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Special Issue "Amide Bond Activation"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: 30 November 2018

Special Issue Editor

Guest Editor
Prof. Dr. Michal Szostak

Department of Chemistry, Rutgers University, 73 Warren St, Newark, NJ 07102, United States
Website | E-Mail
Interests: homogeneous catalysis; organometallic chemistry; N–C activation; amide bonds; cross-coupling; C–H activation; N-heterocyclic carbenes; single electron transfer; synthetic methods; transition metal catalysis

Special Issue Information

Dear Colleagues,

The amide bond represents a privileged motif in chemistry. One fascinating feature of the amide bond is the innate stability achieved by delocalization of the nitrogen lone pair into the carbonyl group. Defying conventional knowledge that characterizes the amide bond as one of the most robust functional groups in synthetic chemistry, recent years have witnessed an explosion of interest in the development of new chemical transformations of amides. An important trend involves chemoselective activation of the N–C amide bond by metal insertion. This thriving class of reactions originates from the classic studies on amide bond destabilization and has a potential to become widely applicable cross-coupling platform. More generally, N–C bond activation emphasizes the significance of ubiquitous amide bonds to participate in a wide range of electrophilic, Lewis acid, radical, and nucleophilic reaction pathways, among other transformations. These methods are beneficial to chemists because they supply valuable compounds by functional group interconversion or functionalization of amides on the fundamental level. Equally relevant are structural and theoretical studies that provide the basis for chemoselective manipulation of amidic resonance. This Special Issue aims to provide a broad survey of recent advances in activation of amides and address various approaches in the field. This Special Issue will contain contributions describing multifaceted aspects of this area. Reviews articles by experts in the field are also welcome.

Prof. Dr. Michal Szostak
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Amides
  • Amide bond
  • Bond functionalization
  • Functional group interconversion
  • Organic synthesis
  • Cross-coupling
  • Catalysis
  • N–C activation
  • Esters
  • O–C activation
  • Resonance
  • Planarity
  • Winkler-Dunitz parameters
  • Twisted amides

Published Papers (7 papers)

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Research

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Open AccessArticle Unexpected Resistance to Base-Catalyzed Hydrolysis of Nitrogen Pyramidal Amides Based on the 7-Azabicyclic[2.2.1]heptane Scaffold
Molecules 2018, 23(9), 2363; https://doi.org/10.3390/molecules23092363
Received: 25 August 2018 / Revised: 10 September 2018 / Accepted: 12 September 2018 / Published: 15 September 2018
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Abstract
Non-planar amides are usually transitional structures, that are involved in amide bond rotation and inversion of the nitrogen atom, but some ground-minimum non-planar amides have been reported. Non-planar amides are generally sensitive to water or other nucleophiles, so that the amide bond is
[...] Read more.
Non-planar amides are usually transitional structures, that are involved in amide bond rotation and inversion of the nitrogen atom, but some ground-minimum non-planar amides have been reported. Non-planar amides are generally sensitive to water or other nucleophiles, so that the amide bond is readily cleaved. In this article, we examine the reactivity profile of the base-catalyzed hydrolysis of 7-azabicyclo[2.2.1]heptane amides, which show pyramidalization of the amide nitrogen atom, and we compare the kinetics of the base-catalyzed hydrolysis of the benzamides of 7-azabicyclo[2.2.1]heptane and related monocyclic compounds. Unexpectedly, non-planar amides based on the 7-azabicyclo[2.2.1]heptane scaffold were found to be resistant to base-catalyzed hydrolysis. The calculated Gibbs free energies were consistent with this experimental finding. The contribution of thermal corrections (entropy term, –TΔS) was large; the entropy term (ΔS) took a large negative value, indicating significant order in the transition structure, which includes solvating water molecules. Full article
(This article belongs to the Special Issue Amide Bond Activation)
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Open AccessArticle Electronic Effect on the Molecular Motion of Aromatic Amides: Combined Studies Using VT-NMR and Quantum Calculations
Molecules 2018, 23(9), 2294; https://doi.org/10.3390/molecules23092294
Received: 6 August 2018 / Revised: 4 September 2018 / Accepted: 4 September 2018 / Published: 8 September 2018
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Abstract
Rotational barrier energy studies to date have focused on the amide bond of aromatic compounds from a kinetic perspective using quantum calculations and nuclear magnetic resonance (NMR). These studies provide valuable information, not only regarding the basic conformational properties of amide bonds but
[...] Read more.
Rotational barrier energy studies to date have focused on the amide bond of aromatic compounds from a kinetic perspective using quantum calculations and nuclear magnetic resonance (NMR). These studies provide valuable information, not only regarding the basic conformational properties of amide bonds but also the molecular gear system, which has recently gained interest. Thus, we investigate the precise motion of the amide bonds of two aromatic compounds using an experimental rotational barrier energy estimation by NMR experiments and a theoretical evaluation of the density functional theory calculation. The theoretical potential energy surface scan method combined with the quadratic synchronous transit 3 method and consideration of additional functional group rotation with optimization and frequency calculations support the results of the variable temperature 1H NMR, with deviations of less than 1 kcal/mol. This detailed experimental and theoretical research strongly supports molecular gear motion in the aromatic amide system, and the difference in kinetic energy indicates that the electronic effect from the aromatic structure has a key role in conformational movements at different temperatures. Our study provides an enhanced basis for future amide structural dynamics research. Full article
(This article belongs to the Special Issue Amide Bond Activation)
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Open AccessArticle K2S2O8-Promoted Aryl Thioamides Synthesis from Aryl Aldehydes Using Thiourea as the Sulfur Source
Molecules 2018, 23(9), 2225; https://doi.org/10.3390/molecules23092225
Received: 30 July 2018 / Revised: 24 August 2018 / Accepted: 29 August 2018 / Published: 1 September 2018
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Abstract
Thiourea as a sulfur atom transfer reagent was applied for the synthesis of aryl thioamides through a three-component coupling reaction with aryl aldehydes and N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMAC). The reaction could tolerate various functional groups and
[...] Read more.
Thiourea as a sulfur atom transfer reagent was applied for the synthesis of aryl thioamides through a three-component coupling reaction with aryl aldehydes and N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMAC). The reaction could tolerate various functional groups and gave moderate to good yields of desired products under the transition-metal-free condition. Full article
(This article belongs to the Special Issue Amide Bond Activation)
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Open AccessArticle Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors
Molecules 2018, 23(7), 1724; https://doi.org/10.3390/molecules23071724
Received: 3 July 2018 / Revised: 10 July 2018 / Accepted: 11 July 2018 / Published: 14 July 2018
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Abstract
Novel primaquine (PQ) and halogenaniline asymmetric fumardiamides 4af, potential Michael acceptors, and their reduced analogues succindiamides 5af were prepared by simple three-step reactions: coupling reaction between PQ and mono-ethyl fumarate (1a) or mono-methyl succinate (1b
[...] Read more.
Novel primaquine (PQ) and halogenaniline asymmetric fumardiamides 4af, potential Michael acceptors, and their reduced analogues succindiamides 5af were prepared by simple three-step reactions: coupling reaction between PQ and mono-ethyl fumarate (1a) or mono-methyl succinate (1b), hydrolysis of PQ-dicarboxylic acid mono-ester conjugates 2a,b to corresponding acids 3a,b, and a coupling reaction with halogenanilines. 1-[bis(Dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) was used as a coupling reagent along with Hünig′s base. Compounds 4 and 5 were evaluated against a panel of bacteria, several Mycobacterium strains, fungi, a set of viruses, and nine different human tumor cell lines. p-Chlorofumardiamide 4d showed significant activity against Staphylococcus aureus,Streptococcus pneumoniae and Acinetobacter baumannii, but also against Candida albicans (minimum inhibitory concentration (MIC) 6.1–12.5 µg/mL). Together with p-fluoro and p-CF3 fumardiamides 4b,f, compound 4d showed activity against Mycobacterium marinum and 4b,f against M. tuberculosis. In biofilm eradication assay, most of the bacteria, particularly S. aureus, showed susceptibility to fumardiamides. m-CF3 and m-chloroaniline fumardiamides 4e and 4c showed significant antiviral activity against reovirus-1, sindbis virus and Punta Toro virus (EC50 = 3.1–5.5 µM), while 4e was active against coxsackie virus B4 (EC50 = 3.1 µM). m-Fluoro derivative 4a exerted significant cytostatic activity (IC50 = 5.7–31.2 μM). Acute lymphoblastic leukemia cells were highly susceptible towards m-substituted derivatives 4a,c,e (IC50 = 6.7–8.9 μM). Biological evaluations revealed that fumardiamides 4 were more active than succindiamides 5 indicating importance of Michael conjugated system. Full article
(This article belongs to the Special Issue Amide Bond Activation)
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Review

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Open AccessReview Direct Transamidation Reactions: Mechanism and Recent Advances
Molecules 2018, 23(9), 2382; https://doi.org/10.3390/molecules23092382 (registering DOI)
Received: 24 August 2018 / Revised: 12 September 2018 / Accepted: 13 September 2018 / Published: 18 September 2018
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Abstract
Amides are undeniably some of the most important compounds in Nature and the chemical industry, being present in biomolecules, materials, pharmaceuticals and many other substances. Unfortunately, the traditional synthesis of amides suffers from some important drawbacks, principally the use of stoichiometric activators or
[...] Read more.
Amides are undeniably some of the most important compounds in Nature and the chemical industry, being present in biomolecules, materials, pharmaceuticals and many other substances. Unfortunately, the traditional synthesis of amides suffers from some important drawbacks, principally the use of stoichiometric activators or the need to use highly reactive carboxylic acid derivatives. In recent years, the transamidation reaction has emerged as a valuable alternative to prepare amides. The reactivity of amides makes their direct reaction with nitrogen nucleophiles difficult; thus, the direct transamidation reaction needs a catalyst in order to activate the amide moiety and to promote the completion of the reaction because equilibrium is established. In this review, we present research on direct transamidation reactions ranging from studies of the mechanism to the recent developments of more applicable and versatile methodologies, emphasizing those reactions involving activation with metal catalysts. Full article
(This article belongs to the Special Issue Amide Bond Activation)
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Open AccessReview Transition-Metal-Free Activation of Amide Bond by Arynes
Molecules 2018, 23(9), 2145; https://doi.org/10.3390/molecules23092145
Received: 3 August 2018 / Revised: 20 August 2018 / Accepted: 24 August 2018 / Published: 27 August 2018
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Abstract
Highly reactive arynes activate the N–C and C=O bonds of amide groups under transition metal-free conditions. This review highlights the insertion of arynes into the N–C and C=O bonds of the amide group. The insertion of arynes into the N–C bond gives the
[...] Read more.
Highly reactive arynes activate the N–C and C=O bonds of amide groups under transition metal-free conditions. This review highlights the insertion of arynes into the N–C and C=O bonds of the amide group. The insertion of arynes into the N–C bond gives the unstable four-membered ring intermediates, which are easily converted into ortho-disubstituted arenes. On the other hand, the selective insertion of arynes into the C=O bond is observed when the sterically less-hindered formamides are employed to give a reactive transient intermediate. Therefore, the trapping reactions of transient intermediates with a variety of reactants lead to the formation of oxygen atom-containing heterocycles. As relative functional groups are activated, the reactions of arynes with sulfinamides, phosphoryl amides, cyanamides, sulfonamides, thioureas, and vinylogous amides are also summarized. Full article
(This article belongs to the Special Issue Amide Bond Activation)
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Open AccessFeature PaperReview Recent Uses of N,N-Dimethylformamide and N,N-Dimethylacetamide as Reagents
Molecules 2018, 23(8), 1939; https://doi.org/10.3390/molecules23081939
Received: 13 July 2018 / Revised: 30 July 2018 / Accepted: 31 July 2018 / Published: 3 August 2018
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Abstract
N,N-Dimethylformamide and N,N-dimethylacetamide are multipurpose reagents which deliver their own H, C, N and O atoms for the synthesis of a variety of compounds under a number of different experimental conditions. The review mainly highlights the corresponding
[...] Read more.
N,N-Dimethylformamide and N,N-dimethylacetamide are multipurpose reagents which deliver their own H, C, N and O atoms for the synthesis of a variety of compounds under a number of different experimental conditions. The review mainly highlights the corresponding literature published over the last years. Full article
(This article belongs to the Special Issue Amide Bond Activation)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of the paper: Review
Tentative title: Direct transamidation reactions: Mechanism and recent advances
Authors: Paola Acosta-Guzman, Alejandra Mateus-Gómez and Diego Gamba-Sánchez*
Affiliation: Laboratory of Organic Synthesis, Bio and Organocatalysis, Chemistry Department, Universidad de los Andes, Carrera 1 No 18A-12 Q:305, Bogotá 111711, Colombia
Abstract: Amides are undeniably one of the most important compounds in nature and chemical industry; they are present in biomolecules, materials, pharmaceuticals and many other molecules. Unfortunately, the traditional synthesis of amides suffers of some important drawbacks, principally the use of stoichiometric activators or the use of highly reactive carboxylic acid derivatives. In recent years the transamidation reaction has emerged as a valuable alternative to prepare amides. The reactivity of amides makes difficult its direct reaction with nitrogen nucleophiles, thus the direct transamidation reaction needs a catalyst in order to activate the amide moiety and to promote the completion of the reaction, because equilibrium is established. In this review, we present the direct transamidation reaction since the studies of its mechanism, until the recent developments of more applicable and versatile methodologies, emphasizing in activation with metal catalyst.

Type of the paper: Review
Tentative Title: Transition-Metal-Free Activation of Amide Bond by Arynes
Author: Hideto Miyabe
Affiliation: School of Pharmacy, Hyogo University of Health Sciences, Minatojima 1-3-6, Chuo-ku, Kobe 650-8530, Japan
Abstract: The reaction of amide and the relative functional groups with arynes has made great advances in synthetic chemistry. This review highlights the insertion of arynes into the C=O bond as a C=O bond activation of amides and the insertion of arynes into the C-N bond as a C-N bond activation of amines. Additionally, the reactions of arynes with imides, thioureas, sulfinamides, sulfonamides and vinylogous amides as the relative functional groups are summarized.

Title: Ruthenium catalytic systems comprising a labile cyclooctadiene ligand and N-heterocyclic carbene precursors for the atom-economic alcohol amidation with amines
Author: Cheng Chen
Affiliation: State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, China
Abstract: Transition-metal-catalyzed amide bond formation from alcohols and amines is an atom-economic and eco-friendly route. Herein, we identified a highly active in situ N-heterocyclic carbene (NHC)/ruthenium (Ru) catalytic system for this amide synthesis. Various substrates, including sterically hindered ones, could be directly transformed into the corresponding amides with the catalyst loading as low as 0.25 mol%. In this system, we replaced the p-cymene ligand of the ruthenium source with a relatively labile cyclooctadiene (cod) ligand so as to more efficiently obtain the poly-carbene species. Expectedly, the weaker cod ligand could be more easily substituted with multiple mono-NHC ligands. Further HR-MS analysis has confirmed that several poly-NHC ruthenium complexes were generated from the in situ catalytic system.
Keywords: ruthenium (Ru), N-heterocyclic carbene (NHC), in situ, amide bond, synthesis

Title: Heteroatom Substitution at Amide Nitrogen — Resonance Reduction and HERON Reactions
Author: Steve Glover
Affiliation: Department of Chemistry, School of Science and Technology, University of New England, Armidale NSW Australia
Abstract: This review describes how resonance in amides is strongly affected upon substitution at nitrogen by two electronegative atoms. Nitrogen becomes strongly pyramidal and resonance stabilisation, which can be reliably evaluated computationally, can be reduced to as little as 50%. However, this occurs without significant twisting about the amide bond, which is borne out both experimentally and theoretically. In certain configurations, reduced resonance and pronounced anomeric effects between heteroatom substituents are instrumental in driving the HERON (Heteroatom Rearrangements On Nitrogen) reaction, in which the more electronegative atom migrates from nitrogen to the carbonyl carbon in concert with heterolysis of the amide bond to generate acyl derivatives and heteroatom-substituted nitrenes.

Title: Amide Bond Activation of Biological Molecules
Author: Monika Raj
Affiliation: Auburn University, Auburn, AL, USA
Abstract: Amide bonds are most prevalent structures not only in small organic compounds but also a core moiety present in various biomolecules (peptides, proteins, DNA, RNA). The amide bonds are responsible for the 3-D structures adopted by these biological molecules and their functions. The main focus of this review article is to report the methodologies for the activation of the unactivated amide bonds present in biomolecules, which includes enzymatic approach, metal complexes and non-metal based methods. Also, this article discusses some of the applications of these amide bond activation approaches in sequencing of proteins, synthesis of peptide acids, esters, amides, and thioesters.

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