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Group (IV) Metal-Catalyzed Direct Amidation: Synthesis and Mechanistic Considerations
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Hans Adolfsson)
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The amide unit constitutes the backbone of proteins, and it is present in a large number of pharmaceutically active molecules, polymeric materials such as nylon and Kevlar, as well as in food additives like aspartame. Amides are produced in enormous amounts every year, thus, environmentally friendly and selective methods for their formation are of great importance. This thesis deals with the direct formation of amides from non-activated carboxylic acids and amines with the aid of group (IV) metal complexes. Water is the only by-product of this environmentally benign process. This fact stands in contrast to the most common methods for amide formation to date, which involve the use of waste-intensive, expensive and often toxic coupling reagents. The catalytic protocols presented herein use titanium, zirconium and hafnium complexes under mild reaction conditions to produce amides in good to excellent yields. Furthermore, carbamates are demonstrated to be suitable sources of gaseous amines for the formation of primary and tertiary amides under catalytic conditions. In addition, preliminary results from on-going mechanistic investigations of the zirconium- and hafnium-catalyzed processes are presented.

Abstract [sv]

Amidbindningen är en kemisk enhet som utgör ryggraden i proteiner, och som även återfinns i en stor mängd läkemedelsmolekyler, polymera material som nylon och Kevlar, samt i tillsatser i livsmedelsindustrin, exempelvis aspartam. Amider produceras i enorma mängder varje år, och det är av stor vikt att utveckla miljövänliga och selektiva metoder för deras framställning. Denna avhandling behandlar direkt amidering av icke-aktiverade karboxylsyror och aminer med hjälp av katalytiska mängder metallkomplex, baserade på titan, zirkonium och hafnium. Den enda biprodukten från denna amideringsreaktion är vatten. Jämfört med de metoder som generellt används idag för amidsyntes, så är de presenterade metoderna avsevärt mer miljövänliga med avseende på toxicitet hos reagensen såväl som på mängden avfall som genereras. Dessutom redovisas här en katalytisk metod för syntes av primära och tertiära amider genom att använda olika karbamat som källa till gasformiga aminer, vilka annars kan vara praktiskt svåra att arbeta med. Preliminära resultat från en pågående mekanistisk studie av de zirkonium- och hafnium-katalyserade processerna är också inkluderade.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2015. , 77 p.
Keyword [en]
catalysis, amide, carboxylic acid, amino acid, titanium, zirconium, hafnium
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-116955ISBN: 978-91-7649-163-8 (print)OAI: oai:DiVA.org:su-116955DiVA: diva2:809569
Public defence
2015-06-12, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Accepted.

Available from: 2015-05-21 Created: 2015-05-04 Last updated: 2015-06-24Bibliographically approved
List of papers
1. Direct Amide Coupling of Non-activated Carboxylic Acids and Amines Catalysed by Zirconium(IV) Chloride
Open this publication in new window or tab >>Direct Amide Coupling of Non-activated Carboxylic Acids and Amines Catalysed by Zirconium(IV) Chloride
2012 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 13, 3822-3826 p.Article in journal (Refereed) Published
Keyword
amides, amines, carboxylic acids, homogeneous catalysis, zirconium
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-76257 (URN)10.1002/chem.201104055 (DOI)000301775300002 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2012-05-25 Created: 2012-05-10 Last updated: 2017-12-07Bibliographically approved
2. Zirconium(IV) chloride catalyzed amide formation from carboxylic acids and amines: N-Benzyl-2-(phenylthio)acetamide and (S)-tert-butyl 2-(benzylcarbamoyl)pyrrolidine-1-carboxylate
Open this publication in new window or tab >>Zirconium(IV) chloride catalyzed amide formation from carboxylic acids and amines: N-Benzyl-2-(phenylthio)acetamide and (S)-tert-butyl 2-(benzylcarbamoyl)pyrrolidine-1-carboxylate
(English)In: Organic Syntheses, ISSN 0078-6209Article in journal (Refereed) Accepted
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-116890 (URN)10.15227/orgsyn.092.0227 (DOI)
Available from: 2015-05-04 Created: 2015-05-04 Last updated: 2017-12-04Bibliographically approved
3. Titanium(IV) Isopropoxide as an Efficient Catalyst for Direct Amidation of Nonactivated Carboxylic Acids
Open this publication in new window or tab >>Titanium(IV) Isopropoxide as an Efficient Catalyst for Direct Amidation of Nonactivated Carboxylic Acids
2012 (English)In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 23, no 15, 2201-2204 p.Article in journal (Refereed) Published
Abstract [en]

Secondary and tertiary amides are formed in high yields, in an efficient and environmentally benign titanium(IV) isopropoxide catalyzed direct amidation of carboxylic acids with primary and secondary amines.

Keyword
amides, titanium, catalysis, carboxylic acids, amines
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-81823 (URN)10.1055/s-0032-1316993 (DOI)000308634800009 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:3;

Available from: 2012-11-07 Created: 2012-11-01 Last updated: 2017-12-07Bibliographically approved
4. Hafnium-Catalyzed Direct Amide Formation at Room Temperature
Open this publication in new window or tab >>Hafnium-Catalyzed Direct Amide Formation at Room Temperature
2015 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 5, no 6, 3271-3277 p.Article in journal (Refereed) Published
Abstract [en]

Herein, the first example of a metal-catalyzed protocol for direct amidation of non-activated carboxylic acids at ambient temperature (26 °C) is presented. The mild reaction conditions give rise to high yields of a range of amides in reaction times as short as 90 minutes, employing a commercial hafnium complex, [Hf(Cp)2Cl2], as catalyst. Amino acids are transformed into their corresponding amides without racemization, and the catalyst displays full selectivity for the amidation of carboxylic acids over esters. Electronic properties of the carboxylic acids were found to have a strong influence on the rate of the amidation reaction, and the need for a balanced amount of molecular sieves was observed to be highly important for optimal reaction outcome.

Keyword
hafnium, amidation, carboxylic acid, Lewis acids, catalysis
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-116889 (URN)10.1021/acscatal.5b00385 (DOI)000355964300012 ()
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2015-05-04 Created: 2015-05-04 Last updated: 2017-12-04Bibliographically approved
5. Direct Catalytic Formation of Primary and Tertiary Amides from Non-Activated Carboxylic Acids, Employing Carbamates as Amine Source
Open this publication in new window or tab >>Direct Catalytic Formation of Primary and Tertiary Amides from Non-Activated Carboxylic Acids, Employing Carbamates as Amine Source
2012 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 354, no 13, 2531-2536 p.Article in journal (Refereed) Published
Abstract [en]

The operationally simple titanium(IV)- or zirconium(IV)-catalyzed direct amidation of non-activated carboxylic acids with ammonium carbamates generates primary, and tertiary N,N-dimethyl-substituted amides in good to excellent yields.

Keyword
amides, carboxylic acids, catalysis, titanium, zirconium
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-81253 (URN)10.1002/adsc.201200436 (DOI)000308329300025 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:3;

Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2017-12-07Bibliographically approved

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