HYDROPHOBIC AND ANTIHYDROPHOBIC EFFECTS

ON ORGANIC REACTIONS

Symposium in Honor of

Mike Wasielewski

Ronald Breslow

Columbia University

Some Diels-Alder Reactions in water solution

1. Faster in water than in other solvents.

2. Even in a case in which reaction is faster in isooctane than in methanol.

3. Reaction speeds with additives that increase the hydrophobic effect (LiCl) but slows with an antihydrophobic additive (guanidinium chloride).

4. More selective for endo addition in water, and ON WATER.

Selective Diels-Alder Reactions in Aqueous Solutions and Suspensions

R. Breslow, U. Maitra, and D. Rideout Tetrahedron Lett. 1983, 24, 1901-1904

Abstract: Diels-Alder reactions show high endo/exo selectivities in aqueous suspensions

“Even with a considerable layer of “neat” diene-dienophile solution the selectivities suggest that much of the reaction occurs in or at the

water phase. This is consistent with our rough rate measurements.”

“Thus water as a medium for Diels-Alder reactions, and other processes, is of practical interest even with poorly soluble substrates.”

Hydrophobic Effects on Simple Organic Reactions in Water

R. Breslow, Acts. Chem. Res. 1991, 24, 159-164

Interestingly, a high preference for endo addition was found even with

suspensions in which the cyclopentadiene was over 90%

undissolved.

Selectivity Produced by Hydrophobic Packing

of Reagents and Substrate in Water O

O

O3SOO

O3SO

O

O3SO

HOH

OHH

Li+ RBH3-

H2O+

A B

A:B ratio

R D2O 4M LiCl/D2O 1:1 CD3OD/D2O

H 13:87 14:86 10:90

Ph 60:40 69:31 32:68

C6F5 78:22 85:15 46:54

Mark R. Biiscoe, Christopher Uyeda, and RBOrg. Lett. 2004, 6, 4331-4334

Hydrophobic packing is not permitted in peracid transition state.

Hydrophobic packing is permittedin dioxirane transition state.

Considerations in Choosing a Hydrophobic Oxidant: T.S. Geometry

Peracid Dioxirane

Houk, K. N.; Liu, J.; DeMello, N. C.; Condroski, K. R. J. Am. Chem. Soc. 1997, 119, 10147-10152

OO

H

OO O

Or

O

Considerations in Choosing a Hydrophobic Oxidant: Stability of the Reagent

Not isolatable -- Formed in situEpoxidation by oxone can occur

(accelerated in H2O)Potential for Bayer-Villager oxidation

Dioxiranes Oxaziridiniums

Isolations are precedentedNo Bayer-Villager oxidationVery similar to dioxiranes in T.S. of epoxidation (spiro and highly synchronous)

Biscoe, M.; Breslow, R.. J. Am. Chem. Soc. 2005, 127, 10812-10813

Ar

ON

Ar

ON

Ar

OONMe3

N

O

BF4

N

O

BF4

Hydrophobically-Directed Selective Epoxidations

N

O

BF4

OO

Oxaziridinium 1 Oxaziridinium 2 DimethyldioxiraneDMDO

Ar O

O

O

O

NaHCO3/H2O Ar O

O

O

OOOOxidant

A B

N

O

Ph

BF4

Product ratio of A:B with G‡ (kcal/mol) in parentheses

O

O

Oxaz. 1 DMDO

Phenyl

4-CF3-Phenyl

2-Naphthyl

96.5:3.5 (-1.967) 98.1:1.9 (-2.339)

84:16 (-0.983) 92.7:7.3 (-1.507)

98.7:1.3 (-2.568) 68:32 (-0.447)

99.7:0.3 (-3.443)

Ar Oxaz. 2

99.9+:0.1 (-4.096) 92.0:8.0 (-1.448)

66:34 (-0.393)

22:78 (0.751)

4-CF3-Phenyl(1:1 H2O:iPrOH)

54:46 (-0.022) 69:31 (-0.474) 22:78 (0.751)

99.8:0.2 (-3.684)

Hydrophobically Undirected Epoxidations

O

O

O

ONa

OH

F

F

F

F

O

OOHMg

2

O

O

O

O

OH

Mg MonoperoxyphthalateMMPP

PerfluoroperoxyphthalatePFPP

Peracetic AcidPAA

O

O

Ar O

O

O

O

NaHCO3/H2O Ar O

O

O

OOOOxidant

A B

Product ratio of A:B with G‡ (kcal/mol) in parentheses

MMPP PAA

Phenyl

4-CF3-Phenyl

2-Naphthyl

44:56 (0.155) 44:56 (0.155)

16:84 (0.983) 18:82 (0.879)

47:53 (0.071) 50:50 (0.000) 72:28 (-0.560)

93.3:6.7 (-1.562)

Ar PFPP

92.9:7.1 (-1.525) 93.2:6.8 (-1.552)

75:25 (-0.651)

35:65 (0.367)

The Benzoin Condensation

O OH

CN

OH

CNH

H

OHCN

OH

CNHOHO-

HHO O

O H

HCN

CNHO

Benzoin

r.d.s.-

Salt Effects on the Rate of the Benzoin Condensation in Water

RelativeRate

LiCl

LiClO4

Concentration

1. LiCl and LiClO4 effects indicate there is Hydrocarbon Overlap in the transition state.

How much? What is the exact shape of the transition state?

2. Can we use Quantitative Antihydrophobic Effects to learn?

3. For example, the effect of the addition of small amounts, 3.5 to 7 mole%, of EtOH.

Benzoin Condensation

Deducing TS Geometries from Solvent Effects

• Use antihydrophobic agents, but not salts.

• With 20% v/v ethanol, mole fraction is 7.2%,13 waters per ethanol.

• Partitioning of the alcohols into the benzaldehyde layer is negligible, < 3%.

• Thus the solubility effect is not perturbed by partitioning.

A cosolvent lowers the free energy of S, TS, and P

Go

Relating TS Geometries to Solvent Effects

• From the magnitude of the rate effect of a cosolvent compared with the effect on substrate solubility, we propose that we can say how much of the substrate hydrophobic surface becomes hidden from solvent in the TS.

• For example, if the rate effect and the solubility effect are the same in a bimolecular dimerization reaction, we propose that one full hydrophobic substrate surface becomes hidden in the TS, e.g. two half surfaces.

Solubilities

• From the relative solubility of a compound in water and in water with some added EtOH, we can see how EtOH lowers the free energy of the starting material.

• We find that the free energy change G°is proportional to the amount of exposed benzene surface in a solute.

Some Relationships

1. Solubilities are equilibrium constants. Therefore changes in solubilities with added antihydrophobic agents can be described as G°s.

2. We find that (S/So) for a solute with two exposed phenyl groups is (S/So)2 that for a solute with one exposed phenyl group. [So is the solubility in water, S is the solubility with added cosolvent]

3. Therefore the G°s are proportional to the amount of exposed phenyl surface.

Relative water solubility G°s with a few mol% EtOH

CH=O

1.000

O

O

1.9; 2.0

O

1.95; 2.0

1.0

H2N O

O OH

1.5

O

1.5; 1.7

N

H

O

2.0

Some Relationships

1.G°(2) = •G°(1)

therefore

2. log(S/S0)2 = •log(S/S0)1

3. log(k0/k) = h•log(S/S0)

where h is the fraction of the original hydrophobic surface that becomes inaccessible to solvent in the transition state (assuming no other effects).

Diels-Alder Dimerization of Cyclopentadiene

In the transition state, about one face of each cyclopentadiene (Cp) is covered, not in contact with the solvent, Therefore added EtOH will lower the transition state energy about as much as it lowers the energy of ONE Cp, so the rate will be lowered about as much as the solubility of one Cp is increased.

Finding: 92% of a Cp surface is covered in the TS.

2

Cp

Cp dimerization in water and 5, 10, 15 v/v% EtOH, 25°C

3.4

3.45

3.5

3.55

3.6

-1.46 -1.44 -1.42 -1.4 -1.38 -1.36 -1.34

y = 4.7931 + 0.92019x R= 0.98265

- log(k)

log(S)

Anthracenecarbinol with N-Methylmaleimide

1. Effect of EtOH additive: in the t.s. the maleimide covers ca. 27% of the anthracene surface.

2. In the product (from solubility change) only 10% is still covered.

NMe

O

OH

OH

OH

HN

CH3

O

OH

HN

Me

O OH

O

Transition State

+

0

0.5

1

1.5

2

2.5

3

0 20 40 60 80 100 120 140

The Effect of Ethanol on the Rate of the

Benzoin Condensation in Water

Water

10% EtOH

20% EtOH

y = -0.01990 + 0.022988x R= 0.99965

y = -0.01434 + 0.017529x R= 0.99833

y = -0.00548 + 0.012079x R= 0.99825

[PhCHO]

-1

-[PhCHO]

o

-1

(M

-1

)

Time (min)

CHO

O

OH

KCN

H2

O/EtOH

65

o

C

1

1.5

2

2.5

1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6

y = 0.048399 + 0.90051x R= 0.95915

Relative k

2

-1

Relative Solubility

CHO

O

OH

KCN

H2

O/ROH

65

o

C

Relative k

2

-1

vs Relative Solubility

Cosolvent Effects on Nucleophilic Reactions in Water

Sorting out effects on hydrophobic character from effects on ionic character

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0 20 40 60 80 100 120 140

The Effect of Ethanol on the Rate of

Nucleophilic Substitution in Water

Water

10% EtOH

20% EtOH

y = 0.00218 + 0.0063967x R= 0.99995

y = 0.01782 + 0.0052253x R= 0.99814

y = 0.01062 + 0.0039597x R= 0.99850

[PhNH

2]

-1

-[PhNH

2

]

o

-1

Time (min)

H

N

CO2

Na

NH2

CO2

Na

Cl

+

Na2

CO3

H2

O 25

o

C

N

ClNaO2C

MeHN

Me

CO2Na

k(20% EtOH/k(water) = 0.62

ClNaO2C CO2Na

-OO

Me MeO-

k(20% EtOH)/k(water)

1.05

0.60

How to Sort out the Many Effects?

1. Phenoxide ion nucleophile becomes MORE hydrophobic in the transition state.

2. Benzyl chloride electrophile becomes LESS hydrophobic in the transition state.

3. Chloride ion is less well solvated when EtOH is added.

4. Does the phenoxide ion stack with the benzyl chloride?

R. Breslow, Accts. Chem. Res. 3, 471 (2004)

DMSO as Cosolvent

1. In water (v/v) it is 50% more antihydrophobic than EtOH, judged by solubility increases.

2. It is more polar than EtOH. Dielectric constant: Water, 78.5; 20% v/v DMSO, 77.1; 20% v/v EtOH, 72.1.

3. Therefore the contrast in results with DMSO vs. EtOH can be used to sort out solvent polarity and hydrophobic effects.

Two Competing Displacement Reactions with the Same Reactants

and Same Leaving Groups

The contrast in cosolvent and substituent effects supports our conclusions on the geometry of the phenoxide reactions.

Displacements by Phenoxide and 2,6-Dimethylphenoxide Ions

O

+

Cl

CO2

- O

CO2

-

-20% EtOH3% slower

O

+

Cl

CO2

- O CH2

-

Me MeCO2

Me Me 20% EtOH6% faster

-

CH2

CO2-HO

Me

Me

+

formed only in water 20% EtOH35% slower

36% yield

64% yield

same total rate

O vs. C Alkylation of Phenoxide Ions by a Benzyl Chloride in

Water

StericHindrance?

O - O -

Me Me

100%36%

64%

O -

Me Me

46%

36%

18%

CH3

CH3

O -

H2C

CO2 -Cl

Oblique overlap in the para coupling of dimethylphenoxide with the benzyl chloride.

The reaction is comparably fast with a phenoxide carrying ortho ethyl groups, but isopropyl groups slow it greatly.

Oxygen coupling is almost unaffected by these substituents, as expected if oxygen alkylation does not involve hydrophobic overlap.

O vs. C Alkylation of Phenoxide Ions by a Benzyl Chloride in

Water

O -

Et Et

30%

25%

45%

R R

O

Bz

O -

Me2HC CHMe2

75%

9%

16%

isoPropyl Groups Block the Face of the Benzene Ring More

than they Block the Oxygen

O -

Me

Me

H

Hydrophobic Overlap is More Important than Steric Hindrance

CH3

CH3

H2C

CO2 -

Cl

- O

Alkylation of p-Substituted Phenoxide Ions in Water with p-

Carboxybenzyl Chloride

O -

X

X = Me 16% ortho alkylation

X = MeO, Cl, CN, NO2 only O alkylation

DMSO vs. EtOHp-carboxybenzyl chloride

rate effect of cosolvents in water

Nucleophile 20% EtOH 20% DMSO

• PhNHMe 0.75 0.60

• PhO - 0.97 1.0

• 2,6diMePhO- (O) 1.06 1.25

• “ (para-alk) 0.65 0.56

The Effects of Substituents and of Cosolvents Show that C-Alkylation By

a Benzyl Halide Involves Packing of Hydrophobic Surfaces, but O-

Alkylation Does NOT!

This Confirms our Previous Picture for Phenoxide O-Alkylation

With EtOH vs. DMSO and MeSMe vs. Cl- Leaving Groups,

and p-Nitrobenzyl vs. p-Carboxybenzyl, we also

Confirm that Benzylation of N-Methylaniline DOES Involve Hydrophobic Stacking of the

Phenyl Groups

Coworkers

Transition State Geometries

Kevin Groves

Uljana Mayer

Zhaoning Zhu

Richard Connors

Tao Guo

Atom Transfers Sherin Halfon

Mark Biscoe Eric Kool

Chris Uyeda Carmelo Rizzo

Uday Maitra

Darryl Rideout

Support: NIH, NSF, ONR