undergrad research

Rapid Regioselective Oxidations of Secondary Alcohols

with Polymeric DABCO-Bromine Complex (PDB)

Apryl Bronley-DeLancey The University of Tampa Department of Chemistry

What is oxidation?

The outcome of oxidation reactions of alcohols depends on the substituents on the carbinol carbon.

In order for each oxidation step to occur, there must be H on the carbinol carbon.

*http://www.chem.ucalgary.ca/courses/351/Carey/Ch15/ch15-4-6.html

Aldehydes and Ketones

H3CCCH3

O

HCH

O

Formaldehyde Acetone

Aldehydes must have at least one hydrogen bound to the carbonyl carbon.

Ketones have two carbons bound to the carbonyl carbon

•Primary alcohols can be oxidized to aldehydes or further to carboxylic acids. In aqueous media, the carboxylic acid is usually the major product. PCC or PDC, which are used in dichloromethane, allow the oxidation to be stopped at the intermediate aldehyde.


•Secondary alcohols can be oxidized to ketones but usually no further •Tertiary alcohols cannot be oxidized (no carbinol C-H)

NBr2

N NBr Br2CH2Cl2, 0o C

+-

Bisquinuclidiniumbromine(I) Bromide"BQBB"

Hypervalent (10 e-) bromine is a good source of "active bromine", a mild oxidant.

Stable, decomposition resistant, yellow/orange solid.

Shown to be somewhat selective in oxidizing 2o alcohols over 1o alcohols

R R

OH

H R H

OH

H+

0.5 eqiv. BQBBCH2Cl2/H2O R R

O

R H

OH

H+

(1) "Selective oxidation of secondary alcohols by bis(quinuclidinium)bromine(I) bromide. A 2-coordinate bromine(I) positive halogen reagent." Blair, L. K.; Bledsoe, R. K.; Burberry, K.; Struss, J. A., Unpublished.(2) Blair, L. K.; Hobbs S.; Bagnoli, N.; Husband, L.; Badika, N. J. Org. Chem. 1992, 57, 1600.

“BQBB” Synthesis and Utility

R H

O

R

R R

O

H RN RR

-H+

+H+ R H

O

R

- RN RR

Br +

R H

O

R

Br

RN RR

RN RR

H Br

Rate of reaction is slow in CH2Cl2; may rely on disassociation of BQBBRN RR

BrRNRR R

N RR

Br +

RNRR

Rates and yields are enhanced by running reactions in biphasic CH2Cl2/H2O

Rates enhanced by adding H+ catalyst (PPTS) or stochiometric amounts of Ag+ (AgBF4).

Oxidations with BQBB

Alcohol Product Cat./ Reagent

Reaction Times

Yield %

2-pentanol 2-pentanone AgBF4 5 min. 90

2,4-dimethyl-3-pentanol

2,4-dimethyl-3-pentanone

AgBF4 5 min. 100

cyclopentanol cyclopentanone PPTS 3 hrs. 97

2-pentanol 2-pentanone PPTS 3 hrs. 95

1-pentanol pentanal AgBF4 5 min. 65

1-octanol octanal AgBF4 5 min. 51

CH2Cl2/H2O (PPTS)CH2Cl2 (AgBF4)

BQBB

R R'H

R R'

OOH

Oxidations with BQBB

Polymeric DABCO Bromine Complex

NN N2 Br2

NBr BrCCl4, 25o C

+

Polymeric DABCO Bromine Complex"PDB"

N N

N

Hypervalent (10 e-) bromine/Br3- is a good source of two equivalents of

"active bromine".

Ionic polymer, stable, decomposition resistant, yellow, insoluble solid.

Shown to be very selective in oxidizing 2o alcohols over 1o alcohols

Reactions are extremely slow (~4-80 hrs.) probably due to poor solubility.

Oxidations required additional DABCO.

Br3-

2-4 equiv. DABCO0.5 equiv. PDB, CH3CN, 25o - 50oC

R R'H R R'

OOH

Alcohol Rxn. Time % Yield Ketone/Aldehyde

% Mass Balance

89 hrs 56% 91%

15.5 hrs 70% 95%

3 hrs 52% 100%

16 hrs 26% 80%

3.2 hrs 10% 81%

3.0 11% 77%

OH

OH

OH

OH

OH

CH3 CH2 CH2 OH5

3 equiv. DABCOCH3CN, 50oCR R'

HR R'

OOH 0.5 equiv. PDB

Blair, L. K.; Baldwin, J.; Smith, W. C. J. Org. Chem., 42, 1816, 1977.

Literature Summary

BQBB reactions involving "catalytic" PPTS employed 1.1 equivalents . in biphasic CH2Cl2/H2O.

BQBB/AgBF4 reactions performed in the absence of H2O.

PDB reactions performed without catalysts or coreagents in the absence of H2O.

PDB reactions required additional amine (DABCO) to aid reaction and remove HBr as reactions progressed.

Explore catalyst loading for BQBB oxidations.

Mimic BQBB reaction conditions for PDB oxidations.

Use 2-pentanol as a basis system, then expand to other alcohols and diols.

Explore the use of chiral amines to construct asymmetric oxidants.

Explore PDB and/or BQBB as oxidants to convert amines to imines and/or aldehydes and ketones.

Research Objectives

Catalyst Loading with BQBB

1.1 equiv. BQBBOH O

PPTS, CH2Cl2/H2O2 hr.

Equiv. Catalyst Recovered Alcohol

% Yield Ketone Mass Balance

1.1 27.8 83.4 111.20.5 29.0 78.2 107.2

0.25 22.8 81.6 104.40.1 26.5 76.7 103.2.01 32.7 75.3 108.00 27.3 77.8 105.1

0 (no H2O) 94.8 7.3 102.1

OHOH

OH

OH

OH

OH

OH

Recovered Alcohol: % Yield Ketone: Mass Balance:

19.9% 94.4% 114.3%

43.7% 21.1% 64.8%

0.0% Quant.*

27.2% 65.5% 92.7%

24.1% 48.0% 72.1%

23.3% 63.6% 86.8%

37.5% 53.5% 91.0%


- Reacts Rapidly - Product May React Further

CH2Cl2/H2O, 25oC

0.55 equiv. PDB

R R'H R R'

OOH

2 hr rxn time

With PDB. . . Just Add Water

OH

OH

OH

OH

OH

OH


4.1% 93.9% 98.0%

0.0% 90.3% 90.3%

8.3% 84.9% 93.2%

0.0% 89.3% 89.3%

0.0% 83.9% 83.9%

3.2% 83.7% 86.9%


CH2Cl2/H2O, 25oC

0.55 equiv. PDB

R R'H R R'

OOH

20 hr. rxn time

20 Hour Oxidations of Secondary Alcohols

CH2Cl2/H2O, 25oC

0.55 equiv. PDB

R HH R H

OOH

OHOH

OHOH

79.9% 8.7% 88.6%

63.3% 28.9% 92.2%

0.0% 97.1% 97.1%

84.3% 7.3% 91.6%

Recovered Alcohol: % Yield Aldehyde: Mass Balance:

2 hr. Oxidations

20 hr. Oxidations

67.1% 26.9% 94.0%

14.2% 85.3% 99.5%

0.0% 91.5% 91.5%

53.8% 44.0% 97.8%

Recovered Alcohol: % Yield Aldehyde: Mass Balance:

Oxidations of Primary Alcohols

OH 0.55 equiv. PDB

CH2Cl2/H2O, 25 oC

15 min.

O

OH0.55 equiv. PDB

CH2Cl2/H2O, 25 oC

15 min.

O

No recovered alcohol! Quantitative after 15 min.?

86.0 % recovered alcohol 9.6% yield

Allylic Alcohols vs. Benzyl Alcohols

Reactivity of Benzyl SystemsPiano stool complexes are common for many oranometallic complexes h5 and h6 examples:

ML

LL M

L LM

LLL M

L L

Could the bromine(I) of PDB and BQBB behave similarly slowing the rate of reaction? For example:

Br

N N

OH

Metallic Bromine?!?!?

Can we synthesize the following complex to verify a previously undiscovered metallic-like behavior of bromine?

BrN NBr-- Na +

BQBB Na+NaH

-H2

+

X-Ray crystallography studies of the cyclopenadienyl-BQBB complex should verify the presence of the first bromine(I) piano stool complex.

Conclusions

BQBB oxidations do not require PPTS catalyst or co-reagents when performed in biphasic CH2Cl2/H2O.

PDB oxidations are much faster in biphasic CH2Cl2/H2O compared to CH3CN/DABCO system.

Rates of oxidation using PDB appear to favor allylic alcohols over benzylic and secondary alcohols. The piano stool complexing phenomenon may explain this behavior.

Oxidations appear to be very sluggish with primary alcohols.

Future Directions

R R'

NH2

H

[O]

R R'

NH

R R'

O

Active bromine complexes have been reported to oxidize amines to ketones or aldehydes. Can the biphasic PDB system acheive this? .

Reports suggest an imine intermediate, yet the imine is not isolated. If this oxidation works, can we stop at the imine?

Asymmetric BQBB-like Oxidants

N

N

TBSO

N

OTBSN

Br

Br -

N

N

TBSO Br22

N NBr2 N N

Br+

-Br

Can we construct asymmetric oxidants using sparteine or cinchona alkaloid derivatives?

Sparteine reaction has been attempted: Very exothermic! Produces a thick . orange semi-solid.

The reaction between quinidine derivative and bromine is low yielding.

None of these asymmetric oxidants have been characterized.

AcknowledgementsMatt DeLancey W. David Barnhart Mike Palmer (Sun Labs) The University of Tampa (Delo Grant) Dr. John Struss Dr. Larry Blair (Berea College)

http://www.staff.livjm.ac.uk/pacfisma/cartlnk.html

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