Planar Amides Research Articles

Understanding the Structure‐Activity Relationship of Ni‐Catalyzed Amide C−N Bond Activation using Distortion/Interaction Analysis

AbstractTransition metal‐catalyzed amide C−N bond activation has emerged as a powerful strategy to utilize amides in synthetic transformations. The key mechanistic basis for the rational design of amide reagents is the structure‐activity relationship of amide C−N bond activation. In this work, the controlling factors of Ni/PCy3‐catalyzed amide C−N bond activation barrier are elucidated with density functional theory (DFT) calculations and distortion/interaction analysis. We found that the substrate distortion is the key factor that differentiates the amide reactivity in the C−N bond activation. The substrate distortion of amide is associated with two distinctive structure‐activity relationships. The general planar amides undergo a classic three‐membered ring oxidative addition to cleave the C−N bond, in which the C−N heterolytic bond dissociation energy has a linear relationship with the activation barrier. The twisted amides have a chelation‐assisted transition state for the amide C−N bond cleavage, and the twisted angle τ can serve as a predictive parameter for the reactivity of the twisted amides. The understanding of the structure‐activity relationship of amide C−N bond activation provides a rational and predictive basis for future reaction designs involving transition metal‐catalyzed amide C−N bond activation.

Well-Defined Palladium(II)-NHC Precatalysts for Cross-Coupling Reactions of Amides and Esters by Selective N-C/O-C Cleavage.

Transition-metal-catalyzed cross-coupling reactions represent a most powerful tool for the rapid construction of C-C and C-X bonds available to synthetic chemists. Recently, tremendous progress has been made in the burgeoning area of cross-coupling reactions of amides and esters enabled by regio- and chemoselective acyl C-X (X = N, O) cleavage using well-defined Pd(II)-NHC complexes. The use of N-heterocyclic carbenes as ligands in palladium-catalyzed cross-couplings permits reactions of amides and esters that were previously impossible using palladium or could be achieved only under harsh conditions. These reactions provide an attractive method to synthetic chemists to manipulate the traditionally inert amide and ester bonds with the broad cross-coupling generality inherent to palladium catalysis. Research in the area of cross-coupling of stable acyl electrophiles can be broadly categorized by the type of electrophile undergoing the cross-coupling. Recent studies have shown that cross-coupling of amides by transition-metal catalysis represents one of the most straightforward and wide-ranging ways of manipulating the classically inert amide bonds into generic acyl-metal intermediates that can be systematically exploited in cross-coupling reactions as a new paradigm in organic synthesis. The key to achieving high chemoselectivity of the process is control of amidic resonance (nN to πC═O* conjugation, rotation of ca. 15-20 kcal/mol in planar amides), enabling oxidative addition of the N-C amide bond to a metal in a rational and predictable manner. This mode of catalysis has been extended to C(acyl)-O cross-coupling reactions of aryl esters, where selective C-O bond cleavage is accomplished through a rational match of aryl ester electrophiles and nucleophilic metal catalysts. These two types of transition-metal-catalyzed cross-coupling reactions represent an attractive concept in synthetic chemistry because of the ubiquity of esters and amides as precursors in organic synthesis. Furthermore, the high stability of amides and esters provides unprecedented opportunities for orthogonal cross-coupling strategies in the presence of other electrophiles. In this Account, we highlight advances that have taken place in the past few years in the field of cross-coupling of amides and esters, focusing on both (1) the stereoelectronic properties of well-defined Pd(II)-NHC complexes that have been critical to realize this challenging cross-coupling manifold and (2) the role of the isomerization barrier of the acyl electrophiles undergoing the cross-coupling. In a broader sense, the chemistry described here provides a practical approach to functionalize common amide and ester functional groups in organic synthesis and establishes straightforward access to acyl-metal intermediates that enable nonconventional cross-coupling strategies.

Suzuki-Miyaura Cross-Coupling of N-Acylpyrroles and Pyrazoles: Planar, Electronically Activated Amides in Catalytic N-C Cleavage.

The formation of C-C bonds from amides by catalytic activation of the amide bond has been thus far possible by steric distortion. Herein, we report the first example of a general Pd-catalyzed Suzuki-Miyaura cross-coupling of planar amides enabled by the combination of (i) electronic-activation of the amide nitrogen in N-acylpyrroles and pyrazoles and (ii) the use of a versatile Pd-NHC catalysis platform. The origin and selectivity of forming acylmetals, including the role of twist, are discussed.

Resonance Destabilization in N-Acylanilines (Anilides): Electronically-Activated Planar Amides of Relevance in N-C(O) Cross-Coupling.

Transition-metal-catalyzed activation of amide N-C(O) bonds proceeds via selective metal insertion into the carbon-nitrogen amide bond. Herein, we demonstrate that N-acylanilines (anilides), the first class of planar amides that have been shown to undergo selective amide N-C cross-coupling reactions, feature a significantly decreased barrier to rotation around the amide N-C(O) bond. Most significantly, we demonstrate that amide nN → π*C═O resonance in simple anilides can be varied by as much as 10 kcal/mol. The data have important implications for the design of N-C(O) amide cross-coupling reactions and control of the molecular conformation of anilides by resonance effects.

Nickel-Catalyzed Deamidative Step-Down Reduction of Amides to Aromatic Hydrocarbons

To date, cleavage of the C−N bond in aromatic amides has been achieved in molecules with a distorted constitutional framework around the nitrogen atom. In this report, a nickel-catalyzed reduction of planar amides to the corresponding lower hydrocarbon homologue has been reported. This involves a one-pot reductive cleavage of the C−N bond followed by a tandem C−CO bond break in the presence of a hydride source. Substrate scope circumscribes deamidation examples which proceed via oxidative addition of nickel in the amide bonds of nontwisted amides. Mechanistic studies involving isolation and characterization of involved intermediates via different spectroscopic techniques reveal a deeper introspection into the plausible catalytic cycle for the methodology.

Uncovering the Importance of Proton Donors in TmI2‐Promoted Electron Transfer: Facile CN Bond Cleavage in Unactivated Amides

The amide bond is one of the most ubiquitious functional groups in chemistry and biology.1 To date, the majority of strategies to functionalize amide bonds have focused on activation of the carbonyl group towards nucleophilic addition,2 however only few examples of the selective activation of σ C–N bonds in amides have been reported. In this regard, the cleavage of a σ C−N bond in amides was achieved in several highly innovative but very specialized bridged lactams, in which one of the C−N bonds was sufficiently distorted from planarity (Figure 1 a).3 Functionalization of the C−N bond in electronically activated phthalimides has also been described.4 However, a general method for the activation of σ C−N bonds in amides is unknown despite its considerable potential to advance the synthetic application of amide linkages in chemistry and biology.

Uncovering the Importance of Proton Donors in TmI2‐Promoted Electron Transfer: Facile CN Bond Cleavage in Unactivated Amides

Uncovering the Importance of Proton Donors in TmI₂‐Promoted Electron Transfer: Facile CN Bond Cleavage in Unactivated Amides

Acid‐Catalyzed Reactions of Twisted Amides in Water Solution: Competition between Hydration and Hydrolysis

The acid-catalyzed reactions of twisted amides in water solution were investigated by using cluster-continuum model calculations. In contrast to the previous widely suggested concerted hydration of the C=O group, our calculations show that the reaction proceeds in a practically stepwise manner, and that the hydration and hydrolysis channels of the C-N bond compete. The Eigen ion (H(3)O(+)) is the key species involved in the reaction, and it modulates the hydration and hydrolysis reaction pathways. The phenyl substitution in the twisted amide not only activates the N-CO bond, but also stabilizes the hydrolysis product through n(N)→π(phenyl) delocalization, leading exclusively to the hydrolysis product of the ring-opened carboxylic acid. Generally, the twisted amides are more active than the planar amides, and such a rate acceleration results mainly from the increase in exothermicity in the first N-protonation step; the second step of the nucleophilic attack is less affected by the twisting of the amide bond. The present results show good agreement with the available experimental observations.

Proximity effects in nucleophilic addition reactions to medium-bridged twisted lactams: remarkably stable tetrahedral intermediates.

The reactions of a series of strained bicyclic and tricyclic one-carbon bridged lactams with organometallic reagents have been investigated. These amides permit isolation of a number of remarkably stable hemiaminals upon nucleophilic addition to the twisted amide bonds present in the lactam precursors. The factors that affect the stability of the resulting bridged hemiaminals are presented. In some cases, the hemiaminals were found to collapse to the open-form amino ketones in a manner expected for traditional carboxylic acid derivatives. Transannular N...C=O interactions were also observed in some nine-membered amino ketones. Additionally, tricyclic bridged lactams were found to react with some nucleophiles that typically react with ketones but not with planar amides. The effect of geometry on the reactivity of amide bonds and the amide bond distortion range that marks the boundary of amide-like and ketone-like carbonyl reactivity of lactams are also discussed.

Synthesis and structural analysis of 2-quinuclidonium tetrafluoroborate

The amide functional group is one of the most fundamental motifs found in chemistry and biology, and it has been studied extensively for the past century. Typical acyclic amides are planar. But the amide groups of bicyclic bridgehead lactams are highly twisted, and this distortion from planarity can dramatically affect the stability and reactivity of these amides; it also increases the basicity of the nitrogen so that it often behaves more like an amine than a typical planar amide. As a result, the structures and reactivity profiles of these 'anti-Bredt' amides differ significantly from those of planar amides. It is possible that this twisting phenomenon is not exclusive to cyclic systems-non-planarity may also be a critical biological design element that leads to amide ground-state destabilization and alters the reactivity, selectivity and mechanism of various protein and enzymatic processes (such as amide hydrolysis). The intriguing qualities of these twisted amides were first recognized in 1938 (ref. 11), wherein one of the simplest families was introduced--molecules containing the 1-azabicyclo[2.2.2]octan-2-one system. But the parent member of this group, 2-quinuclidone (molecule 1 in this paper), has not yet been unambiguously synthesized. Here, we report the chemical synthesis, isolation and full characterization of the HBF4 salt of 1. Critical to the success of the synthesis and isolation was the decision to generate 1 by a route other than classical amide bond formation. We anticipate that these results will provide a greater understanding of the properties of amide bonds.

Studies of structure and dynamics in a nominally symmetric twisted amide by NMR and electronic structure calculations

Amides that are twisted around the C—N bond show unusual spectroscopy and reactivity when compared with planar amides. The diacyl derivatives of 3,4,7,8-tetramethyl-2,5-dithioglycoluril are intriguing examples of this class, since the crystal structures show that the two acyl groups are twisted by different amounts on either side of the molecule owing to a combination of steric and electronic effects. However, the 1H NMR spectra in solution at room temperature exhibit only one acyl resonance, so there must be fast interconversion among pairs of equivalent structures of each compound. We have prepared a number of derivatives with different acyl groups, both on the glycoluril framework as well as on its dithio analogue. The chemical exchange in solution was slowed down sufficiently by cooling to see individual sites for only two compounds: the dithiodipivaloyl and the dithiodiadamantyl derivatives. The barriers were estimated at 41 kJ mol–1 for the dipivaloyl derivative and 45 kJ mol–1 for diadamantyl derivative. The results show that rotation around the twisted amide bond is slowed by both the steric size of the acyl group and the presence of the thioureido group vs. the ureido group in the glycoluril core. In the solid-state 13C NMR spectra, there is no evidence for any dynamics, even for the diacetyl derivative at ambient temperature. Electronic structure calculations predict a geometry for the dipivaloyl derivative very close to that observed in the crystal structure. These results indicate that the crystal confines, but does not distort the molecule. A mechanism for the exchange is proposed. The relevance of these results to the mechanism of Claisen-like condensations in diacylglycolurils is also discussed.Key words: 1H and 13C NMR, exchange, dynamics, CP/MAS, solids, line shape analysis, amides, twisted amides, atropisomers, glycoluril.

Reactivity of β-lactams and phosphonamidates and reactions with β-lactamase

Abstract

Energy analysis on small to medium sized H-bonded complexes

Dimers (water-methanol, guanine-cytosine) as well as trimers (methanol-water-imidazole, formamide-methylformate-formamide), are studied as H-bonded complexes of increasing complexity. All the investigated conformations have been fully optimized. In particular, it is the first time that all the intra-and intermolecular parameters of the guanine-cytosine complex are left variable. In minimal basis sets, the planar conformation has been found to be a first-order critical point. The minimal basis set MINI-1 has been adapted to provide nearly planar amides. The stability of the complexes is accounted for by four energy components of the same order: the first-order term (electrostatic + exchange), the polarization, the charge transfer and the correlation terms. In the case of the studied trimers, the energy components, apart from the electrostatic one, have been found to be nearly additive.

An AB initio comparative study of the electronic properties of sulfonamides and amides

A comparative ab initio study of amides and sulfonamides has been carried out using minimal, extended and polarization basis sets. Rotational barriers and tautomerism are discussed comparatively. The two main conclusions of this study are the absence in sulfonamides of a conjugation of the type present in planar amides and the relative insensitivity of the total energy to nitrogen hybridization in sulfonamides in contrast with amides.

Chiroptical properties of 1-carbapenam and orbital mixing in nonplanar amides

Optical rotatory properties of β-lactam structures are calculated using semiempirical Extended Hückel and CNDO wavefunctions. Possible interpretations of CD and UV absorption data for a recently reported 5-epi-1-carbapenam, (5S)-1-azabicyclo-[3.2.0] heptan-7-one, are proposed. This compound lacks the sulfur of a penicillin nucleus, but still shows a Cotton effect at 231 nm. Analysis is aided by calculations on some monocyclic β-lactams, N-methyl-3-aminoazetidin-2-ones, where the Me carbon is incrementally bent out of the plane of the 4-membered ring. When N is pyramidal, the n and π orbitals of planar amides become mixed into two orbitals which correctly yield opposite signs for the Cotton effects at 231 nm and at just below 200 nm. A correspondence is proposed between the CD bands of 5-epi-1-carbapenam and those observed for another carbocyclic, nonplanar lactam, 4-azatricyclo(4.4.0.0 3,8] decan-5-one. The origin of the spectroscopically relevant orbitals of penams, penam sulfoxides, and other β-lactams is shown in a correlation diagram. In the spectral calculations, shortcomings of the semiempirical methods are encountered and discussed.

Antamanide. Evidence for a conformational change and non planar amide groups

Detailed CD- and UV-studies indicate a conformational change in antamanide by interaction with cations or polar solvents. The conformation formed on addition of water is similar to that of the complex. A model for antamanide already suggested by Ovchinnikov's (1) group is confirmed by CD-data and by substitutions in position 1 and 4 (2). The unusually high negative dichroism at about 230 nm is ascribed to n → π ∗ transitions of transoid tertiary amide groups distorted out of plane. Non planar amides probably also determine the dichroic properties of enniatin B (3) and of some acetylproline derivatives (4).