14 research outputs found
Model-Based Virtual PK/PD Exploration and Machine Learning Approach to Define PK Drivers in Early Drug Discovery
While
poor translatability of preclinical efficacy models
can be
responsible for clinical phase II failures, misdefinition of the optimal
PK properties required to achieve therapeutic efficacy can also be
a contributing factor. In the present work, the pharmacological dependency
of PK end points in driving efficacy is demonstrated for six common
pharmacological processes via model-based analysis. The analysis shows
that the response is driven by multiple pharmacology-specific PK end
points that change with how the response is defined. Moreover, the
results demonstrate that the most important chemical structural features
influencing response are specific to both target and downstream pharmacology,
meaning the design and screening criteria must be defined uniquely
for each target and corresponding pharmacology. The model-based virtual
exploration of PK/PD relationships presented in this work offers one
approach to identify target pharmacology-specific PK drivers and the
associated potency-ADME space early in discovery to increase the probability
of success and, ultimately, clinical attrition
Evaluation of the Role of Water in the H<sub>2</sub> Bond Formation by Ni(II)-Based Electrocatalysts
We
investigate the role of water in the H–H bond formation by
a family of nickel molecular catalysts that exhibit high rates for
H<sub>2</sub> production in acetonitrile solvent. A key feature leading
to the high reactivity is the Lewis acidity of the NiÂ(II) center and
pendant amines in the diphosphine ligand that function as Lewis bases,
facilitating H–H bond formation or cleavage. Significant increases
in the rate of H<sub>2</sub> production have been reported in the
presence of added water. Our calculations show that molecular water
can displace an acetonitrile solvent molecule in the first solvation
shell of the metal. One or two water molecules can also participate
in shuttling a proton that can combine with a metal hydride to form
the H–H bond. However the participation of the water molecules
does not lower the barrier to H–H bond formation. Thus these
calculations suggest that the rate increase due to water in these
electrocatalysts is not associated with the elementary step of H–H
bond formation or cleavage but rather with the proton delivery steps.
We attribute the higher barrier in the H–H bond formation in
the presence of water to a decrease in direct interaction between
the protic and hydridic hydrogen atoms forced by the water molecules
Computing Free Energy Landscapes: Application to Ni-based Electrocatalysts with Pendant Amines for H<sub>2</sub> Production and Oxidation
A general strategy is reported for
the computational exploration
of catalytic pathways of molecular catalysts. Our results are based
on a set of linear free energy relationships derived from extensive
electronic structure calculations that permit predicting the thermodynamics
of intermediates, with accuracy comparable to experimental data. The
approach is exemplified with the catalytic oxidation and production
of H<sub>2</sub> by [NiÂ(diphosphine)<sub>2</sub>]<sup>2+</sup> electrocatalysts
with pendant amines incorporated in the second coordination sphere
of the metal center. The analysis focuses upon prediction of thermodynamic
properties including reduction potentials, hydride donor abilities,
and p<i>K</i><sub>a</sub> values of both the protonated
Ni center and the pendant amine. It is shown that all of these chemical
properties can be estimated from the knowledge of only the two redox
potentials for the NiÂ(II)/NiÂ(I) and NiÂ(I)/Ni(0) couples of the nonprotonated
complex, and the p<i>K</i><sub>a</sub> of the parent primary
aminium ion. These three quantities are easily accessible either experimentally
or theoretically. The proposed correlations reveal intimate details
about the nature of the catalytic mechanism and its dependence on
chemical structure and thermodynamic conditions such as applied external
voltage and species concentration. This computational methodology
is applied to the exploration of possible catalytic pathways, identifying
low and high-energy intermediates and, consequently, possibly avoiding
bottlenecks associated with undesirable intermediates in the catalytic
reactions. We discuss how to optimize some of the critical reaction
steps to favor catalytically more efficient intermediates. The results
of this study highlight the substantial interplay between the various
parameters characterizing the catalytic activity, and form the basis
needed to optimize the performance of this class of catalysts
Hydrogen Production Using Nickel Electrocatalysts with Pendant Amines: Ligand Effects on Rates and Overpotentials
A Ni-based electrocatalyst for H<sub>2</sub> production, [NiÂ(8P<sup>Ph</sup><sub>2</sub>N<sup>C<sub>6</sub>H<sub>4</sub>Br</sup>)<sub>2</sub>]Â(BF<sub>4</sub>)<sub>2</sub>,
featuring eight-membered cyclic
diphosphine ligands incorporating a single amine base, 1-<i>para</i>-bromophenyl-3,7-triphenyl-1-aza-3,7-diphosphacycloheptane (8P<sup>Ph</sup><sub>2</sub>N<sup>C<sub>6</sub>H<sub>4</sub>Br</sup>) has
been synthesized and characterized. X-ray diffraction studies reveal
that the cation of [NiÂ(8P<sup>Ph</sup><sub>2</sub>N<sup>C<sub>6</sub>H<sub>4</sub>Br</sup>)<sub>2</sub>(CH<sub>3</sub>CN)]Â(BF<sub>4</sub>)<sub>2</sub> has a distorted trigonal bipyramidal geometry. In CH<sub>3</sub>CN, [NiÂ(8P<sup>Ph</sup><sub>2</sub>N<sup>C<sub>6</sub>H<sub>4</sub>Br</sup>)<sub>2</sub>]<sup>2+</sup> is an electrocatalyst
for reduction of protons, and it has a maximum turnover frequency
for H<sub>2</sub> production of 800 s<sup>–1</sup> with a 700
mV overpotential (at <i>E</i><sub>cat/2</sub>) when using
[(DMF)ÂH]ÂOTf as the acid. Addition of H<sub>2</sub>O to acidic CH<sub>3</sub>CN solutions of [NiÂ(8P<sup>Ph</sup><sub>2</sub>N<sup>C<sub>6</sub>H<sub>4</sub>Br</sup>)<sub>2</sub>]<sup>2+</sup> results in
an increase in the turnover frequency for H<sub>2</sub> production
to a maximum of 3300 s<sup>–1</sup> with an overpotential of
760 mV at <i>E</i><sub>cat/2</sub>. Computational studies
carried out on [NiÂ(8P<sup>Ph</sup><sub>2</sub>N<sup>C<sub>6</sub>H<sub>4</sub>Br</sup>)<sub>2</sub>]<sup>2+</sup> indicate the observed
catalytic rate is limited by formation of nonproductive protonated
isomers, diverting active catalyst from the catalytic cycle. The results
of this research show that proton delivery from the exogenous acid
to the correct position on the proton relay of the metal complex is
essential for fast H<sub>2</sub> production
Ab Initio-Based Kinetic Modeling for the Design of Molecular Catalysts: The Case of H<sub>2</sub> Production Electrocatalysts
Design of fast, efficient electrocatalysts
for energy production
and energy utilization requires a systematic approach to predict and
tune the energetics of reaction intermediates and the kinetic barriers
between them as well as to tune reaction conditions (e.g., concentration
of reactants, acidity of the reaction medium, and applied electric
potential). Thermodynamics schemes based on the knowledge of p<i>K</i><sub>a</sub> values, hydride donor ability, redox potentials,
and other relevant thermodynamic properties have been demonstrated
to be very effective for exploring possible reaction pathways. We
seek to identify high-energy intermediates, which may represent a
catalytic bottleneck, and low-energy intermediates, which may represent
a thermodynamic sink. In this study, working on a well-established
Ni-based bioinspired electrocatalyst for H<sub>2</sub> production,
we performed a detailed kinetic analysis of the catalytic pathways
to assess the limitations of our current (standard state) thermodynamic
analysis with respect to prediction of optimal catalyst performance.
To this end, we developed a microkinetic model based on extensive
ab initio simulations. The model was validated against available experimental
data, and it reproduces remarkably well the observed turnover rate
as a function of the acid concentration and catalytic conditions,
providing valuable information on the main factors limiting catalysis.
Using this kinetic analysis as a reference, we show that indeed a
purely thermodynamic analysis of the possible reaction pathways provides
us with valuable information, such as a qualitative picture of the
species involved during catalysis, identification of the possible
branching points, and the origin of the observed overpotential, which
are critical insights for electrocatalyst design. However, a significant
limitation of this approach is understanding how these insights relate
to rate, which is an equally critical piece of information. Taking
our analysis a step further, we show that the kinetic model can easily
be extended to different catalytic conditions by using linear free
energy relationships for activation barriers based on simple thermodynamics
quantities, such as p<i>K</i><sub>a</sub> values. We also
outline a possible procedure to extend it to other catalytic platforms,
making it a general and effective way to design catalysts with improved
performance
High Catalytic Rates for Hydrogen Production Using Nickel Electrocatalysts with Seven-Membered Cyclic Diphosphine Ligands Containing One Pendant Amine
A series of Ni-based electrocatalysts, [NiÂ(7P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup>)<sub>2</sub>]Â(BF<sub>4</sub>)<sub>2</sub>, featuring seven-membered cyclic diphosphine ligands incorporating
a single amine base, 1-<i>para</i>-X-phenyl-3,6-triphenyl-1-aza-3,6-diphosphacycloheptane
(7P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup>, where X = OMe, Me,
Br, Cl, or CF<sub>3</sub>), have been synthesized and characterized.
X-ray diffraction studies have established that the [NiÂ(7P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup>)<sub>2</sub>]<sup>2+</sup> complexes
have a square planar geometry, with bonds to four phosphorus atoms
of the two bidentate diphosphine ligands. Each of the complexes is
an efficient electrocatalyst for hydrogen production at the potential
of the NiÂ(II/I) couple, with turnover frequencies ranging from 2400
to 27 000 s<sup>–1</sup> with [(DMF)ÂH]<sup>+</sup> in
acetonitrile. Addition of water (up to 1.0 M) accelerates the catalysis,
giving turnover frequencies ranging from 4100 to 96 000 s<sup>–1</sup>. Computational studies carried out on the [NiÂ(7P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup>)<sub>2</sub>]<sup>2+</sup> family
indicate the catalytic rates reach a maximum when the electron-donating
character of X results in the p<i>K</i><sub>a</sub> of the
NiÂ(I) protonated pendant amine matching that of the acid used for
proton delivery. Additionally, the fast catalytic rates for hydrogen
production by the [NiÂ(7P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup>)<sub>2</sub>]<sup>2+</sup> family relative to the analogous [NiÂ(P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup><sub>2</sub>)<sub>2</sub>]<sup>2+</sup> family are attributed to preferred formation of endo protonated
isomers with respect to the metal center in the former, which is essential
to attain suitable proximity to the reduced metal center to generate
H<sub>2</sub>. The results of this work highlight the importance of
precise p<i>K</i><sub>a</sub> matching with the acid for
proton delivery to obtain optimal rates of catalysis
High Catalytic Rates for Hydrogen Production Using Nickel Electrocatalysts with Seven-Membered Cyclic Diphosphine Ligands Containing One Pendant Amine
A series of Ni-based electrocatalysts, [NiÂ(7P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup>)<sub>2</sub>]Â(BF<sub>4</sub>)<sub>2</sub>, featuring seven-membered cyclic diphosphine ligands incorporating
a single amine base, 1-<i>para</i>-X-phenyl-3,6-triphenyl-1-aza-3,6-diphosphacycloheptane
(7P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup>, where X = OMe, Me,
Br, Cl, or CF<sub>3</sub>), have been synthesized and characterized.
X-ray diffraction studies have established that the [NiÂ(7P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup>)<sub>2</sub>]<sup>2+</sup> complexes
have a square planar geometry, with bonds to four phosphorus atoms
of the two bidentate diphosphine ligands. Each of the complexes is
an efficient electrocatalyst for hydrogen production at the potential
of the NiÂ(II/I) couple, with turnover frequencies ranging from 2400
to 27 000 s<sup>–1</sup> with [(DMF)ÂH]<sup>+</sup> in
acetonitrile. Addition of water (up to 1.0 M) accelerates the catalysis,
giving turnover frequencies ranging from 4100 to 96 000 s<sup>–1</sup>. Computational studies carried out on the [NiÂ(7P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup>)<sub>2</sub>]<sup>2+</sup> family
indicate the catalytic rates reach a maximum when the electron-donating
character of X results in the p<i>K</i><sub>a</sub> of the
NiÂ(I) protonated pendant amine matching that of the acid used for
proton delivery. Additionally, the fast catalytic rates for hydrogen
production by the [NiÂ(7P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup>)<sub>2</sub>]<sup>2+</sup> family relative to the analogous [NiÂ(P<sup>Ph</sup><sub>2</sub>N<sup>C6H4X</sup><sub>2</sub>)<sub>2</sub>]<sup>2+</sup> family are attributed to preferred formation of endo protonated
isomers with respect to the metal center in the former, which is essential
to attain suitable proximity to the reduced metal center to generate
H<sub>2</sub>. The results of this work highlight the importance of
precise p<i>K</i><sub>a</sub> matching with the acid for
proton delivery to obtain optimal rates of catalysis
Incorporating Amino Acid Esters into Catalysts for Hydrogen Oxidation: Steric and Electronic Effects and the Role of Water as a Base
Four derivatives of a hydrogen oxidation catalyst, [NiÂ(P<sup>Cy</sup><sub>2</sub>N<sup>Bn‑R</sup><sub>2</sub>)<sub>2</sub>]<sup>2+</sup> (Cy = cyclohexyl, Bn = benzyl, R = OMe, COOMe, CO-alanine-methyl
ester, CO-phenylalanine-methyl ester), have been prepared to investigate
steric and electronic effects on catalysis. Each complex was characterized
spectroscopically and electrochemically, and thermodynamic data were
determined. Crystal structures are also reported for the −OMe
and −COOMe derivatives. All four catalysts were found to be
active for H<sub>2</sub> oxidation. The methyl ester (R = COOMe) and
amino acid ester containing complexes (R = CO-alanine-methyl ester
or CO-phenylalanine-methyl ester) had rates slower (4 s<sup>–1</sup>) than that of the parent complex (10 s<sup>–1</sup>), in
which R = H, which is consistent with the lower amine p<i>K</i><sub>a</sub>'s and less favorable Δ<i>G</i><sub>H<sub>2</sub></sub>'s found for these electron-withdrawing substituents.
Dynamic processes for the amino acid ester containing complexes were
also investigated and found not to hinder catalysis. The electron-donating
methyl ether derivative (R = OMe) was prepared to compare electronic
effects and has a catalytic rate similar to that of the parent complex.
In the course of these studies, it was found that water could act
as a weak base for H<sub>2</sub> oxidation, although catalytic turnover
requires a higher potential and utilizes a different sequence of catalytic
steps than when using a base with a higher p<i>K</i><sub>a</sub>. Importantly, these catalysts provide a foundation upon which
larger peptides can be attached to [NiÂ(P<sup>Cy</sup><sub>2</sub>N<sup>Bn</sup><sub>2</sub>)<sub>2</sub>]<sup>2+</sup> hydrogen oxidation
catalysts in order to more fully investigate and implement the effects
of the outer coordination sphere
Incorporating Amino Acid Esters into Catalysts for Hydrogen Oxidation: Steric and Electronic Effects and the Role of Water as a Base
Four derivatives of a hydrogen oxidation catalyst, [NiÂ(P<sup>Cy</sup><sub>2</sub>N<sup>Bn‑R</sup><sub>2</sub>)<sub>2</sub>]<sup>2+</sup> (Cy = cyclohexyl, Bn = benzyl, R = OMe, COOMe, CO-alanine-methyl
ester, CO-phenylalanine-methyl ester), have been prepared to investigate
steric and electronic effects on catalysis. Each complex was characterized
spectroscopically and electrochemically, and thermodynamic data were
determined. Crystal structures are also reported for the −OMe
and −COOMe derivatives. All four catalysts were found to be
active for H<sub>2</sub> oxidation. The methyl ester (R = COOMe) and
amino acid ester containing complexes (R = CO-alanine-methyl ester
or CO-phenylalanine-methyl ester) had rates slower (4 s<sup>–1</sup>) than that of the parent complex (10 s<sup>–1</sup>), in
which R = H, which is consistent with the lower amine p<i>K</i><sub>a</sub>'s and less favorable Δ<i>G</i><sub>H<sub>2</sub></sub>'s found for these electron-withdrawing substituents.
Dynamic processes for the amino acid ester containing complexes were
also investigated and found not to hinder catalysis. The electron-donating
methyl ether derivative (R = OMe) was prepared to compare electronic
effects and has a catalytic rate similar to that of the parent complex.
In the course of these studies, it was found that water could act
as a weak base for H<sub>2</sub> oxidation, although catalytic turnover
requires a higher potential and utilizes a different sequence of catalytic
steps than when using a base with a higher p<i>K</i><sub>a</sub>. Importantly, these catalysts provide a foundation upon which
larger peptides can be attached to [NiÂ(P<sup>Cy</sup><sub>2</sub>N<sup>Bn</sup><sub>2</sub>)<sub>2</sub>]<sup>2+</sup> hydrogen oxidation
catalysts in order to more fully investigate and implement the effects
of the outer coordination sphere
Incorporating Amino Acid Esters into Catalysts for Hydrogen Oxidation: Steric and Electronic Effects and the Role of Water as a Base
Four derivatives of a hydrogen oxidation catalyst, [NiÂ(P<sup>Cy</sup><sub>2</sub>N<sup>Bn‑R</sup><sub>2</sub>)<sub>2</sub>]<sup>2+</sup> (Cy = cyclohexyl, Bn = benzyl, R = OMe, COOMe, CO-alanine-methyl
ester, CO-phenylalanine-methyl ester), have been prepared to investigate
steric and electronic effects on catalysis. Each complex was characterized
spectroscopically and electrochemically, and thermodynamic data were
determined. Crystal structures are also reported for the −OMe
and −COOMe derivatives. All four catalysts were found to be
active for H<sub>2</sub> oxidation. The methyl ester (R = COOMe) and
amino acid ester containing complexes (R = CO-alanine-methyl ester
or CO-phenylalanine-methyl ester) had rates slower (4 s<sup>–1</sup>) than that of the parent complex (10 s<sup>–1</sup>), in
which R = H, which is consistent with the lower amine p<i>K</i><sub>a</sub>'s and less favorable Δ<i>G</i><sub>H<sub>2</sub></sub>'s found for these electron-withdrawing substituents.
Dynamic processes for the amino acid ester containing complexes were
also investigated and found not to hinder catalysis. The electron-donating
methyl ether derivative (R = OMe) was prepared to compare electronic
effects and has a catalytic rate similar to that of the parent complex.
In the course of these studies, it was found that water could act
as a weak base for H<sub>2</sub> oxidation, although catalytic turnover
requires a higher potential and utilizes a different sequence of catalytic
steps than when using a base with a higher p<i>K</i><sub>a</sub>. Importantly, these catalysts provide a foundation upon which
larger peptides can be attached to [NiÂ(P<sup>Cy</sup><sub>2</sub>N<sup>Bn</sup><sub>2</sub>)<sub>2</sub>]<sup>2+</sup> hydrogen oxidation
catalysts in order to more fully investigate and implement the effects
of the outer coordination sphere