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Brønsted Acid-Catalyzed Intramolecular Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer
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2015 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, no 14, p. 4646-4649Article in journal (Refereed) Published
Abstract [en]

The hydroxyl group of enantioenriched benzyl, propargyl, allyl, and alkyl alcohols has been intramolecularly displaced by uncharged O-, N-, and S-centered nucleophiles to yield enantioenriched tetrahydrofuran, pyrrolidine, and tetrahydrothiophene derivatives with phosphinic acid catalysis. The five-membered heterocyclic products are generated in good to excellent yields, with high degree of chirality transfer, and water as the only side-product. Racemization experiments show that phosphinic acid does not promote S(N)1 reactivity. Density functional theory calculations corroborate a reaction pathway where the phosphinic acid operates as a bifunctional catalyst in the intramolecular substitution reaction. In this mechanism, the acidic proton of the phosphinic acid protonates the hydroxyl group, enhancing the leaving group ability. Simultaneously, the oxo group of phosphinic acid operates as a base abstracting the nucleophilic proton and thus enhancing the nucleophilicity. This reaction will open up new atom efficient techniques that enable alcohols to be used as nucleofuges in substitution reactions in the future.

Place, publisher, year, edition, pages
2015. Vol. 137, no 14, p. 4646-4649
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-117729DOI: 10.1021/jacs.5b02013ISI: 000353177100014OAI: oai:DiVA.org:su-117729DiVA, id: diva2:818891
Funder
Swedish Research CouncilStiftelsen Olle Engkvist ByggmästareThe Wenner-Gren FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineKnut and Alice Wallenberg FoundationAvailable from: 2015-06-09 Created: 2015-06-01 Last updated: 2019-04-01Bibliographically approved
In thesis
1. Direct Catalytic Nucleophilic Substitution of Non-Derivatized Alcohols
Open this publication in new window or tab >>Direct Catalytic Nucleophilic Substitution of Non-Derivatized Alcohols
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on the development of methods for the activation of the hydroxyl group in non-derivatized alcohols in substitution reactions. The thesis is divided into two parts, describing three different catalytic systems.

The first part of the thesis (Chapter 2) describes nucleophilic allylation of amines with allylic alcohols, using a palladium catalyst to generate unsymmetrical diallylated amines. The corresponding amines were further transformed by a one-pot ring-closing metathesis and aromatization reaction to afford β-substituted pyrroles with linear and branched alkyl, benzyl, and aryl groups in overall moderate to good yields.

The second part (Chapters 3 and 4) describes the direct intramolecular stereospecific nucleophilic substitution of the hydroxyl group in enantioenriched alcohols by Lewis acid and Brønsted acid/base catalysis.

In Chapter 3, the direct intramolecular substitution of non-derivatized alcohols has been developed using Fe(OTf)3 as catalyst. The hydroxyl groups of aryl, allyl, and alkyl alcohols were substituted by the attack of O- and N-centered nucleophiles, to provide five- and six-membered heterocycles in up to excellent yields with high enantiospecificities. Experimental studies showed that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile of the substrate. Competition and catalyst-substrate interaction experiments demonstrated that this transformation proceeds via an SN2-type reaction pathway.

In Chapter 4, a Brønsted acid/base catalyzed intramolecular substitution of non-derivatized alcohols was developed. The direct intramolecular and stereospecific substitution of different alcohols was successfully catalyzed by phosphinic acid (H3PO2). The hydroxyl groups of aryl, allyl, propargyl, and alkyl alcohols were substituted by O-, N-, and S-centered nucleophiles to generate five- and six-membered heterocycles in good to excellent yields with high enantiospecificities. Mechanistic studies (both experiments and density functional theory calculations) have been performed on the reaction forming five-membered heterocyclic compounds. Experimental studies showed that phosphinic acid does not promote SN1 reactivity. Rate-order determination indicated that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile. DFT calculations corroborated with a reaction pathway in which the phosphinic acid has a dual activation mode and operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the nucleophile and nucleofuge, resulting in a unique bridging transition state in an SN2-type reaction mechanism.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2017. p. 76
Keywords
nucleophilic substitution, catalysis, alcohols, stereospecific, Lewis acid, Brønsted acid/base, bifunctional, heterocycles
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-146426 (URN)978-91-7649-917-7 (ISBN)978-91-7649-918-4 (ISBN)
Public defence
2017-10-05, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.

Available from: 2017-09-12 Created: 2017-08-30 Last updated: 2017-10-12Bibliographically approved
2. Theoretical Investigations of C–O Activation in Biomass
Open this publication in new window or tab >>Theoretical Investigations of C–O Activation in Biomass
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on using computational chemistry approaches to study how biobased molecules interact with both homo- and heterogeneous catalysts. The reaction mechanisms of such transformations have also been studied.

The first section comprises studies of interactions between organic molecules and a heterogeneous catalyst in the palladium-catalyzed depolymerization of models of lignin derivatives. From experiments, it was proposed that a keto intermediate and its enol tautomer play a significant role in the β-O-4′ bond cleavage. The study in the first section of this thesis has been divided into three parts. First, simplified models of the keto intermediate and its enol tautomer were used to investigate the adsorption to a Pd(111) surface. By using a combination of periodic density functional theory (DFT) calculations and a constrained minima hopping method, the most stable adsorption which is the so-called global minimum, was found to be an enol adsorbed to the surface.

In the second part, the study was expanded to cope with models of lignin which were used in experiments. In addition, we studied the effect of adsorbate coverage, where two different Pd(111) super cells were compared. The optimizations were performed via dispersion-corrected density functional theory (DFT-D3). The molecules were found to bind more strongly to the surface at low coverages. These results support the experimental data and show that the tautomerization has an important role during lignin depolymerization. 

The third part relates to using a multilevel procedure to study the interaction of fragments derived from lignin depolymerisation with a palladium catalyst in a solvent mixture. Specifically, QM calculations and MD simulations based on the ReaxFF approach were combined to explore the reaction mechanisms occurring on Pd surfaces with lignin derivatives obtained from a solvolysis reaction. The strongest adsorptions were found to be between the aromatic rings and the Pd surfaces.

The second section focuses on a Brønsted acid-catalyzed nucleophilic substitution of the hydroxyl group in alcohols. Experimentally, phosphinic acid (H3PO2) was found to be an excellent catalyst for the direct intramolecular substitution of non-derivatized alcohols proceeding with good to excellent chirality transfer. In this section, benzylic alcohols with internal O-, N-, and S-centered nucleophiles were used in the calculations. By using a hybrid functional method, we found a bicyclic transition state where the proton of the H3PO2 protonates the leaving hydroxyl group, and the oxo-group of the same catalyst partially deprotonates the nucleophile. The transition state energies for the reactions were determined computationally. The calculations support an SN2 mechanism, which corresponds to the experimental data where inversion of the stereogenic carbon was observed.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2019. p. 77
Keywords
DFT calculations, global minima hopping, reactive force field, lignin, palladium, nucleophilic substitution
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-167592 (URN)978-91-7797-709-4 (ISBN)978-91-7797-710-0 (ISBN)
Public defence
2019-05-22, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

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

Available from: 2019-04-25 Created: 2019-04-01 Last updated: 2019-04-10Bibliographically approved

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