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Publications (10 of 12) Show all publications
Daver, H., Rebek, J. & Himo, F. (2020). Modeling the Reaction of Carboxylic Acids and Isonitriles in a Self-Assembled Capsule. Chemistry - A European Journal, 26(47), 10861-10870
Open this publication in new window or tab >>Modeling the Reaction of Carboxylic Acids and Isonitriles in a Self-Assembled Capsule
2020 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 26, no 47, p. 10861-10870Article in journal (Refereed) Published
Abstract [en]

Quantum chemical calculations were used to study the reaction of carboxylic acids with isonitriles inside a resorcinarene-based self-assembled capsule. Experimentally, it has been shown that the reactions betweenp-tolylacetic acid andn-butyl isonitrile or isopropyl isonitrile behave differently in the presence of the capsule compared both with each other and also with their solution counterparts. Herein, the reasons for these divergent behaviors are addressed by comparing the detailed energy profiles for the reactions of the two isonitriles inside and outside the capsule. An energy decomposition analysis was conducted to quantify the different factors affecting the reactivity. The calculations reproduce the experimental findings very well. Thus, encapsulation leads to lowering of the energy barrier for the first step of the reaction, the concerted alpha-addition and proton transfer, which in solution is rate-determining, and this explains the rate acceleration observed in the presence of the capsule. The barrier for the final step of the reaction, the 1,3 O -> N acyl transfer, is calculated to be higher with the isopropyl substituent inside the capsule compared withn-butyl. With the isopropyl substituent, the transition state and the product of this step are significantly shorter than the preceding intermediate, and this results in energetically unfavorable empty spaces inside the capsule, which cause a higher barrier. With then-butyl substituent, on the other hand, the carbon chain can untwine and hence uphold an appropriate guest length.

Keywords
density functional calculations, host-guest systems, molecular capsules, reaction mechanisms, self-assembly
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-184396 (URN)10.1002/chem.202001735 (DOI)000550797000001 ()32428333 (PubMedID)
Available from: 2020-10-07 Created: 2020-10-07 Last updated: 2022-02-25Bibliographically approved
Brea, O., Daver, H., Rebek, J. & Himo, F. (2019). Mechanism(s) of thermal decomposition of N-Nitrosoamides: A density functional theory study. Tetrahedron, 75(8), 929-935
Open this publication in new window or tab >>Mechanism(s) of thermal decomposition of N-Nitrosoamides: A density functional theory study
2019 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 75, no 8, p. 929-935Article in journal (Refereed) Published
Abstract [en]

The thermal decomposition of N-nitrosoamides has experimentally been demonstrated to depend on several factors, such as temperature, solvent and the substituents on the substrate. Consequently, a number of reaction mechanisms have been proposed for this process in the literature. In this work, we present a comprehensive computational investigation in which we examine the detailed reaction mechanisms for two N-nitrosoamides (with aliphatic and aromatic substituents) in two different solvents (mesitylene and methanol). It is shown that the reaction mechanism can change dramatically with the nature of the substrate and the choice of solvent. Importantly, it is found that the polar solvent stabilizes ion-pairs that are unstable in the non-polar solvent, which can play a key role in the mechanism.

Keywords
Nitrosoamides, Reaction mechanism, Density functional theory, Transition state, Computational chemistry
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-166696 (URN)10.1016/j.tet.2018.12.054 (DOI)000458708500001 ()
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2022-02-26Bibliographically approved
Brea, O., Daver, H., Rebek, J. & Himo, F. (2019). Modeling Decomposition of N-Nitrosoamides in a Self-Assembled Capsule. Journal of Organic Chemistry, 84(11), 7354-7361
Open this publication in new window or tab >>Modeling Decomposition of N-Nitrosoamides in a Self-Assembled Capsule
2019 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, no 11, p. 7354-7361Article in journal (Refereed) Published
Abstract [en]

Density functional theory calculations are employed to investigate the mechanism and energies of the decomposition of N-nitrosoamides in the presence of a resorcinarene-based self-assembled nanocapsule. From experiments, it is known that confinement in the capsule inhibits the thermal decomposition of these compounds. N-Nitrosoamides with both aromatic and aliphatic substituents are considered here and the calculations show that, for both kinds, binding to the capsule leads to a significant increase in the energy barrier of the rate-determining step, the 1,3 N -> O acyl transfer reaction. A distortion-interaction analysis is conducted to probe the reasons behind the inhibition of the reaction. In addition, we characterized hypothetical intermediates that might be involved in the formation of the decomposition products inside the capsule. Interestingly, it is found that the capsule stabilizes ion-pair species that are unstable in mesitylene solution. Finally, a possible explanation is proposed for the observed encapsulation of the decomposition product of only one of the substrates.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-170856 (URN)10.1021/acs.joc.9b01034 (DOI)000471212000074 ()31062978 (PubMedID)
Available from: 2019-07-24 Created: 2019-07-24 Last updated: 2022-02-26Bibliographically approved
Das, B., Daver, H., Pyrkosz-Bulska, M., Gumienna-Kontecka, E., Himo, F. & Nordlander, E. (2018). An Unsymmetric Ligand with a N5O2 Donor Set and Its Corresponding Dizinc Complex: A Structural and Functional Phosphoesterase Model. European Journal of Inorganic Chemistry (36), 4004-4013
Open this publication in new window or tab >>An Unsymmetric Ligand with a N5O2 Donor Set and Its Corresponding Dizinc Complex: A Structural and Functional Phosphoesterase Model
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2018 (English)In: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, no 36, p. 4004-4013Article in journal (Refereed) Published
Abstract [en]

To mimic the active sites of the hydrolytic enzyme zinc phosphotriesterase, a new dinucleating unsymmetric ligand, PICIMP (2-{[2-hydroxy-5-methyl-3-({[(1-methyl-1H-imidazol-2-yl)methyl](pyridin-2-ylmethyl)amino}methyl)benzyl][(1-methyl-1H-imidazol-2-yl)methyl]amino}acetic acid), has been synthesized and characterized. The hydrolytic efficacy of the complex solution (PICIMP/ZnCl2 = 1:2) has been investigated using bis-(2,4-dinitrophenyl)phosphate (BDNPP), a DNA analogue substrate. Speciation studies were undertaken by potentiometric titrations at varying pH for both the ligand and the corresponding dizinc complex to elucidate the formation of the active hydrolysis catalyst; these studies reveal that the dinuclear zinc(II) complexes, [Zn-2(PICIMP)](2+) and [Zn-2(PICIMP)(OH)](+) predominate in solution above pH 4. The obtained pK(a) of 7.44 for the deprotonation of water suggests formation of a bridging hydroxide between the two Zn-II ions. Kinetic investigations of BDNPP hydrolysis over the pH range 5.5-10.5 have been performed. The cumulative results indicate the hydroxo-bridged dinuclear Zn-II complex [Zn-2(PICIMP)(mu-OH)](+) as the effective catalyst. Density functional theory calculations were performed to investigate the detailed reaction mechanism. The calculations suggest that the bridging hydroxide becomes terminally coordinated to one of the zinc ions before performing the nucleophilic attack in the reaction.

Keywords
Metalloenzymes, Phosphoester hydrolysis, Active sites, Coordination chemistry
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-162032 (URN)10.1002/ejic.201701416 (DOI)000445850600002 ()
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2022-02-26Bibliographically approved
Daver, H., Algarra, A. G., Rebek, J., Harvey, J. N. & Himo, F. (2018). Mixed Explicit-Implicit Solvation Approach for Modeling of Alkane Complexation in Water-Soluble Self-Assembled Capsules. Journal of the American Chemical Society, 140(39), 12527-12537
Open this publication in new window or tab >>Mixed Explicit-Implicit Solvation Approach for Modeling of Alkane Complexation in Water-Soluble Self-Assembled Capsules
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2018 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 39, p. 12527-12537Article in journal (Refereed) Published
Abstract [en]

The host-guest binding properties of a water-soluble resorcinarene-based cavitand are examined using density functional theory methodology. Experimentally, the cavitand has been observed to self-assemble in aqueous solution into both 1:1 and 2:1 host/guest complexes with hydrophobic guests such as n-alkanes. For n-decane, equilibrium was observed between the 1:1 and 2:1 complexes, while 1:1 complexes are formed with shorter n-alkanes and 2:1 complexes are formed with longer ones. These findings are used to assess the standard quantum chemical methodology. It is first shown that a rather advanced com- putational protocol (B3LYP-D3(BJ)/6-311+G(2d,2p) with COSMO-RS and quasi-rigid-rotor-harmonic-oscillator) gives very large errors. Systematic examination of the various elements of the methodology shows that the error stems from the implicit solvation model. A mixed explicit-implicit solvation protocol is developed that involves a parametrization of the hydration free energy of water such that water cluster formation in water is predicted to be thermoneutral. This new approach is demonstrated to lead to a major improvement in the calculated binding free energies of n-alkanes, reproducing very well the 1:1 versus 2:1 host/guest binding trends.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-161988 (URN)10.1021/jacs.8b06984 (DOI)000446920100035 ()30185035 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2022-02-26Bibliographically approved
Daver, H., Harvey, J. N., Rebek, Jr., J. & Himo, F. (2017). Quantum Chemical Modeling of Cycloaddition Reaction in a Self-Assembled Capsule. Journal of the American Chemical Society, 139(43), 15494-15503
Open this publication in new window or tab >>Quantum Chemical Modeling of Cycloaddition Reaction in a Self-Assembled Capsule
2017 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, no 43, p. 15494-15503Article in journal (Refereed) Published
Abstract [en]

Dispersion-corrected density functional theory is used to study the cycloaddition reaction between phenyl acetylene and phenyl azide inside a synthetic, self-assembled capsule. The capsule is first characterized computationally and a previously unrecognized structure is identified as being the most stable. Next, an examination of the free energies of host-guest complexes is conducted, considering all possible reagent, solvent and solvent impurity combinations as guests. The experimentally observed relative stabilities of host-guest complexes are quite well reproduced, when the experimental concentrations are taken into account. Experimentally, the presence of the host capsule has been shown to accelerate the cycloaddition reaction and to yield exclusively the 1,4-regioisomer product. Both these observations are reproduced by the calculations. A detailed energy decomposition analysis shows that reduction of the entropic cost of bringing together the reactants along with a geometric destabilization of the reactant supercomplex are the major contributors to the rate acceleration compared to the background reaction. Finally, a sensitivity analysis is conducted to assess the stability of the results with respect to the choice of methodology.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-148255 (URN)10.1021/jacs.7b09102 (DOI)000414506400034 ()
Available from: 2017-10-19 Created: 2017-10-19 Last updated: 2022-02-28Bibliographically approved
Daver, H. (2017). Quantum Chemical Modeling of Phosphoesterase Mimics and Chemistry in Confined Spaces. (Doctoral dissertation). Stockholm: Department of Organic Chemistry, Stockholm University
Open this publication in new window or tab >>Quantum Chemical Modeling of Phosphoesterase Mimics and Chemistry in Confined Spaces
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, density functional theory is employed in the study of two kinds of systems that can be considered to be biomimetic in their own ways. First, three binuclear metal complexes, synthesized by the group of Prof. Ebbe Nordlander, have been investigated. The complexes are designed to resemble the active sites of phosphatase enzymes and have been examined in complexes where either two Zn(II) ions or one Fe(III) and one Mn(II) ion are bound. These dinuclear compounds were studied as catalysts for the hydrolysis of bis(2,4-dinitrophenyl) phosphate and the transesterification of 2-hydroxypropyl p-nitrophenyl phosphate, which are model systems for the same reactions occurring in DNA or RNA. It was found that the two reactions take place in similar ways: a hydroxide ion that is terminally bound to one of the metal centers acts either as a nucleophile in the hydrolysis reaction or as a base in the transesterification. The leaving groups depart in an effectively concerted manner, and the formed catalyst-product complexes are predicted to be the resting states of the catalytic cycles. The rate-determining free energy barriers are identified from the catalyst-product complex in one catalytic cycle to the transition state of nucleophilic attack in the next.

Another type of biomimetic modeling is made with an aim of imitating the conceptual features of selective binding of guests and screening them from solute-solvent interactions. Such features are found in so-called nanocontainers, and this thesis is concerned with studies of two capsules synthesized by the group of Prof. Julius Rebek, Jr. First, the cycloaddition of phenyl acetylene and phenyl azide has experimentally been observed to be accelerated in the presence of a capsule. Computational studies were herein performed on this system, and a previously unrecognized structure of the capsule is discovered. Two main factors are then identified as sources of the rate acceleration compared to the uncatalyzed reaction, namely the reduction of the entropic component and the selective destabilization of the reactant supercomplex over the transition state.

In the second capsule study, the alkane binding trends of a water-soluble cavitand was studied. It is found that implicit solvation models fail severely in reproducing the experimental equilibrium observed between binding of n-decane by the cavitand monomer and encapsulation in the capsule dimer. A mixed explicit/implicit solvation protocol is developed to better quantify the effect of hydrating the cavitand, and a simple correction to the hydration free energy of a single water molecule is proposed to remedy this. The resulting scheme is used to predict new hydration free energies of the cavitand complexes, resulting in significant improvement vis-à-vis experiments.

The computational results presented in this thesis show the usefulness of the quantum chemical calculations to develop understanding of experimental trends observed for substrate binding and catalysis. In particular, the methodology is shown to be versatile enough such that experimental observations can be reproduced for such diverse systems as studied herein.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2017. p. 59
Keywords
density functional theory, catalysis, phosphoester hydrolysis, transesterification, supramolecular chemistry, inclusion complex, host-guest chemistry, cycloaddition
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-148259 (URN)978-91-7797-016-3 (ISBN)978-91-7797-017-0 (ISBN)
Public defence
2017-12-01, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 14:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 5: Manuscript.

Available from: 2017-11-08 Created: 2017-10-19 Last updated: 2022-02-28Bibliographically approved
Daver, H., Das, B., Nordlander, E. & Himo, F. (2016). Theoretical Study of Phosphodiester Hydrolysis and Transesterification Catalyzed by an Unsymmetric Biomimetic Dizinc Complex. Inorganic Chemistry, 55(4), 1872-1882
Open this publication in new window or tab >>Theoretical Study of Phosphodiester Hydrolysis and Transesterification Catalyzed by an Unsymmetric Biomimetic Dizinc Complex
2016 (English)In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 55, no 4, p. 1872-1882Article in journal (Refereed) Published
Abstract [en]

Density functional theory calculations have been used to investigate the reaction mechanisms of phosphodiester hydrolysis and transesterification catalyzed by a dinuclear zinc complex of the 2-(N-isopropyl-N-((2-pyridyl)methyl)-aminomethyl)-6-(N-(carboxylmethyl)-N-((2-pyridyl)methyl)amino-methyl)-4-methylphenol (IPCPMP) ligand, mimicking the active site of zinc phosphotriesterase. The substrates bis(2,4)-dinitrophenyl phosphate (BDNPP) and 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP) were employed as analogues of DNA and RNA, respectively. A number of different mechanistic proposals were considered, with the active catalyst harboring either one or two hydroxide ions. It is concluded that for both reactions the catalyst has only one hydroxide bound, as this option yields lower overall energy barriers. For BDNPP hydrolysis, it is suggested that the hydroxide acts as the nucleophile in the reaction, attacking the phosphorus center of the substrate. For HPNP transesterification, on the other hand, the hydroxide is proposed to act as a Bronsted base, deprotonating the alcohol moiety of the substrate, which in turn performs the nucleophilic attack. The calculated overall barriers are in good agreement with measured rates. Both reactions are found to proceed by essentially concerted associative mechanisms, and it is demonstrated that two consecutive catalytic cycles need to be considered in order to determine the rate-determining free energy barrier.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-128552 (URN)10.1021/acs.inorgchem.5b02733 (DOI)000370395000060 ()26812142 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2016-06-17 Created: 2016-03-30 Last updated: 2022-02-23Bibliographically approved
Daver, H. (2015). Quantum Chemical Modelling of Biomimetic Phosphoesterase Complexes. (Licentiate dissertation). Stockholm: Department of Organic Chemistry, Stockholm University
Open this publication in new window or tab >>Quantum Chemical Modelling of Biomimetic Phosphoesterase Complexes
2015 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Phosphoesterases are a class of enzymes that catalyze hydrolysis of phosphoester bonds. They facilitate the modification of nucleic acid sequences, as well as the breakdown of rest products of warfare agents and insecticides. In this thesis, three biomimetic complexes that perform the same tasks are studied using density functional theory.

Two of the catalysts contain a dizinc core while the third binds an Fe(III) ion and a Mn(II)ion. These complexes catalyze the hydrolysis of the phosphodiester substrate bis-(2,4)-dinitrophenyl phosphate (BDNPP). The substrate is analogous to the phosphoric link between two nucleotides in DNA, and the system is thus a model for cleaving bonds between nucleotides.

By means of computational modelling, the reaction mechanisms are investigated in detail. Different binding modes of the substrates to the catalysts are considered and several mechanistic proposals are evaluated. Conclusions are drawn on the basis of free energy barriers calculated for the different mechanisms.

In all studied reactions, a hydroxide bridging the metals becomes terminally coordinated to one of the zinc ions and then attacks the phosphorus center in a nucleophilic fashion. Leaving group dissociation takes place without a barrier.

One of the catalysts was also studied binding a model substrate for RNA, namely hydroxy-2-isopropyl p-nitrophenyl phosphate (HPNP). The hydroxide was found to act as a base, activating the alcohol moiety of the substrate which in turn performs the nucleophilic attack on the phosphorus center.

Common for all studied systems is that the catalyst-product complex is calculated to be the most stable species. Hence, this complex is suggested to be the resting state of the catalytic cycle. The free energy barriers of the reactions are associated with going from the catalystproduct complex of one catalytic cycle to the transition state for nucleophilic attack in the next. Calculated barriers are in good agreements with experiments.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2015. p. 30
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-123485 (URN)
Presentation
2015-12-17, A501-507, Arrheniuslaboratoriet, Svante Arrhenius väg 16 C, Stockholm, 14:00 (English)
Supervisors
Available from: 2015-11-27 Created: 2015-11-27 Last updated: 2022-02-23Bibliographically approved
Das, B., Daver, H., Pyrkosz-Bulska, M., Persch, E., Barman, S. K., Mukherjee, R., . . . Nordlander, E. (2014). A dinuclear zinc(II) complex of a new unsymmetric ligand with an N(5)0(2) donor set; A structural and functional model for the active site of zinc phosphoesterases. Journal of Inorganic Biochemistry, 132, 6-17
Open this publication in new window or tab >>A dinuclear zinc(II) complex of a new unsymmetric ligand with an N(5)0(2) donor set; A structural and functional model for the active site of zinc phosphoesterases
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2014 (English)In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 132, p. 6-17Article in journal (Refereed) Published
Abstract [en]

The dinuclear complex [Zn-2(DPCPMP)(pivalate)](C10(4)), where DPCPMP is the new unsymmetrical ligand [2-(N-(3-((bis((pyridin-2-yl)methyl)amino)methyl)-2-hydroxy-5-methylbenzyl)-N-((pyridin2-y1)methyl)amino)acetic acid], has been synthesized and characterized. The complex is a functional model for zinc phosphoesterases with dinuclear active sites. The hydrolytic efficacy of the complex has been investigated using bis-(2,4-dinitrophenyl)phosphate(BDNPP), a DNA analog, as substrate. Speciation studies using potentiometric titrations have been performed for both the ligand and the corresponding dizinc complex to elucidate the formation of the active hydrolysis catalyst; they reveals that the dinuclear zinc(II) complexes, [Zn-2(DPCPMP)](2) and [Zn-2(DPCPMP)(OH)1 predominate the solution above pH 4. The relatively high pKa of 8.38 for water deprotonation suggests that a terminal hydroxide complex is formed. Kinetic investigations of BDNPP hydrolysis over the pH range 5.5-11.0 and with varying metal to ligand ratio (metal salt:ligand = 0.5:1 to 3:1) have been performed. Variable temperature studies gave the activation parameters triangle H double dagger = 95.6 kJ mol(-1), triangle S double dagger = 44.8 J mo1(-1) K-1, and 6,triangle G double dagger = 108.0 kJ mo1-1. The cumulative results indicate the hydroxido-bridged dinuclear Zn(II) complex [Zn-2(DPCPMP)(mu-OH)] (+) as the effective catalyst. The mechanism of hydrolysis has been probed by computational modeling using density functional theory (DFF). Calculations show that the reaction goes through one concerted step (S(N)2 type) in which the bridging hydroxide in the transition state becomes terminal and performs a nucleophilic attack on the BDNPP phosphorus; the leaving group dissociates simultaneously in an overall inner sphere type activation. The calculated free energy barrier is in good agreement with the experimentally determined activation parameters.

Keywords
Zinc phosphoesterases, Dinuclear active sites, DNA analog, Transition state
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-102972 (URN)10.1016/j.jinorgbio.2013.08.001 (DOI)000333443800003 ()
Funder
Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Institute
Note

AuthorCount:10;

Available from: 2014-04-28 Created: 2014-04-25 Last updated: 2022-02-23Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7803-5033

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