the prins-pinacol reaction
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Organic Pedagogical Electronic Network
The Prins-Pinacol Reaction
Andy ClevengerUniversity of Utah
N
HO
HO
O
R
R1 R2CHOBF3.OEt2CH2Cl2 N
O
O
O
R2
R1
R
OH
OHCHO
Lewis acidCH2Cl2
O
CHO
Overview
(top) Reddy, B.V.S.; Reddy, S.G.; Reddy, M.R.; Bhadra, M.P.; Sarma, A.V.S. Org. Biomol. Chem. 2014, 12, 7257-7260(bottom) Cloninger, M.J.; Overman, L.E. J. Am. Chem. Soc. 1999, 121, 1092-1093
The Prins-Pinacol reaction is a two step process. It begins with the Prins reaction, which is the attack by a nucleophilic alkene on a Lewis acid-activated aldehyde. This forms a cationic intermediate. The pinacol rearrangement is a methyl shift which pushes the cation on to an oxygen, which is then deprotonated.
OHOH
RCHOBF3.OEt2
O
O
R
R2
OHR1
OH
R3CHO
acid
O R3R2
OR1
History
Prins: https://en.wikipedia.org/wiki/Prins_reactionPinacol: https://en.wikipedia.org/wiki/Pinacol_rearrangement
In 1919, Dutch chemist Hendrick Jacobus Prins found the first step of this reaction by combining styrene and formaldehyde in concentrated H2SO4.
formaldehydeH2SO4
HO OH
The pinacol rearrangement was first found by Wilhelm Rudolph Fittig in 1860. It is an acid-catalyzed method for converting a 1,2-diol into a carbonyl.
OHOH H+O
Prins-Pinacol Mechanism: Forming the Activated Carbonyl
Reddy, B.V.S.; Reddy, S.G.; Durgaprasad, M.; Bhadra, M.P.; Sridhar, B. Org. Biomol. Chem. 2015, 13, 8729-8733.
N
HO
HO
O
O
HR
LA
N
O
HO
O
H
ORLA
H2O
N
O
HO
O
ORLA
N
O
HO
O
R
In this first step, the more exposed alcohol attacks the activated aldehyde. The oxygen on the activated aldehyde is removed as the Lewis Acid complex and a
highly reactive oxocarbenium ion is formed.
Prins-Pinacol Mechanism: Prins Reaction
Reddy, B.V.S.; Reddy, S.G.; Durgaprasad, M.; Bhadra, M.P.; Sridhar, B. Org. Biomol. Chem. 2015, 13, 8729-8733.
N
O
HO
O
R
identical to OOH
NR
Prins OOH
NR
The alkene attacks the activated carbonyl and forms the six-membered ring in the Prins reaction. The cation is now at a more stable tertiary center.
Prins-Pinacol Mechanism: Pinacol Rearrangement
Reddy, B.V.S.; Reddy, S.G.; Durgaprasad, M.; Bhadra, M.P.; Sridhar, B. Org. Biomol. Chem. 2015, 13, 8729-8733.
OR
OHN
O
Pinacol
N
O
O
O
R
H deprotonation
N
O
O
O
R
In this pinacol rearrangement, there is an aryl methyl shift. The C-C bond shifts to the carbocation position while one of the lone pairs on the alcohol closes down to form a carbonyl. With deprotonation, the Prins-
Pinacol reaction is complete.
Driving Forces Behind the Prins-Pinacol Reaction
Reddy, B.V.S.; Reddy, S.G.; Reddy, M.R.; Bhadra, M.P.; Sarma, A.V.S. Org. Biomol. Chem. 2014, 12, 7257-7260
• Most of the force driving this reaction to completion is the increased stability of the cation.
• Ring strain relief can also drive this reaction to completion.
In this example, the strained four membered ring reacts and becomes a fused pyran-cyclopentanone compound which has much less ring strain.
OHOH
RCHOBF3.OEt2
O
O
R
Prins-Pinacol Applications• Complex backbones of natural products
• Stereoselective tetrahydropyran synthesis
• Many natural product syntheses• Convienent reaction pathway to establish a carbonyl and close a ring
system
N
O
O
O
R
R2
OHR1
OH
R3CHO
acid
O R3R2
OR1
Questions
Why can’t the Prins-Pinacol reaction occur on a ketone instead of an aldehyde?
A) Steric hindrance-the alkene can’t attack the oxocarbenium ionB) The oxocarbenium ion will not be able to formC) The carbonyl will not be activated by the Lewis acidD) The alkene can’t attack the ketone oxocarbenium ion due to reduced reactivity
Questions
What is the role of the Lewis acid in the Prins-Pinacol reaction?
A) It stabilizes the oxocarbenium ion
B) It activates the aldehyde for attack by an alcohol
C) It stabilizes the carbocation intermediate
D) It deprotonates the protonated carbonyl at the end of the reaction
Questions
Which of these compounds is the correct Prins-Pinacol product for the given reaction?
A) C)
B)
HO formaldehydeBF3.OEt2
OH
O
HO
O
OH
O
OH
Questions
What can be a driving force behind the Prins-Pinacol reaction?
A) Ring strain reliefB) Increased carbocation stabilityC) Increased stability with the formation of a carbonylD) All of the above
Questions
What functional group can undergo the Prins-Pinacol reaction with an aldehyde?
A) A 1,2-diolB) A 1,2-diketone C) An alpha, gamma-hydroxyl alkeneD) An ester
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Contributed by: Andy Clevenger (Undergraduate)
University of Utah, 2016
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