Non-Classical C–H···X Hydrogen Bonding and Its Role in Asymmetric Organocatalysis

Abstract

Non-classical hydrogen bonds (NCHBs) have attracted significant interest in the past decade particularly because of their important role in asymmetric catalytic systems. These weak interactions (<4 kcal/mol) offer much flexibility in the preorganization of molecular entities required to achieve high enantioselectivity. Herein, we review some recent important organocatalytic asymmetric reactions where a NCHB serves as a critical factor in determining the stereoselectivity. 1 Introduction 2 Hydrogen Bonds (HBs) and Non-Classical Hydrogen Bonds (NCHBs) 3 Early Developments in NCHBs 4 Selected Examples of NCHBs in Organic Transformations 5 Recent Examples of NCHBs in Enantioselective Reactions 6 Conclusions and Outlook Keywords non-classical hydrogen bond, enantioselectivity, organocatalysis, mechanism, DFT Manjaly J. Ajitha completed her Ph.D. in 2013 under the guidance of Dr. C. H. Suresh at NIIST (CSIR), India. Her doctoral research focused on DFT studies on (S)-proline and N-heterocyclic carbene (NHC) mediated organocatalytic reactions. After that, she moved to South Korea for post-doctoral studies with Prof. Yousung Jung at KAIST. Currently, she is working as a post-doctoral fellow with Prof. Kuo-Wei Huang at KAUST. Her main focus of research is DFT studies of transition-metal catalysis and organocatalysis including the investigation of the reaction mechanism and development of improved catalysts by fine tuning stereoelectronic properties of the active sites of the catalyst.

Stereospecific [3+2] Cycloaddition of Chiral Arylallenes with C,N-Cyclic Azomethine Imines

“…On the basis of the observations described above and previous reports, , a plausible mechanism was proposed for the axial-to-central chirality transfer cycloaddition reaction (Scheme ). As α,β-selective cycloaddition with allenes 2 may exploit concerted or stepwise pathways, density functional theory (DFT) calculations were conducted to elucidate the observed selectivity (see the Supporting Information for details).…”

Control of Selectivity in Homogeneous Catalysis through Noncovalent Interactions

“…[45,46,70,71] In fact, not only strong (15-45 kcal/mol) and moderate (4-15 kcal/mol) hydrogen bonds, but also weak non-classical hydrogen bonds (CÀ H•••Nu with energy of < 4 kcal/mol) [72] have attracted a significant interest particularly on account of their crucial role in asymmetric catalytic reactions. [73][74][75] Both inter-and intramolecular versions of normal, negative, positive or resonance assisted hydrogen bonds can act as effective stabilizing interactions of intermediates or transition states in synthesis and in homogeneous catalysis, [11,76,77] which are responsible for the high reactivity and selectivity of the corresponding synthetic transformations. For example, the enantioselectivity and regioselectivity of the phosphine-catalyzed [3 + 2] annulation between benzyl buta-2,3-dienoate or tert-butyl buta-2,3-dienoate and naphthalen-2yl 2-phenylacrylate or (E/Z)-N-butylidene-P,P-diphenylphosphinic amide was originated/directed by intra-or intermolecular H-bonds, respectively (Scheme 5).…”

“…Among noncovalent interactions, hydrogen bonding is recognized as one of the most active phenomena/players in the control of selectivity in organocatalysis, metal complex or cooperative catalysis [45,46,70,71] . In fact, not only strong (15–45 kcal/mol) and moderate (4‐15 kcal/mol) hydrogen bonds, but also weak non‐classical hydrogen bonds (C−H⋅⋅⋅Nu with energy of <4 kcal/mol) [72] have attracted a significant interest particularly on account of their crucial role in asymmetric catalytic reactions [73–75] . Both inter‐ and intramolecular versions of normal, negative, positive or resonance assisted hydrogen bonds can act as effective stabilizing interactions of intermediates or transition states in synthesis and in homogeneous catalysis, [11,76,77] which are responsible for the high reactivity and selectivity of the corresponding synthetic transformations.…”

Computational molecular refinement to enhance enantioselectivity by reinforcing hydrogen bonding interactions in major reaction pathway

“…Hydrogen bonding is a ubiquitous interaction that is universally used in the formation of organized molecular structures. It has also played an important role in the development of enantioselective reactions using not only organocatalysts 7 but also transition metal catalysts. 8,9 Because hydrogen bonding interaction, as broadly defined, is highly directional and electrostatic, it can be readily recognized visually; this allows the strength of the interaction to be controlled at the intended location by changing the electronic property around the bond.…”

“…Enantioselective catalysis using a chiral Brønsted acid has been a useful tool in organic synthesis. 7,10 Since the introduction of 1,1′-bi-2-naphthol (BINOL)-derived chiral phosphoric acids (CPAs) as privileged chiral Brønsted acid catalysts, 11 continuous efforts have been devoted to achieving a broad range of unprecedented catalytic enantioselective reactions by improving the acidity and the chiral environment. 12–14 Such catalytic enantioselective reactions have been achieved because the acid/base dual function of the monofunctional phosphate moiety of CPAs is able to strictly define substrate location through hydrogen bonding and other interactions.…”