epoxidation

epoxide

olefin

epoxide

Highly reactive because of its structure

Often used as synthetic intermediate
compound to make something

Prilezhaev Epoxidation
+

+
Lower pKa, higher reactivity

Electron-rich alkenes are more reactive

mCPBA(meta-Chloroperbenzoic acid) are widely
used
(relatively safe, and high reactivity)
Lecture material,
http://www.organic-chemistry.org/chemicals/oxidations/meta-chloroperbenzoicacid.shtm

Alkenes reactivity

Lecture material,

features
In epoxidation
Stereochemistry of olefin maintained
Rate insensitive to solvent polarity
(concerted mechanism, no ionic intermediates)
Less hindered face of olefin attacked
mCPBA
CH2Cl2

R = H 20 min
R = CH3 24 h

99%
<10%

1%
90%

Lecture material

Exocyclic olefins
Depends on hinder or not
RCOOOH

Less stable product

Less hindered face

Lecture material

Henbest epoxidation
If compounds has OH (allylic alcohol)
RCO3H

91%
If OH = OAc , 57%

9%
43%

Lecture material
Henbest,H.B.; Wilson, R.A. J. Chem. Soc. 1957, 1958-1965.

Butterfly transition state

Mechanism: butterfly
mechanism of Bartlett, involving
the interaction of the nucleophilic
alkene with the electrophilic
peracid.
Bartlett, P.D. Rec. Prog. Chem. 1950, 11, 4751.

If OH
Hydrogen bond works to fix
likely to come same face
Lecture material
Henbest,H.B.; Wilson, R.A. J. Chem. Soc. 1957, 1958-1965.
Freccero, M.; Gandolfi, R.; Sarzi-Amad, M.; Rastelli, A. J. Org. Chem. 2000, 65, 2030.

Conformation affect

Lecture material

Metal catalyzed epoxidation

More powerful directing effects
Rate acceleration up to 1000 x
tBuOOH
VO(acac)2
83%

0%

100%

May be used to differentiate between an

allylic alcohol and an unactivated olefin.
Lecture material

Metal catalyzed epoxidation

Chemo/regioselectivity
VO(acac)2
T-BuOOH
benzene

98% isomeric purity

VO(acac)2
T-BuOOH
benzene

95% isomeric purity

Lecture material
Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136.

Catalytic cycle
VO(acac)2 : Vanadyl acetylacetonate
tBuOOH

tBuOH

Ligand exchange

Lecture material

Epoxidation of acyclic allylic alcohol

Lecture material

Sharpless asymmetric epoxidation

D-()-diethyltartrate
(S,S)

Ti(OiPr)4
tBuOOH

70-90% yield
>90% ee

L-(+)-diethyltartrate
(R,R)
Lecture material
Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I. Ed.; Wiley-VCH: New York; 2000.

Mnemonic model

Point by left hand , thumbOH

Knucklenegative
Palmpositive
Lecture material

mechanism

Lecture material, Koskinen, Ari. Asymmetric synthesis of natural products

Commercial synthesis of -blocker

B-blocker medicine for nerve
Ar(Aryl)OH, NaH

1)SAE
2)NsCl
Ns:2Nitrobenzenesulfonyl

iPrNH2

(S)-propranolol
Lecture material

Kinetic resolution
Slow

fast

Kinetic resolution
Separating racemic mixture by reaction speed
Sharpless, K. B., et al. J. Am. Chem. Soc. 1981, 103, 6237.

Kinetic resolution
(+)-DIPT
Ti(Oi-Pr)4

CH2Cl2

fast

98%

2%

Kfast/Kslow = 100

(+)-DIPT
Ti(Oi-Pr)4

CH2Cl2

slow

38%

62%

At the result
> 96% ee

>96% ee

Sharpless, K. B., et al. J. Am. Chem. Soc. 1981, 103, 6237.

Jacobsen epoxidation
Doesnt need OH

cis

trans

cis

O is above the Mn

Lecture material
Koskinen, Ari. Asymmetric synthesis of natural products
Jacobsen Epoxidation
Jacobsen, E.J. Tetrahedron 1994, 50, 4323.

Katsuki epoxidation
Similar compound

Lecture material
Koskinen, Ari. Asymmetric synthesis of natural products

Stepwise mechanism

Lecture material

DMDO (Dimethyl Dioxirane)

High reactivity at mild condition
Good for nature, easily removed
But sometimes react with heteroatoms or
hydroxyl groups
Can react with tertiary carbon atom

acetone
Lecture material
http://www.chem-station.com/odos/2009/08/-oxidation-with-dioxirane.html (not English)

DMDO reactions

Bn : benzene
Lecture material

Shi epoxidation
3-substituted C=C (2-cis, trans in some papers)
Catalysts break down under acid condition

dioxirane
Lecture material

Using enzymes

Phillip A. Lichtor and Scott J. Miller ,Nat Chem. 2012 Dec; 4(12): 990995.
Published online 2012 Oct 14. doi: 10.1038/nchem.1469