The Prins-Pinacol Reaction

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.

Contributed by: Andy Clevenger (Undergraduate), University of Utah, 2016

1. The Prins-Pinacol Reaction Andy Clevenger University of Utah

2. 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.

3. History Prins : https://en.wikipedia.org/wiki/Prins_reaction Pinacol : 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 H 2 SO 4 . 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.

4. 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. 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.

5. 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. 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.

6. 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. 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.

7. 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.

8. 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

9. 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 ion B) The oxocarbenium ion will not be able to form C) The carbonyl will not be activated by the Lewis acid D) The alkene can’t attack the ketone oxocarbenium ion due to reduced reactivity

10. 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

11. Questions Which of these compounds is the correct Prins-Pinacol product for the given reaction? A) C) B )

12. Questions What can be a driving force behind the Prins-Pinacol reaction? A) Ring strain relief B) Increased carbocation stability C) Increased stability with the formation of a carbonyl D) All of the above

13. Questions What functional group can undergo the Prins-Pinacol reaction with an aldehyde? A) A 1,2-diol B) A 1,2-diketone C) An alpha, gamma-hydroxyl alkene D) An ester

14. Contributed by: Andy Clevenger (Undergraduate) University of Utah, 2016