The identification of fast, chemoselective bond-forming reactions is one of the major contemporary challenges in chemistry. We show that chemoselective amide-forming ligations of potassium acyltrifluoroborates (KATs) and O-carbamoylhydroxylamines proceed in the presence of all unprotected functional groups with a second-order rate constant of 20 M(-1) s(-1). PEG chains, lipids, biotin, and dyes were introduced onto an unprotected 31-mer peptide (a GLP-1 analogue) with equimolar ratios of reactants within minutes at 1 mM and within 1 h at 100 μM, even with Mw 20,000 PEG. This conjugation reaction provides a new approach to the synthesis of molecules such as protein-protein and protein-polymer conjugates.

The further development of the field of catalysis is based on the discovery, understanding, and implementation of novel activation modes that allow unprecedented transformations and open new perspectives in synthetic chemistry. In this context, the recently introduced concept of frustrated Lewis pair (FLP) from the Stephan research group represents a fundamental and novel strategy to develop catalysts based on main-group elements for small-molecule activation.[1] These sterically encumbered Lewis acid-base systems are not able to form a stable donor-acceptor adduct, nevertheless, an intermolecular association of the Lewis acidic (LA) and basic (LB) components to a unique "frustrated complex" was proposed. [2,3] Our research group has also shown that this encounter pair cleaves hydrogen in a cooperative manner and the steric congestion implies a strain, which can be directly utilized for bond activation. [2] Using steric hindrance as a critical design element, several combinations of bulky Lewis acid-base pairs were effectively probed for heterolytic cleavage of hydrogen. [4][5][6] Moreover, this remarkable capacity of FLPs was exploited in metal-free hydrogenation procedures.[7] Additionally, the bifunctional and unquenched nature of the FLPs makes them capable of reacting with alkenes, [8] dienes, [9] acetylenes, [10] and THF.[5f]Although this type of reactivity represents a breakthrough in main-group chemistry, its enhanced and non-orthogonal nature obviously limits the synthetic applicability of FLPs. Herein we report an attempt to develop frustrated Lewis pairs with orthogonal reactivity and improved functional-group tolerance for catalytic metal-free hydrogenation. The previously reported FLP-based hydrogen activation relied mostly on tris(pentafluorophenyl)borane [11] (1) as the LA component.[12] Because of the hard-type Lewis acidity of boron in 1 and its inactivation by common oxygen-and/or nitrogen-containing molecules, careful substrate design was needed for successful catalytic hydrogenation reactions. This synthetic limitation triggered us to develop FLP catalysts that have a broader range of applications and possible selectivity in reduction processes.Our design concept for increased functional-group tolerance is based on the simple hypothesis that steric hindrance in FLPs is a relative phenomenon (Figure 1): further increase of congestion around the boron center in FLP I and its parallel decrease around the LB could lead to a Lewis pair (FLP II) that may have a markedly higher tolerance for the functionalities of common organic molecules. Thus, the steric demands imposed on the boron center by additional orthoaryl substituents are such that they can prevent or markedly decrease the complexation ability with normal Lewis bases but still allow the cleavage of the small hydrogen molecule. Additionally, we assumed that the increased shielding around boron in FLP II could preclude its addition to olefins, therefore creating a unique opportunity to investigate the chemoselectivity of FLP-catalyzed hydroge...

Catalytic hydrogenation that utilizes frustrated Lewis pair (FLP) catalysts is a subject of growing interest because such catalysts offer a unique opportunity for the development of transition-metal-free hydrogenations. The aim of our recent efforts is to further increase the functional-group tolerance and chemoselectivity of FLP catalysts by means of size-exclusion catalyst design. Given that hydrogen molecule is the smallest molecule, our modified Lewis acids feature a highly shielded boron center that still allows the cleavage of the hydrogen but avoids undesirable FLP reactivity by simple physical constraint. As a result, greater latitude in substrate scope can be achieved, as exemplified by the chemoselective reduction of α,β-unsaturated imines, ketones, and quinolines. In addition to synthetic aspects, detailed NMR spectroscopic, DFT, and (2)H isotopic labeling studies were performed to gain further mechanistic insight into FLP hydrogenation.

Potassium acyltrifluoroborates (KATs) are fascinating functional groups whose further exploration is limited by poor synthetic access. Documented herein is the design and synthesis of a new reagent for their one-step preparation from aryl- and heteroarylhalides. The reagent is a stable, soluble zwitterion prepared by S-alkylation of a novel thioformamide trifluoroboronate. The KATs are prepared by adding one equivalent of nBuLi to a mixture of the aryl halide and the reagent at -78 °C. This protocol is suitable for the preparation of KATs containing pyridines, esters, nitro groups, and halides.

The further development of the field of catalysis is based on the discovery, understanding, and implementation of novel activation modes that allow unprecedented transformations and open new perspectives in synthetic chemistry. In this context, the recently introduced concept of frustrated Lewis pair (FLP) from the Stephan research group represents a fundamental and novel strategy to develop catalysts based on main-group elements for small-molecule activation. [1] These sterically encumbered Lewis acid-base systems are not able to form a stable donor-acceptor adduct, nevertheless, an intermolecular association of the Lewis acidic (LA) and basic (LB) components to a unique "frustrated complex" was proposed. [2,3] Our research group has also shown that this encounter pair cleaves hydrogen in a cooperative manner and the steric congestion implies a strain, which can be directly utilized for bond activation. [2] Using steric hindrance as a critical design element, several combinations of bulky Lewis acid-base pairs were effectively probed for heterolytic cleavage of hydrogen. [4][5][6] Moreover, this remarkable capacity of FLPs was exploited in metal-free hydrogenation procedures. [7] Additionally, the bifunctional and unquenched nature of the FLPs makes them capable of reacting with alkenes, [8] dienes, [9] acetylenes, [10] and THF. [5f] Although this type of reactivity represents a breakthrough in main-group chemistry, its enhanced and non-orthogonal nature obviously limits the synthetic applicability of FLPs. Herein we report an attempt to develop frustrated Lewis pairs with orthogonal reactivity and improved functional-group tolerance for catalytic metal-free hydrogenation.The previously reported FLP-based hydrogen activation relied mostly on tris(pentafluorophenyl)borane [11] (1) as the LA component. [12] Because of the hard-type Lewis acidity of boron in 1 and its inactivation by common oxygen-and/or nitrogen-containing molecules, careful substrate design was needed for successful catalytic hydrogenation reactions. This synthetic limitation triggered us to develop FLP catalysts that have a broader range of applications and possible selectivity in reduction processes.Our design concept for increased functional-group tolerance is based on the simple hypothesis that steric hindrance in FLPs is a relative phenomenon (Figure 1): further increase of congestion around the boron center in FLP I and its parallel decrease around the LB could lead to a Lewis pair (FLP II) that may have a markedly higher tolerance for the functionalities of common organic molecules. Thus, the steric demands imposed on the boron center by additional orthoaryl substituents are such that they can prevent or markedly decrease the complexation ability with normal Lewis bases but still allow the cleavage of the small hydrogen molecule. Additionally, we assumed that the increased shielding around boron in FLP II could preclude its addition to olefins, therefore creating a unique opportunity to investigate the chemoselectivity of FLP-catalyzed h...

The metal‐free catalytic hydrogenation of unsaturated imines, ketones, and quinolines that utilizes frustrated Lewis pair catalysts is investigated.

Potassium acyltrifluoroborates (KATs) are fascinating functional groups whose further exploration is limited by poor synthetic access. Documented herein is the design and synthesis of a new reagent for their one-step preparation from aryl-and heteroarylhalides. The reagent is a stable, soluble zwitterion prepared by S-alkylation of a novel thioformamide trifluoroboronate. The KATs are prepared by adding one equivalent of nBuLi to a mixture of the aryl halide and the reagent at À78 8C. This protocol is suitable for the preparation of KATs containing pyridines, esters, nitro groups, and halides.Potassium acyltrifluoroborates (KATs) are fascinating func-Scheme 1. One-step synthesis of acyltrifluoroborates.

The evolution of deep and shallow flowers is a response to a “race” with pollinating organisms that determines the length and form of the bill of hummingbirds. Likewise, the selection of the Lewis basic component for a frustrated Lewis pair is dictated by the steric congestion around the boron center of the Lewis acid. In their Communication on T. Soós and co‐workers show that this “selection phenomenon” can be exploited as a design concept for metal‐free hydrogenation catalysts.