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Quantum Chemical Studies of Aromatic Substitution Reactions
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, density functional theory (DFT) is used to investigate the mechanisms and reactivities of electrophilic and nucleophilic aromatic substitution reactions (SEAr and SNAr respectively). For SEAr, the σ-complex intermediate is preceded by one (halogenation) or two (nitration) π-complex intermediates. Whereas the rate-determining transition state (TS) for nitration resembles the second π-complex, the corresponding chlorination TS is much closer to the σ-complex. The last step, the expulsion of the proton, is modeled with an explicit solvent molecule in combination with PCM and confirmed to be a nearly barrierless process for nitration/chlorination and involves a substantial energy barrier for iodination. It is also shown for nitration that the gas phase structures and energetics are very different from those in polar solvent. The potential energy surface for SNAr reactions differs greatly depending on leaving group; the σ-complex intermediate exist for F-/HF, but for Cl-/HCl or Br-/HBr the calculations indicate a concerted mechanism. These mechanistic results form a basis for the investigations of predictive reactivity models for aromatic substitution reactions. For SEAr reactions, the free energy of the rate-determining TS reproduces both local (regioselectivity) and global reactivity (substrate selectivity) with good to excellent accuracy. For SNAr reactions good accuracies are obtained for Cl-/HCl or Br-/HBr as leaving group, using TS structures representing a one-step concerted mechanism. The σ-complex intermediate can be used as a reactivity indicator for the TS energy, and for SEAr the accuracy of this method varies in a way that can be rationalized with the Hammond postulate. It is more accurate the later the rate-determining TS, that is the more deactivated the reaction. For SNAr reactions with F-/HF as leaving group, the same method gives excellent accuracy for both local and global reactivity irrespective of the degree of activation.

Place, publisher, year, edition, pages
Stockholm: Universitetsservice US AB, Stockholm , 2017. , p. 74
Series
TRITA-CHE-Report, ISSN 1654-1081
National Category
Physical Chemistry
Research subject
Theoretical Chemistry and Biology
Identifiers
URN: urn:nbn:se:kth:diva-206964ISBN: 978-91-7729-324-8 (electronic)OAI: oai:DiVA.org:kth-206964DiVA, id: diva2:1094572
Public defence
2017-06-07, Sal F3, Lindstedtsvägen 26, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

QC 20170510

Available from: 2017-05-10 Created: 2017-05-10 Last updated: 2017-05-10Bibliographically approved
List of papers
1. Validation of a Computational Model for Predicting the Site for Electrophilic Substitution in Aromatic Systems
Open this publication in new window or tab >>Validation of a Computational Model for Predicting the Site for Electrophilic Substitution in Aromatic Systems
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2010 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 14, p. 4696-4705Article in journal (Refereed) Published
Abstract [en]

We have investigated the scope and limitations of a method for predicting the regioisomer distribution in electrophilic aromatic substitution reactions that are under kinetic control. This method is based on calculation of the relative stabilities of the sigma-complex intermediates using density functional theory. Predictions from this method can be used quantitatively for halogenations; it agreed to an accuracy of about 1 kcal/mol with experimental observations in 10 of the 11 investigated halogenation reactions. For nitrations, the method gave useful predictions for heterocyclic substrates. The method failed for nitration of monosubstituted benzenes, and we expect that more elaborate model systems, including explicit solvent molecules, will be necessary to obtain quantitatively useful predictions for such cases. For Lewis acid promoted Friedel Crafts acylations, the method can be expected to give qualitatively correct predictions, that is, to point out the dominating isomer. For substrates where the regioisomeric outcome is highly dependent on the reaction conditions, the method can only be of qualitative use if the concentration of the free Lewis acid is high during the reaction. We have also compared the predictive capacity of the method to that of a modern reactivity index, the average local ionization energy, I(r). The latter method is found to predict the regisolectivity in halogenations and nitrations qualitatively correctly if the positions for the I(r) minima (I-S,I-min) are not too sterically hindered but fails for qualitative predictions of F C reactions. The downscaled I-S,I-min values also perform well for the quantitative prediction of regioisomer distributions of halogenations. The accuracy is slightly lower than that for the new method.

Keywords
FRIEDEL-CRAFTS ACYLATION, LOCAL IONIZATION ENERGIES, NITROGEN-HETEROCYCLES, CONJUGATED MOLECULES, STABLE CARBOCATIONS, RATE CONSTANTS, GROUND-STATES, NITRATION, BENZENE, MECHANISM
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-29508 (URN)10.1021/jo100310v (DOI)000279569500004 ()2-s2.0-77954549902 (Scopus ID)
Note

QC 20110202. Detta är ett delarbete i en doktorsavhandling.

Available from: 2011-02-02 Created: 2011-02-02 Last updated: 2017-12-11Bibliographically approved
2. A pragmatic procedure for predicting regioselectivity in nucleophilic substitution of aromatic fluorides
Open this publication in new window or tab >>A pragmatic procedure for predicting regioselectivity in nucleophilic substitution of aromatic fluorides
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2011 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 52, p. 3150-3153Article in journal (Refereed) Published
Abstract [en]

The scope and limitations of a method for predicting the regioisomer distribution in kinetically controlled nucleophilic substitution reactions of aromatic fluorides have been investigated. This method is based on calculating the relative stabilities of the isomeric σ-complex intermediates using DFT. A wide set of substrates and anionic nucleophiles have been investigated. Predictions from this method can be used quantitatively—these agree to an average accuracy of ±0.5 kcal/mol with experimental observations in eleven of the twelve investigated reactions.

Place, publisher, year, edition, pages
Elsevier, 2011
Keywords
Nucleophilic substitution; Regioselectivity; Computational; sigma-Complex; DFT
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-204496 (URN)10.1016/j.tetlet.2011.04.032 (DOI)000292350800023 ()2-s2.0-79956042668 (Scopus ID)
Note

Artikeln ingår som ett delarbete i en doktorsavhandling. QC 20170411

Available from: 2017-03-27 Created: 2017-03-27 Last updated: 2017-11-29Bibliographically approved
3. Predicting Regioselectivity in Nucleophilic Aromatic Substitution
Open this publication in new window or tab >>Predicting Regioselectivity in Nucleophilic Aromatic Substitution
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2012 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, no 7, p. 3262-3269Article in journal (Refereed) Published
Abstract [en]

We have investigated practical and computationally efficient methods for the quantitative prediction of regioisomer distribution in kinetically controlled nucleophilic aromatic substitution reactions. One of the methods is based on calculating the relative stabilities of the isomeric sigma-complex intermediates using DFT. We show that predictions from this method can be used quantitatively both for anionic nucleophiles with F- as leaving group, as well as for neutral nucleophiles with HF as leaving group. The sigma-complex approach failed when the leaving group was Cl/HCl or Br/HBr, both for anionic and neutral nucleophiles, because of difficulties in finding relevant sigma-complex structures. An approach where we assumed a concerted substitution step and used such transition state structures gave quantitatively useful results. Our results are consistent with other theoretical works, where a stable sigma-complex has been identified in some cases, whereas others have been indicated to proceed via a concerted substitution step.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-93912 (URN)10.1021/jo202569n (DOI)000302388000023 ()2-s2.0-84859611539 (Scopus ID)
Note

QC 20120507. Artikeln ingår som ett delarbete i en doktorsavhandling.

Available from: 2012-05-07 Created: 2012-05-03 Last updated: 2017-12-07Bibliographically approved
4. Utilizing the sigma-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides
Open this publication in new window or tab >>Utilizing the sigma-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides
2013 (English)In: Beilstein Journal of Organic Chemistry, ISSN 2195-951X, E-ISSN 1860-5397, Vol. 9, p. 791-799Article in journal (Refereed) Published
Abstract [en]

A computational approach using density functional theory to compute the energies of the possible sigma-complex reaction intermediates, the "sigma-complex approach", has been shown to be very useful in predicting regioselectivity, in electrophilic as well as nucleophilic aromatic substitution. In this article we give a short overview of the background for these investigations and the general requirements for predictive reactivity models for the pharmaceutical industry. We also present new results regarding the reaction rates and regioselectivities in nucleophilic substitution of fluorinated aromatics. They were rationalized by investigating linear correlations between experimental rate constants (k) from the literature with a theoretical quantity, which we call the sigma stability (SS). The SS is the energy change associated with formation of the intermediate sigma-complex by attachment of the nucleophile to the aromatic ring. The correlations, which include both neutral (NH3) and anionic (MeO-) nucleophiles are quite satisfactory (r = 0.93 to r = 0.99), and SS is thus useful for quantifying both global (substrate) and local (positional) reactivity in SNAr reactions of fluorinated aromatic substrates. A mechanistic analysis shows that the geometric structure of the sigma-complex resembles the rate-limiting transition state and that this provides a rationale for the observed correlations between the SS and the reaction rate.

Place, publisher, year, edition, pages
Beilstein-institut, 2013
Keywords
computational, DFT, nucleophilic aromatic substitution, reactivity, substrate selectivity, reactive intermediates
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-123629 (URN)10.3762/bjoc.9.90 (DOI)000318481600002 ()2-s2.0-84877285731 (Scopus ID)
Note

QC 20130613. Denna artikel ingår som ett delarbete i en doktorsavhandling.

Available from: 2013-06-13 Created: 2013-06-13 Last updated: 2017-05-17Bibliographically approved
5. Theoretical investigation of regioselectivity in electrophilic aromatic nitration
Open this publication in new window or tab >>Theoretical investigation of regioselectivity in electrophilic aromatic nitration
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The potential energy surfaces in gas phase and in aqueous solution for the nitration of benzene, chlorobenzene and phenol have been elucidated with density functional theory at the M06-2X/6-311G(d,p) level combined with the polarizable continuum solvent model (PCM). Three reaction intermediates have been identified along both surfaces: the unoriented π-complex (I), the oriented reaction complex (II) and the σ-complex (III). In order to obtain quantitatively reliable results for positional selectivity and for modeling the expulsion of the proton, it is crucial to take solvent effects into consideration. The results are in agreement with Olah´s conclusion from over 40 years ago that the transition state leading to (II) is the rate-determining step in activated cases, while it is the one leading to (III) for deactivated cases. The simplified reactivity approach of using the free energy for the formation of (III) as a model of the ratedetermining transition state, has previously been shown to be very successful for halogenations, but problematic for nitrations. These observations are rationalized with the geometric and energetic resemblance, and lack of resemblance respectively, between (III) and the corresponding rate determining transition state. At this level of theory, neither the σ-complex (III) nor the reaction complex (II) can be used to accurately model the rate-determining transition state for nitrations.

National Category
Physical Chemistry
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-206952 (URN)
Note

QC 20170510

Available from: 2017-05-10 Created: 2017-05-10 Last updated: 2017-05-17Bibliographically approved
6. An investigation into rate-determining factors in electrophilic aromatic halogenation
Open this publication in new window or tab >>An investigation into rate-determining factors in electrophilic aromatic halogenation
(English)Manuscript (preprint) (Other academic)
Abstract [en]

We have studied the halogenations of monosubstituted benzenes in polar, protic solvents at the PCMM06-2X/6-311G(d,p) level. We verify that the reaction with Cl2 proceeds through a C-atom coordinated π-complex and a rate-determining transition state for the formation of the σ-complex.

The last step of this reaction proceeds in two steps – first the dissociation of Cl- and then the abstraction of the proton with a weak base. The use of the σ-complex as a model for the ratedetermining transition state is more accurate the later this transition state comes along the reaction coordinate, and thus, it is in general more accurate for halogenations than for nitrations, and for halogenations the more deactivated the substrate. The bromination of anisole with Br2 is shown to have a much later rate-determining transition state than the corresponding reaction with Cl2. The energy barrier for the abstraction of the proton in the iodination of anisole and phenol was several times higher than the corresponding step in chlorination and nitration, and the transition state structure obtained with ICl as electrophile is for both substrates consistent with a concerted reaction without the formation of a stable σ-complex. The computed hydrogen kinetic isotope effects are in good agreement with experiment.

National Category
Theoretical Chemistry
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-206963 (URN)
Note

QC 20170510

Available from: 2017-05-10 Created: 2017-05-10 Last updated: 2017-05-17Bibliographically approved

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Output format
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