-methylitaconic acid2-methyleneglutaric acid

XOOC

COOX

XO2C

CO2X

XOOC

COOX

X = H / R /

Newcomb, M; Miranda, N. J. Am. Chem. Soc. 2003, 125, 4080.

Potential Energy Profile Analysis

Tri-radical intermediate

HOOC

COOH

HO2C

CO2H

HOOC

COOH

12.1 12.1

8.6Energy (kcal/mol)

Reaction Co-ordinate

12.1

Reactant


Apparent Paradox in MGM Catalyzed Isomerization

• Rate Constant for cyclization estimated to be 2000 s-1

• Estimation is coupled with partioning of intermediate cyclopropyl carbinyl radical, overall rate constant is estimated to be 10E-3 s-1

,

• Unusual mechanism is possibly involved with polar effects operative

HO2C

CO2H

HO2C

CO2HHO2C

CO2H

Scheme A:

O2C

CO2

O2C

CO2

O2CCO2

Scheme B:


Catalytic Mechanism Devoid of 3-exo Cyclization

O2C

H

CO2

H

O2C CO2

H H

CO2

O2CO2C

CO2

HHH

O2C

CO2

HH H

HMethylene-glutarate-Mutase

• Fragmentation results formation of a radical that is stabilized by a through space polar-captodative orbital interactions.

Solvent Polarity Effect and Limited Acid Catalysis

GS

OCoA G O

S CoA G SCoA

O

G= CO2H (MCM catalyzed rearrangement)G=CH3

(Isobutyryl CoA Mutase catalyzed rearrangement)

PhPh

PhSe

X

OPhPh X

OPhPh

OX

PhPh

X

OX

O

Ph

Ph

X

O

Ph

PhBu3SnH

X=H/Me/SEt

hv

Daublain, P.; Horner, J. H.; Kuznetsov, A.; Newcomb, M. J. Am. Chem. Soc. 2004, 126, 5368.

Solvent Polarity and Acid Catalysis

CF3CH2OH

AcOH

MeCN

CH2Cl2THF

Cyclohexane

Gasphase

ET(30)

logk

30 40 50 60 70 80

5

7

9

11

TFA(M)

kobs X 10-6

CH2Cl2

Hexane

A: Observed rate constant for reaction of 1st intermediateB: Rate constant of reactions of 1st intermediate in presence ofTFA in CH2Cl2 and in hexane


“Partial Protonated” radical

H2N CH C

CH2

OH

O

N

NH

PhPh

O

X

HO

O

CF3

Histidine• Catalytic role of His244 in the catalytic site of MCM catalyzed reaction• Mechanistic reconsiderations - Role of surrounding water in nucleophilicassistance

GNu OX

SCoA

X= or H

G Nu OX

SCoA+ G SCoA

Nu OX




(2) MGM catalyzed isomerization

(3) Silyl enol ether mediated 5-exo and 6-endo cyclizations,and general approach to 4-allyl-oxyl radical cyclizations

Cyclization of Silyl-enol Ether Radical Cations

OTBDMS OOTBDMS

6-endoO

I

O O

6-endo

+

O

5-exo

hv

hv, AIBN

Bunte, J. O.; Heilmann, E. K.; Hein, B.; Mattay, J.; Eur. J. Org. Chem. 2004, 3535.Curran, D. P.; Chang, C. T.; J. Org. Chem. 1989, 54, 3140.

Selectivity in 5-exo or 6-endo Radical Cyclization

+

5-exo2.0E-6

6-endo2.6E-6

ProcessRate Constant

• No apparent preference in the formation of a tertiary vs a primary radical

• Can be explained in terms of assuming 5-exo process reversible, besides suitable thermodynamics

Bunte, J. O.; Heilmann, E. K.; Hein, B.; Mattay, J.; Eur. J. Org. Chem. 2004, 3535.

Steps Involved in photo-cylization ofsilyl-enol ether

O O

hv

-e

SiR3 SiR3 Nu O

OO

Mesolytic

Si–O cleavage

6-endocyclization

H atom abstraction


Geometrical Changes Induced by One Electron Oxidation

O Si

-e

O Si

a(C-O-Si):136.1(+8.4)

a(O-Si-C):100.8(-8.2)

d(C-C):1.42(+0.08) A

d(C-O):1.28(-0.08) Ad(Si-O):1.80(+0.11) A

o

o

o

• Weakened Si-O bond leads to a facile SN2- like substitution induced by solvent or other nucleophile


Selectivities in Five vs Six-membered Photo-cyclizations of Silyl-enol Ethers

Case I

OTMS O O O

H

H HHH H

H H+ +

Case II 31%41% 28%

OTMSHH

H H

HH

+

O O

90% 10%


Calculated Energy Profile for Case I

OTMS O O O

H

H HHH H

H H+ +

O

H OH O

HH O

OHH

0.0

Energy

-1.15

-2.49 -8.39

-9.40

+21-25

+17.9

0.0

+19.72

+21-25

kcal/mol

NOT TO SCALE


Potential Energy Profile for Case II

OTMSHH

H H

HH

+

O O

O

OHH OHH

OHOH

2.79 2.79

0.0

-7.46-6.16

Energy

23.5

19

2522

Numbers in kcal/mol


How General Are These 5-exo vs 6-endo Selectivities?

• Substituents that increase in HOMO coefficient along C-5 lead to more 6-endo product

• Substituents that can not cause the increase in C-5 HOMO coefficient lead tomore 5-exo product

R1,

H H

H Me

H C(Me)3

H Ph

Me H

Me Me

Me C(Me)3

5-exo/6-endo

98/2

69/31

46/54

7/93

98/2

82/18

37/63

R2

O MeR2R1 OR1

R2 O

HR2

R1

H-YY H-Y Y

6-endo5-exo

Hartung, J.; Kneuer, R.; Rummey, C.; Bringmann, G. J. Am. Chem. Soc. 2004, 126, 12121.

Reaction Model for Analysis

OR2

O O

O

R2

O

R2

OR2 OR2

OR2 O

R2

R2R2O

R2

O R25-exo-chair

5-exo-boat

6-endo-chair

6-endo-boat

Starting geometry TS cyclized radical

alkoxy radical

Hartung, J.; Kneuer, R.; Rummey, C.; Bringmann, G. J. Am. Chem. Soc. 2004, 126, 12121.

A True Ion or A Polar Radical ?Cl

PhN

N

hv Cl

Ph

CCl4Ph

Cl Cl+ CCl3

PhPh

Cl Cl

Cl ClPh

ClCl Cl

Cl ClCl

ClCl Cl

Cl Cl

Dimerizations

Ph

ClCl

PhPhCl

Cl Ph

++

+

Ph

ClCl CCl3

δ+ δ−

Ph

ClCl CCl3

Ph

ClCCl4

Ph

ClCl CCl3

Ph

Cl Cl

- Polar atom transfer

- Ylide

- Dissociative electron transfer

Jones, M. B.; Jackson, J. E.; Soundararajan, N.; Platz, M. S. J. Am. Chem. Soc. 1988, 110, 5597.

Answer

1.1E8PhMeCCl3CN(pOMe)-PhCCl

4.0E8MeCNCCl3CNPhCCl

8.4E8PhMeCCl2(CN)2PhCCl

1.4E7PhMeCCl3CNPhCCl

3.8E4MeCNCCl4PhCCl

k (M-1 s-1)solventCl donorcarbenePh

ClCl CCl3

δ+ δ-

Ph

ClCl CCl3

Ph

ClCCl4

Ph

ClCl CCl3

Ph

Cl Cl

1

2

3

Substituting Cl by CN:

• Expected to retard the rate for ylide mechanism (2)

• Accelerate the rate for polar atom transfer (1 & 3)

Jones, M. B.; Jackson, J. E.; Soundararajan, N.; Platz, M. S. J. Am. Chem. Soc. 1988, 110, 5597.Jones, M. B.; Maloney, V. M.; Platz, M. S. J. Am. Chem. Soc. 1992, 114, 2163.

Conclusions & Remarks1. Polar effect in radical reactions originates from a polar TS that is often

achieved through, electronic perturbation (from Orbital interactions,medium polarity etc) Geometrical changes and Nonperfect synchronization (NPS)

2. NO catalyzed oxidations, MGM, MCM and ICM catalyzed isomerizations,and radical cyclizations were shown as representative examples where

polar effects were found to be operative

3. Distinguishing a polar radical TS and completely ionic TS can often be challenging

4. Higher level computations can help in understanding polar effects in radical reactions

Diels-Alder Reaction in Water

• Enhanced hydrophobic interaction in the TS

• Internal Pressure

• Higher polarizability of TS

• Increased Endo selectivity

• Problems of solubility & possible remedy by tryingcosolvents, constrained medium (zeolite, micellarmedium etc).

Bresslow, R.; Rideout, D. J. Am. Chem. Soc. 1980, 102, 7816.Otto, S.; Engberts, J. B. Pure Appl. Chem., 2000, 7, 1365.

EDG

EWG

+

EWGEDG

Acknowledgement1. Parents - Asim K Nandi & Parbati Nandi

2. Dr. Jackson, Dr. Dye, Dr. Wagner, Dr. Wulff

3. Michael (SiGNa)

4. Labmates - Simona, Misha, Andrea, Jennifer, Tulika, Karrie, and Kaushik

5. Friends - Sampa, Supriyo, Sanjukta, Aparajita,Sam, Parul, Bani, Brad

6. Roommate - Neil

Typical Dipole-Moments of Radicals

2.52010HOO0.00103N3

0.80287HCC

1.25684ClCHCHCH2

2.87736ClCH2CHCH3

2.38577CH2CHCHOH0.07868CH2CHCH2

0.43937CH3CH2

0.00615CF3

0.00141CH3

Dipole Moments in DebyeSpecies

http://www.colby.edu/chemistry/webmo/mointro.html

Pyramidalization Effects on Energy and Dipole Moment

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

Measure of Solvent Polarity• Energy of charge transfer as a intramolecular (ET ) or intermolecular (Z) process

Z Scale

N

Ph

PhPh

PhPh

O

ET Scale

N

COOCH3

CH2CH3

IN

COOCH3

CH2CH3

Ihv

Reichardt, C. Chem. Rev. 1994, 94, 2319.

Catalytic Mechanism of MCM CatalyzedIsomerization

CoASO

HH

CO2

CoASO

HCO2

HCO2

CoASO

CO2

H

CoASO

CoASO

HH

CO2H

CoASO

HH

CO2H

H

MO of NO

σ∗

σ 2s

σ∗1s

σ 1s

π 2p

π∗ 2pπ∗ 2p

π 2p

σ 2p

σ∗ 2p

E 2s

NO

Captodative Effects

CN OMeOMe

NC

16126

Barrier of C-C rotation in kcal/mol

Factors Responsible For the Selectivities

• Rate constants for cyclizations

• Life-time of the radical intermediates

• Length of the new bond formed (Beckwith-Houk model)

• Endothermicity or exothermicity

• Steric or geometrical optimization


Calculated Charge and Spin Distribution

O Si O Si O

0.010.15+0.18

0.52

0.20

0.690.18

-0.040.03

0.030.03

0.03

+0.29

charge spin spin

0.05

-0.05

TMS:+0.17

+0.17


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