Université de Montréal Clémentine Minozzi Université de Montréal Literature Meeting April 5th 2017

About Prof. Morandi Academic Background BSc ETH Zurich in Biology 2003-2006 MSc ETH Zurich in Chemical Biology 2006-2008  Dr Sc. ETH Zurich in Organic Chemistry 2008-2012 (with Prof. Carreira) Career PDF in Organometallic Chemistry with Prof. Grubbs 2012-2014 Independent Max Planck Research Group Leader 2014 Research interest Shuttle Catalysis Aliphatic C–O Bond Activation Direct Catalytic Synthesis of Unprotected Amines This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Publications : Since 2014, published 12 papers (28 in total) 1 Science 2 ACIE 1 Org. Lett. 2 Chem. Eur. J. 3 ACS Catal. 1 Chem. Comm. 1 Synlett

Synthetic Versatility of Nitriles This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Pollak, P.; Romeder, G.; Hagedorn, F.; Gelbke, H. in Nitriles. Ullman’s encyclopedia of industrial chemistry, 5th copl. Rev. ed., Vol. A17, Wiley-VCH, Weinheim, 1985, pp. 363-376.

Hydrocyanation of Alkenes Hydrocyanation definition : Hydrocyanation is the process in which HCN is added across the double bond of an alkene to form a nitrile Hydrocyanation of alkenes No regio- nor stereoselectivity Toxycity of HCN Huthmacher, K.; Krill, S. in Applied Homogeneous Catalysis with Organometallic Compounds, 2nd ed.; Cornils, B., Hermann, W. A., Eds.; Wiley-VCH: Weinheim, The first report dealing with a homogeneously catalyzed HCN addition to nonfunctionalized alkenes in 1954 Use of [Co2(CO)8] as a precatalyst This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. P. Arthur Jr. , D. C. England, B. C. Pratt, G. M. Whitman, J. Am. Chem. Soc. 1954, 76, 5364.

Hydrocyanation of Alkenes The DuPont Adiponitrile process Adiponitrile is a precursor of hexamethylenediamine necessary for the synthesis of Nylon Tolman developed important concept in catalysis This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. C. A. Tolman, Chem. Rev. 1977, 77, 313 L. Bini, C. Müller, D. Vogt, ChemCatChem 2010; 2, 590–608

Use of Ni(0) and Lewis Acids Nickel-Catalyzed Carbocyanation of Alkynes Acceleration of the oxidative addition of C-CN bond Positive effect on the reductive elimination EDG ligand = essential to form an electron-rich nickel center This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Y. Nakao, A. Yada, S. Ebata, T. Hiyama, J. Am. Chem. Soc. 2007 129, 2428–2429

Postulated Mechanism with Lewis Acids This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Steric repulsion leads the regioselectivity Y. Nakao, A. Yada, S. Ebata, T. Hiyama, J. Am. Chem. Soc. 2007 129, 2428–2429

Importance of Bulky Ligands 𝜋-acceptor character of the ligand increases the stability of the Ni(0) complexes Steric factor of ligands L are defined by Tolman cone angle : Complex with small ligands ( θ= 109°) = do not dissociate Chelate effect of bidentate ligands contributes to the complex stability This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. C. A. Tolman, J. Am. Chem. Soc. 1970, 92, 2953 W. Goertz, P. C. J. Kamer, P. W. N. M. van Leeuwen, D. Vogt, Chem. Eur. J. 2001, 7, 1614.

Importance of Bulky Ligands Cat. % Nitrile % 3PN Turnover 1 61 52 1430 2 79 69 35 This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Bulky bidentate ligands are more active and efficient M. J. Baker, K. N. Harrison, A. G. Orpen, P. G. Pringle, G. Shaw, J. Chem. Soc. Chem. Commun. 1991, 803 L. Bini, C. Müller, D. Vogt, ChemCatChem 2010; 2, 590–608

Hydrogen Cyanide Colorless liquid, very volatile Boiling point is 26 °C Explosive in air from a concentration of 56 000 ppm (5,6%) This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Inhalation of large amounts of cyanide causes immediate unconsciousness, convulsions, and death from respiratory arrest within 1–15 min. G. Romeder, Hydrogen Cyanide. e-EROS Encyclopedia of Reagents for Organic Synthesis 2001

Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836 This Paper Catalytic Transfer Hydrocyanation (forward reaction) Catalytic Retro-Hydrocyanation (reverse reaction) This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836

Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836. This Paper Remaining challenges Overcome the toxicity involved with the use of HCN Accessibility of forward and reverse hydrocyanation Shift the equilibrium of the reaction selectively Strategy This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. HCN-free Ni-catalyzed reaction Use of Ni(0) : very active species in the oxidative addition of polar bonds Use of a Lewis acid as co-catalyst Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836.

Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836. Proposed Mechanism This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836.

Thermodynamic Challenges Studies of driving force of hydrocyanation This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Formation of gaseous disubstituted alkene Studies of driving force of retro-hydrocyanation

Scope of Hydrocyanation Aromatic compounds: This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Styrene derivatives give generally good yields of linear (Anti-Markovnikov) products Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836.

Scope of Hydrocyanation Aliphatic compounds: Compatible with a range of functional groups : F, Cl, ether, ester, ketone, silyl, OBn Heterocyclic compounds: This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836.

End of the scope and limitations Drug precursor and natural compounds: Limitations of the reactions: This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Does not tolerate unprotected alcohols and dienes Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836.

Scope of Retro-Hydrocyanation Styrene synthesis: This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836.

Scope of Retro-Hydrocyanation Aliphatic: Terpene Derivatives: This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836.

Scope of Retro-Hydrocyanation Construction of aromatic rings from dienes: This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Installation of a chiral quaternary vinyl group: Xianjie Fang, Peng Yu and Bill Morandi. Science 2016, 351, 832-836.

Conclusions Mechanistic studies confirm the transfer of CN and D between the two substrates Indicates that it is a syn addition mechanism Catalytic transfer hydrocyanation with catalytic system of Ni(0)/ Lewis Acid Catalytic retro hydrocyanation HCN-free reaction Method compatible with a large scope Good regioselectivity This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications. Weaknesses: Unprotected alcohols and dienes are unreactive under optimized conditions

Thank you For Your Attention This graph was taken from a recent review on named cross-coupling reactions and illustrates the growth in the number of publications associated with these reactions over the past 30 years. In all of the 20 000 publications published since the early nineties, one reaction that caught our eye was the Sonogashira cross-coupling, which has become the third most widely used named cross-coupling in diverse field of applications.