Quantitative In Silico Prediction of the Rate of Protodeboronation by a Mechanistic Density Functional Theory-Aided AlgorithmClick to copy article linkArticle link copied!
- Daniel S. WighDaniel S. WighDepartment of Chemical Engineering and Biotechnology, University of Cambridge, CB3 0AS Cambridge, U.K.More by Daniel S. Wigh
- Matthieu Tissot
- Patrick Pasau
- Jonathan M. GoodmanJonathan M. GoodmanYusuf Hamied Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, U.K.More by Jonathan M. Goodman
- Alexei A. Lapkin*Alexei A. Lapkin*E-mail: [email protected]Department of Chemical Engineering and Biotechnology, University of Cambridge, CB3 0AS Cambridge, U.K.More by Alexei A. Lapkin
Abstract
Computational reaction prediction has become a ubiquitous task in chemistry due to the potential value accurate predictions can bring to chemists. Boronic acids are widely used in industry; however, understanding how to avoid the protodeboronation side reaction remains a challenge. We have developed an algorithm for in silico prediction of the rate of protodeboronation of boronic acids. A general mechanistic model devised through kinetic studies of protodeboronation was found in the literature and forms the foundation on which the algorithm presented in this work is built. Protodeboronation proceeds through 7 distinct pathways, though for any particular boronic acid, only a subset of mechanistic pathways are active. The rate of each active mechanistic pathway is linearly correlated with its characteristic energy difference, which in turn can be determined using Density Functional Theory. We validated the algorithm using leave-one-out cross-validation on a data set of 50 boronic acids and made a further 50 rate predictions on academically and industrially important boronic acids out of sample. We believe this work will provide great assistance to chemists performing reactions that feature boronic acids, such as Suzuki–Miyaura and Chan–Evans–Lam couplings.
This publication is licensed under
License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
Introduction
Scheme 1
A + B → C Intended reaction
A → D Protodeboronation side reaction
A + B → C Intended reaction
A + A → A + D Self-catalytic protodeboronation side reaction
A → D Protodeboronation side reaction
A → B → C
A + A → D
Methodology
Data
General Mechanistic Model for Protodeboronation
Figure 1
Figure 1. Example of each of the mechanistic pathways of protodeboronation relevant to the boronic acids considered in this work. (30) A red box encloses the two stages used for calculation of ΔE for each mechanism; k2cat in the fourth row has no red box, since ΔE was calculated using a simplified version of this mechanism (shown in the fifth row). A detailed description of each mechanistic pathway can be found in the Supporting Information.
Determining Active Mechanisms
Figure 2
Figure 2. Heuristics for determining which mechanistic pathways are active for a particular boronic acid (Z = basic nitrogen, X = S, O). (30)
Algorithmic Protodeboronation Prediction
Scheme 2
1. Choice of Boronic Acid
2. Determine Active Mechanistic Pathways
3. Calculate ΔE for Each Mechanistic Pathway
Scheme 3
4. Linear Regression of ΔE vs log(kn)
Figure 3
Figure 3. Linear regression of log(k) vs ΔE for the k2 and k4 mechanistic pathways.
5. Building a System of Linear Equations Using pKa, pKaH, and Predicted log(kn)
1. | k1: – 1 | ||||
2. | k2: 0.75 | ||||
3. | k2Ar: 0.75 | ||||
4. | k2cat: 2, – 2 | ||||
5. | k3: 2 | ||||
6. | k4: 0.75, – 0.75 | ||||
7. | k5: – 0.75 |
Figure 4
Figure 4. Constructing rate curves for each mechanism given the pKa, pKaH, and slope of mechanistic deactivation with pH.
6. Sum All Rate Curves
Figure 5
Figure 5. Predicted rate vs measured rate for DMOBA.
Quantum Chemistry Calculations
Results and Discussion
Figure 6
Figure 6. Parity plot showing the predictive accuracy of the algorithm. MAE: Mean Absolute Error. MSE: Mean Squared error. R2: Coefficient of Determination.
Predictions for Novel Boronic Acids
Model Explainability and Extrapolation
Future Work
Conclusions
Data Availability
All the code and data associated with this project is freely available on https://github.com/sustainable-processes/protodeboronation-prediction, allowing anyone to generate a protodeboronation rate predictions for BAs that fall within the scope of the model, given appropriate DFT calculations and approximate values for pKa and pKaH (if applicable).
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpca.2c08250.
A detailed explanation of each protodeboronation mechanism, protodeboronation predictions for 50 novel boronic acids, and optimized structures and energies for each relevant mechanism for all 100 molecules (PDF)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Acknowledgments
This work is cofunded by UCB Pharma and Engineering and Physical Sciences Research Council via project EP/S024220/1 EPSRC Centre for Doctoral Training in Automated Chemical Synthesis Enabled by Digital Molecular Technologies.
References
This article references 46 other publications.
- 1Hall, D. G. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2011.Google ScholarThere is no corresponding record for this reference.
- 2Bull, S. D.; Davidson, M. G.; van den Elsen, J. M. H.; Fossey, J. S.; Jenkins, A. T. A.; Jiang, Y.-B.; Kubo, Y.; Marken, F.; Sakurai, K.; Zhao, J.; James, T. D. Exploiting the reversible covalent bonding of boronic acids: recognition, sensing, and assembly. Acc. Chem. Res. 2013, 46, 312– 326, DOI: 10.1021/ar300130wGoogle Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Knu7bN&md5=5bdc35d91fcf90e3167cd362a9066eafExploiting the Reversible Covalent Bonding of Boronic Acids: Recognition, Sensing, and AssemblyBull, Steven D.; Davidson, Matthew G.; van den Elsen, Jean M. H.; Fossey, John S.; Jenkins, A. Toby A.; Jiang, Yun-Bao; Kubo, Yuji; Marken, Frank; Sakurai, Kazuo; Zhao, Jianzhang; James, Tony D.Accounts of Chemical Research (2013), 46 (2), 312-326CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Boronic acids can interact with Lewis bases to generate boronate anions, and they can also bind with diol units to form cyclic boronate esters. Boronic acid based receptor designs originated when Lorand and Edwards used the pH drop obsd. upon the addn. of saccharides to boronic acids to det. their assocn. consts. The inherent acidity of the boronic acid is enhanced when 1,2-, 1,3-, or 1,4-diols react with boronic acids to form cyclic boronic esters (5, 6, or 7 membered rings) in aq. media, and these interactions form the cornerstone of diol-based receptors used in the construction of sensors and sepn. systems. In addn., the recognition of saccharides through boronic acid complex (or boronic ester) formation often relies on an interaction between a Lewis acidic boronic acid and a Lewis base (proximal tertiary amine or anion). These properties of boronic acids have led to them being exploited in sensing and sepn. systems for anions (Lewis bases) and saccharides (diols). The fast and stable bond formation between boronic acids and diols to form boronate esters can serve as the basis for forming reversible mol. assemblies. In spite of the stability of the boronate esters' covalent B-O bonds, their formation is reversible under certain conditions or under the action of certain external stimuli. The reversibility of boronate ester formation and Lewis acid-base interactions has also resulted in the development and use of boronic acids within multicomponent systems. The dynamic covalent functionality of boronic acids with structure-directing potential has led researchers to develop a variety of self-organizing systems including macrocycles, cages, capsules, and polymers. This Account gives an overview of research published about boronic acids over the last 5 years. We hope that this Account will inspire others to continue the work on boronic acids and reversible covalent chem.
- 3Hirai, M.; Tanaka, N.; Sakai, M.; Yamaguchi, S. Structurally Constrained Boron-, Nitrogen-, Silicon-, and Phosphorus-Centered Polycyclic -Conjugated Systems. Chem. Rev. 2019, 119, 8291– 8331, DOI: 10.1021/acs.chemrev.8b00637Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXksFCnsLs%253D&md5=20577226e3e22e6dfc2957b81fc149b9Structurally constrained boron-, nitrogen-, silicon-, and phosphorus-centered polycyclic π-conjugated systemsHirai, Masato; Tanaka, Naoki; Sakai, Mika; Yamaguchi, ShigehiroChemical Reviews (Washington, DC, United States) (2019), 119 (14), 8291-8331CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Incorporation of main group elements into the π-conjugated frameworks is a sophisticated strategy to alter the fundamental nature of the parent conjugated π-systems, giving rise to attractive electronic and photophys. properties that are otherwise inaccessible with classic carbon- or metal-based materials. Out of all π-conjugated heterocycles, those that are structurally constrained by tethered aryl substituents surrounding the main group center deserve a great deal of attention because not only do they commonly possess the max. efficiency of π-conjugation and intermol. interaction, but they also enjoy remarkable thermal and morphol. stabilities that are esp. crucial for solid-state performances. In certain cases, elucidation of the behavior of such compds. may addnl. provide sufficient perspective toward graphene materials doped with main group elements, which are widely considered as potential next-generation optoelectronic materials. In this Review, we will specifically focus on historical developments of structurally constrained polycyclic π-electron systems particularly of those with boron, nitrogen, silicon or phosphorus atoms annulated directly into the center of π-conjugated systems.
- 4von Grotthuss, E.; John, A.; Kaese, T.; Wagner, M. Doping Polycyclic Aromatics with Boron for Superior Performance in Materials Science and Catalysis. Asian Journal of Organic Chemistry 2018, 7, 37– 53, DOI: 10.1002/ajoc.201700495Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVKhtbzF&md5=8a327c8561cce8419392356ca3dac1c5Doping Polycyclic Aromatics with Boron for Superior Performance in Materials Science and Catalysisvon Grotthuss, Esther; John, Alexandra; Kaese, Thomas; Wagner, MatthiasAsian Journal of Organic Chemistry (2018), 7 (1), 37-53CODEN: AJOCC7; ISSN:2193-5807. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. B has one valence electron less than a C atom and an available vacant pz orbital. The incorporation of sp2-hybridized B atoms into the host lattice of a polycyclic arom. hydrocarbon (PAH) is formally related to oxidative doping. A B-contg. B-PAH has an energetically low-lying LUMO and a narrow HOMO-LUMO gap, which renders it a strong Lewis acid/electron acceptor and promotes fluorescence in the visible range of the electromagnetic spectrum. Many methods were developed to access B-PAHs that are deliberately designed for specific tasks. Herein, the authors highlight recent breakthroughs in the field of B-PAH synthesis and the scope of their applications, which range from Lewis acid and redox catalysis to device fabrication. The authors will also report on the dynamic covalent chem. of neutral and anionic B-PAHs, as it is a potential limitation in the design of catalyst systems but can also provide a powerful synthetic tool for the prepn. of otherwise inaccessible B-PAHs.
- 5Jäkle, F. Lewis acidic organoboron polymers. Coord. Chem. Rev. 2006, 250, 1107– 1121, DOI: 10.1016/j.ccr.2006.01.007Google ScholarThere is no corresponding record for this reference.
- 6Hudson, Z. M.; Wang, S. Impact of Donor-Acceptor Geometry and Metal Chelation on Photophysical Properties and Applications of Triarylboranes. Acc. Chem. Res. 2009, 42, 1584– 1596, DOI: 10.1021/ar900072uGoogle Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnslGqtbk%253D&md5=f153c74a8de59beb637d1613f88b4106Impact of Donor-Acceptor Geometry and Metal Chelation on Photophysical Properties and Applications of TriarylboranesHudson, Zachary M.; Wang, SuningAccounts of Chemical Research (2009), 42 (10), 1584-1596CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Three-coordinate organoboron compds. have recently found a wide range of applications in materials chem. as nonlinear optical materials, chem. sensors, and emitters for org. light-emitting diodes (OLEDs). These compds. are excellent electron acceptors due to the empty pπ orbital on the boron center. When accompanied by electron donors such as amines, these mols. possess large electronic dipoles, which promote donor-acceptor charge-transfer upon excitation with light. Because of this, donor-acceptor triarylboranes are often highly luminescent both in the solid state and in soln. In this Account, we describe our research to develop donor-acceptor triarylboranes as efficient blue emitters for OLEDs. Through the use of hole-transporting donor groups such as 1-naphthylphenylamines, we have prepd. multifunctional triarylboranes that can act as the emissive, electron transport, or hole transport layers in OLEDs. We have also examd. donor-acceptor compds. based on 2,2'-dipyridylamine or 7-azaindolyl donors, several of which have fluorescent quantum efficiencies approaching 100%. We are also investigating the chem. of metal-contg. triarylboranes. Our studies show that the electron-deficient boryl group can greatly facilitate metal-to-ligand charge-transfer transitions and phosphorescence. In addn., electroneg. linker groups such as 2,2'-bipyridine can act in synergy with metal chelation to greatly improve the electron-accepting ability and Lewis acidity of triarylboranes. Donor-acceptor triarylboranes developed in our lab. can also serve as a series of "switch-on" sensors for fluoride ions. When the donor and acceptor are linked by rigid naphthyl or nonrigid silane linkers, donor-acceptor conjugation is disrupted and charge transfer occurs primarily through space. The binding of fluoride ions to the boron center disrupts this charge transfer, activating alternative π → π* transitions in the mol. and changing the emission color of the sample. More recently, we have used these nonconjugated linkers to prep. organometallic donor-acceptor triarylboranes in which fluorescence and phosphorescence can simultaneously be obsd. from two different chromophores in the same mol. at ambient temp. These dual emissive mols. remain sensitive to fluoride ions, and give synergistic singlet-triplet emission responses when titrated with F-. Fluoride ions can also act as valuable chem. probes, providing insight into the electronic structure of this new class of optoelectronic materials. We have demonstrated that donor-acceptor triarylboranes are promising materials in anion sensing and electroluminescent device applications. Nonetheless, despite our work and that of other research groups, there is still much to be learned about organometallic and multiply emissive triarylboron systems.
- 7Rao, Y.-L.; Amarne, H.; Wang, S. Photochromic four-coordinate N,C-chelate boron compounds. Coord. Chem. Rev. 2012, 256, 759– 770, DOI: 10.1016/j.ccr.2011.11.009Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjt1yhtr8%253D&md5=7884ef963aea131457af7c8e66f0243cPhotochromic four-coordinate N,C-chelate boron compoundsRao, Ying-Li; Amarne, Hazem; Wang, SuningCoordination Chemistry Reviews (2012), 256 (5-8), 759-770CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)A review. Four-coordinate organoboron compds. with a N,C-chelate backbone have been found recently to display an unusual photoisomerization phenomenon with a distinct change of color. The photoisomerization process is thermally reversible, enabling the potential use of this class of compds. as a new class of photoresponsive materials. This review provides an account of the authors recent investigation on the effect of substitution, π-conjugation and metal chelation on the photoisomerization process of the N,C-chelate organoboron compds. The photoisomerization phenomenon of azobenzene-based organoboron compds. will also be presented.
- 8Brooks, W. L. A.; Sumerlin, B. S. Synthesis and Applications of Boronic Acid-Containing Polymers: From Materials to Medicine. Chem. Rev. 2016, 116, 1375– 1397, DOI: 10.1021/acs.chemrev.5b00300Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVyktr7K&md5=e2ed1dd3f0a1fe53b62e45bc0ee7955dSynthesis and Applications of Boronic Acid-Containing Polymers: From Materials to MedicineBrooks, William L. A.; Sumerlin, Brent S.Chemical Reviews (Washington, DC, United States) (2016), 116 (3), 1375-1397CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Boronic acid-contg. macromols. have been utilized in a no. of biomedical applications, including use in dynamic covalent materials, dual thermo and saccharide responsive hydrogels, sensors, and nanomaterials, often with the goal of detection and treatment of type-1 diabetes, which requires const. monitoring of blood glucose levels and proactive insulin management. The ability of boronic acids to bind with saccharides and potentially undergo an ionization transition makes the materials ideal for diabetes-related applications. Other biomedical applications of boronic acid contg. macromols. include use as potential HIV barriers, sepns. and chromatog., cell capture and culture, enzymic inhibition, and in site-specific radiation therapy. The review addresses each of these potential and current areas of application, with particular attention to the fundamental chem. involved.
- 9Miyaura, N.; Yamada, K.; Suzuki, A. A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides. Tetrahedron Lett. 1979, 20, 3437– 3440, DOI: 10.1016/S0040-4039(01)95429-2Google ScholarThere is no corresponding record for this reference.
- 10Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457– 2483, DOI: 10.1021/cr00039a007Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXoslGiurg%253D&md5=d127b414a75161652876eebc3ed0c486Palladium-Catalyzed Cross-Coupling Reactions of Organoboron CompoundsMiyaura, Norio; Suzuki, AkiraChemical Reviews (Washington, D. C.) (1995), 95 (7), 2457-83CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review with >250 refs. including title reactions and their mechanisms, prepn. of organoboron reagents, alkoxycarbonylation and dimerization.
- 11Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. New N- and O-arylations with phenylboronic acids and cupric acetate. Tetrahedron Lett. 1998, 39, 2933– 2936, DOI: 10.1016/S0040-4039(98)00503-6Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtVOlu7w%253D&md5=56efb58adc883aba3ca4ab908f6864ecNew N- and O-arylation with phenylboronic acids and cupric acetateChan, Dominic M. T.; Monaco, Kevin L.; Wang, Ru-Ping; Winters, Michael P.Tetrahedron Letters (1998), 39 (19), 2933-2936CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)A new method of arylating N-H and O-H contg. compds. at room temp. with phenylboronic acids and cupric acetate in the presence of a tertiary amine promoter is described. Substrates include phenols, amines, anilines, amides, imides, ureas, carbamates, and sulfonamides.
- 12Evans, D. A.; Katz, J. L.; West, T. R. Synthesis of diaryl ethers through the copper-promoted arylation of phenols with arylboronic acids. An expedient synthesis of thyroxine. Tetrahedron Lett. 1998, 39, 2937– 2940, DOI: 10.1016/S0040-4039(98)00502-4Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtVOlu7o%253D&md5=201a8d8742f73d5249058a91dc2f6309Synthesis of diaryl ethers through the copper-promoted arylation of phenols with arylboronic acids. An expedient synthesis of thyroxineEvans, David A.; Katz, Jeffrey L.; West, Theodore R.Tetrahedron Letters (1998), 39 (19), 2937-2940CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)Diaryl ethers are readily synthesized in high yield at room temp. through the copper(II)-promoted coupling of arylboronic acids and phenols. The reaction is tolerant of a wide range of substituents on both coupling partners. These reaction conditions permit the racemization-free arylation of phenolic amino acids, methodol. that has been applied to an efficient synthesis of thyroxine.
- 13Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid/cupric acetate arylation. Tetrahedron Lett. 1998, 39, 2941– 2944, DOI: 10.1016/S0040-4039(98)00504-8Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtVOlu7k%253D&md5=86155b6f6d3f9765b3270cb3aa9fd509New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid/cupric acetate arylationLam, Patrick Y. S.; Clark, Charles G.; Saubern, Simon; Adams, Jessica; Winters, Michael P.; Chan, Dominic M. T.; Combs, AndrewTetrahedron Letters (1998), 39 (19), 2941-2944CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)A new aryl/heteroaryl C-N bond cross-coupling reaction via the arylboronic acid/cupric acetate arylation of N-H contg. heteroarenes has been discovered. This new methodol. is mild, proceeds at room temp. exposed to air, and works for many heteroarenes and arylboronic acid providing good yields of N-arylated heteroarenes.
- 14Liebeskind, L. S.; Srogl, J. Thiol Ester-Boronic Acid Coupling. A Mechanistically Unprecedented and General Ketone Synthesis. J. Am. Chem. Soc. 2000, 122, 11260– 11261, DOI: 10.1021/ja005613qGoogle Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXnsFylsr8%253D&md5=492065027a52db2b2fc18027c5ec6c37Thiol Ester-Boronic Acid Coupling. A Mechanistically Unprecedented and General Ketone SynthesisLiebeskind, Lanny S.; Srogl, JiriJournal of the American Chemical Society (2000), 122 (45), 11260-11261CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A mild and general method for the palladium-catalyzed, copper mediated coupling of thiol esters and boronic acids under base-free conditions was developed. The mechanistic key to this new reaction is the selective activation of a catalytically generated acylpalladium-thiolate in a way that facilitates transmetalation from boron to palladium, while retaining compatibility with the reaction system. The presence of a copper cation and a carboxylate anion was a crit. requirement for the reaction. For example, a mixt. of benzenecarbothioic acid S-[2-(dimethylamino)-2-oxoethyl] ester (thiol ester), phenylboronic acid, Pd2(dba)3-CHCl3, tris(2-furyl)phosphine, 2-thiophenecarboxylic acid copper(1+) salt, and THF was stirred at 50° for 18 h to give, after work-up, 2-methoxybenzophenone in 88% yield.
- 15Cho, C. S.; Uemura, S. Palladium-catalyzed cross-coupling of aryl and alkenyl boronic acids with alkenes via oxidative addition of a carbon-boron bond to palladium(O). J. Organomet. Chem. 1994, 465, 85– 92, DOI: 10.1016/0022-328X(94)87040-3Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXltVyjtLo%253D&md5=622b3a7732473042d4faa47ad32cab40Palladium-catalyzed cross-coupling of aryl and alkenyl boronic acids with alkenes via oxidative addition of a carbon-boron bond to palladium(0)Cho, Chan Sik; Uemura, SakaeJournal of Organometallic Chemistry (1994), 465 (1-2), 85-92CODEN: JORCAI; ISSN:0022-328X.Arylboronic acids, e.g., PhB(OH)2, react with alkenes, e.g., styrene, in HOAc at 25° in the presence of a catalytic amt. of Pd(II) acetate together with NaOAc to give the corresponding aryl-substituted alkenes, e.g., trans-PhCH:CHPh, in high yields. Alkenylboronic acids react with alkenes under similar conditions to give the corresponding conjugated dienes stereospecifically, but the product yields are lower, compared with those from arylboronic acids. Similar treatment of Na tetraphenylborate (NaBPh4) with alkenes also affords the corresponding phenylated alkenes in high yields together with biphenyl and benzene as side products. Oxidative addn. of a C-B bond to palladium(0), formed in situ, to give an organopalladium(II) species is assumed to be the key step of these cross-coupling reactions.
- 16Sakai, M.; Ueda, M.; Miyaura, N. Rhodium-Catalyzed Addition of Organoboronic Acids to Aldehydes. Angew. Chem., Int. Ed. 1998, 37, 3279– 3281, DOI: 10.1002/(SICI)1521-3773(19981217)37:23<3279::AID-ANIE3279>3.0.CO;2-MGoogle Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXksVehsQ%253D%253D&md5=a38fdb13e3a145ec7a0b81caf53dac1dRhodium-catalyzed addition of organoboronic acids to aldehydesSakai, Masaaki; Ueda, Masato; Miyaura, NorioAngewandte Chemie, International Edition (1998), 37 (23), 3279-3281CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)The title reaction of RB(OH)2 (R = Ph, p-anisyl, o-, p-tolyl, p-FC6H4, 2,4,6-Me3C6H2, trans-BuCH:CH) with R1CHO (R1 = Ph, p-F3CC6H4, p-NCC6H4, p-AcC6H4, p-BrC6H4, p-tolyl, p-anisyl, 2-furyl, 1-naphthyl, C5H11, C6H11) in the presence of Rh(acac)(CO)2 in aq. DME gave 31-97% 16 R1RCHOH.
- 17Takezawa, A.; Yamaguchi, K.; Ohmura, T.; Yamamoto, Y.; Miyaura, N. Inter- and Intramolecular Additions of 1-Alkenylboronic Acids or Esters to Aldehydes and Ketones Catalyzed by Rhodium(I) Complexes in Basic, Aqueous Solutions. Synlett 2002, 2002, 1733– 1735, DOI: 10.1055/s-2002-34219Google ScholarThere is no corresponding record for this reference.
- 18Sakai, M.; Hayashi, H.; Miyaura, N. Rhodium-Catalyzed Conjugate Addition of Aryl- or 1-Alkenylboronic Acids to Enones. Organometallics 1997, 16, 4229– 4231, DOI: 10.1021/om9705113Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlvVyhu78%253D&md5=ee6e958f72c00bbd7bca69373c594d65Rhodium-Catalyzed Conjugate Addition of Aryl- or 1-Alkenylboronic Acids to EnonesSakai, Masaaki; Hayashi, Hiroyuki; Miyaura, NorioOrganometallics (1997), 16 (20), 4229-4231CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)The Rh(I)-catalyzed conjugate addn. of aryl- or 1-alkenylboronic acids, R3B(OH)2, to enones, R1CH:CHC(O)R2, was carried out in high yields at 50° in an aq. solvent, giving R1CHR3CH2C(O)R2. A combination of (acac)Rh(CO)2 and dppb was highly effective for the addn. to acyclic and cyclic enones. For example, a 96% yield of 2-phenyl-4-octanone was obtained from PhB(OH)2 and 2-octen-4-one in aq. MeOH in the presence of (acac)Rh(CO)2 and dppb.
- 19Cho, C. S.; Motofusa, S.-i.; Ohe, K.; Uemura, S.; Shim, S. C. A New Catalytic Activity of Antimony(III) Chloride in Palladium(0)-Catalyzed Conjugate Addition of Aromatics to.alpha.,.beta.-Unsaturated Ketones and Aldehydes with Sodium Tetraphenylborate and Arylboronic Acids. Journal of Organic Chemistry 1995, 60, 883– 888, DOI: 10.1021/jo00109a019Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjs1CntLk%253D&md5=56342ec8d56bce0d91bc1b76ca99edc2A New Catalytic Activity of Antimony(III) Chloride in Palladium(0)-Catalyzed Conjugate Addition of Aromatics to α,β-Unsaturated Ketones and Aldehydes with Sodium Tetraphenylborate and Arylboronic AcidsCho, Chan Sik; Motofusa, Shin-ichi; Ohe, Kouichi; Uemura, Sakae; Shim, Sang ChulJournal of Organic Chemistry (1995), 60 (4), 883-8CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A remarkable catalytic effect of Sb(III) chloride is disclosed in Pd(0)-catalyzed conjugate addn. of aroms. to α,β-unsatd. ketones and aldehydes with Na tetraphenylborate and arylboronic acids in HOAc at 25°. Thus, treating benzalacetone with Na tetraphenylborate in the presence of Pd acetate and Sb(III) chloride gave 92% 4,4-diphenyl-2-butanone. Several other metal chlorides such as AlCl3, SnCl4, AsCl3, TiCl4, FeCl3, MoCl5, and CeCl3 are also effective in some cases, but SbCl3 is the salt of choice. Two key steps are proposed for this reaction: one is the oxidative addn. of a C-B bond to Pd(0) forming an arylpalladium species, and the other is the formation of an Sb enolate derived from the initial coordination of SbCl3 to the carbonyl O of an organopalladium intermediate.
- 20Wigh, D. S.; Goodman, J. M.; Lapkin, A. A. A review of molecular representation in the age of machine learning. WIREs Computational Molecular Science 2022, 12, e1603 DOI: 10.1002/wcms.1603Google ScholarThere is no corresponding record for this reference.
- 21Gao, H.; Struble, T. J.; Coley, C. W.; Wang, Y.; Green, W. H.; Jensen, K. F. Using Machine Learning To Predict Suitable Conditions for Organic Reactions. ACS Central Science 2018, 4, 1465– 1476, DOI: 10.1021/acscentsci.8b00357Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1aru77J&md5=fef56b949b8b8febb5d1403327238f4bUsing Machine Learning To Predict Suitable Conditions for Organic ReactionsGao, Hanyu; Struble, Thomas J.; Coley, Connor W.; Wang, Yuran; Green, William H.; Jensen, Klavs F.ACS Central Science (2018), 4 (11), 1465-1476CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Reaction condition recommendation is an essential element for the realization of computer-assisted synthetic planning. Accurate suggestions of reaction conditions are required for exptl. validation and can have a significant effect on the success or failure of an attempted transformation. However, de novo condition recommendation remains a challenging and under-explored problem and relies heavily on chemists' knowledge and experience. In this work, we develop a neural-network model to predict the chem. context (catalyst(s), solvent(s), reagent(s)), as well as the temp. most suitable for any particular org. reaction. Trained on ∼10 million examples from Reaxys, the model is able to propose conditions where a close match to the recorded catalyst, solvent, and reagent is found within the top-10 predictions 69.6% of the time, with top-10 accuracies for individual species reaching 80-90%. Temp. is accurately predicted within ±20 °C from the recorded temp. in 60-70% of test cases, with higher accuracy for cases with correct chem. context predictions. The utility of the model is illustrated through several examples spanning a range of common reaction classes. We also demonstrate that the model implicitly learns a continuous numerical embedding of solvent and reagent species that captures their functional similarity.
- 22Coley, C. W.; Green, W. H.; Jensen, K. F. Machine Learning in Computer-Aided Synthesis Planning. Acc. Chem. Res. 2018, 51, 1281– 1289, DOI: 10.1021/acs.accounts.8b00087Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosFKhsb0%253D&md5=a1ea72c55942f3c0f0a99ab080f96899Machine Learning in Computer-Aided Synthesis PlanningColey, Connor W.; Green, William H.; Jensen, Klavs F.Accounts of Chemical Research (2018), 51 (5), 1281-1289CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)Computer-aided synthesis planning (CASP) is focused on the goal of accelerating the process by which chemists decide how to synthesize small mol. compds. The ideal CASP program would take a mol. structure as input and output a sorted list of detailed reaction schemes that each connect that target to purchasable starting materials via a series of chem. feasible reaction steps. Early work in this field relied on expert-crafted reaction rules and heuristics to describe possible retrosynthetic disconnections and selectivity rules but suffered from incompleteness, infeasible suggestions, and human bias. With the relatively recent availability of large reaction corpora (such as the United States Patent and Trademark Office (USPTO), Reaxys, and SciFinder databases), consisting of millions of tabulated reaction examples, it is now possible to construct and validate purely data-driven approaches to synthesis planning. As a result, synthesis planning has been opened to machine learning techniques, and the field is advancing rapidly. In this Account, we focus on two crit. aspects of CASP and recent machine learning approaches to both challenges. First, we discuss the problem of retrosynthetic planning, which requires a recommender system to propose synthetic disconnections starting from a target mol. We describe how the search strategy, necessary to overcome the exponential growth of the search space with increasing no. of reaction steps, can be assisted through a learned synthetic complexity metric. We also describe how the recursive expansion can be performed by a straightforward nearest neighbor model that makes clever use of reaction data to generate high quality retrosynthetic disconnections. Second, we discuss the problem of anticipating the products of chem. reactions, which can be used to validate proposed reactions in a computer-generated synthesis plan (i.e., reduce false positives) to increase the likelihood of exptl. success. While we introduce this task in the context of reaction validation, its utility extends to the prediction of side products and impurities, among other applications. We describe neural network-based approaches that we and others have developed for this forward prediction task that can be trained on previously published exptl. data. Machine learning and artificial intelligence have revolutionized a no. of disciplines, not limited to image recognition, dictation, translation, content recommendation, advertising, and autonomous driving. While there is a rich history of using machine learning for structure-activity models in chem., it is only now that it is being successfully applied more broadly to org. synthesis and synthesis design. As reported in this Account, machine learning is rapidly transforming CASP, but there are several remaining challenges and opportunities, many pertaining to the availability and standardization of both data and evaluation metrics, which must be addressed by the community at large.
- 23Felton, K.; Wigh, D.; Lapkin, A. Multi-task Bayesian Optimization of Chemical Reactions. 34th Conference on Neural Information Processing Systems; NeurIPS, 2020.Google ScholarThere is no corresponding record for this reference.
- 24Taylor, C. J.; Booth, M.; Manson, J. A.; Willis, M. J.; Clemens, G.; Taylor, B. A.; Chamberlain, T. W.; Bourne, R. A. Rapid, automated determination of reaction models and kinetic parameters. Chemical Engineering Journal 2021, 413, 127017, DOI: 10.1016/j.cej.2020.127017Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1ymu7Y%253D&md5=61b266e4d07ffd08b5cb42540313b82cRapid, automated determination of reaction models and kinetic parametersTaylor, Connor J.; Booth, Megan; Manson, Jamie A.; Willis, Mark J.; Clemens, Graeme; Taylor, Brian A.; Chamberlain, Thomas W.; Bourne, Richard A.Chemical Engineering Journal (Amsterdam, Netherlands) (2021), 413 (), 127017CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)A novel kinetic modeling methodol. is reported whereby identification of the correct reaction model and kinetic parameters is conducted by an autonomous framework combined with transient flow measurements to enable comprehensive process understanding with minimal user input. An automated flow chem. platform was employed to initially conduct linear flow-ramp expts. to rapidly map the reaction profile of three processes using transient flow data. Following exptl. data acquisition, a computational approach was utilized to discriminate between all possible reaction models as well as identify the correct kinetic parameters for each process. Species that are known to participate in the process (starting materials, intermediates, products) are initially inputted by the user prior to flow ramp expts., then all possible model candidates are compiled into a model library based on their potential to occur after mass balance assessment. Parallel computational optimization then evaluates each model by algorithmically altering the kinetic parameters of the model to allow convergence of a simulated kinetic curve to the exptl. data provided. Statistical anal. then dets. the most likely reaction model based on model simplicity and agreement with exptl. data. This automated approach to gaining full process understanding, whereby a small no. of data-rich expts. are conducted, and the kinetics are evaluated autonomously, shows significant improvements on current industrial optimization techniques in terms of labor, time and overall cost. The computational approach herein described can be employed using data from any set of expts. and the code is open-source.
- 25Taylor, C. J.; Seki, H.; Dannheim, F. M.; Willis, M. J.; Clemens, G.; Taylor, B. A.; Chamberlain, T. W.; Bourne, R. A. An automated computational approach to kinetic model discrimination and parameter estimation. React. Chem. Eng. 2021, 6, 1404– 1411, DOI: 10.1039/D1RE00098EGoogle Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVCqsb%252FN&md5=d5e0cdcf8490b91602000b4cf13b8ce2An automated computational approach to kinetic model discrimination and parameter estimationTaylor, Connor J.; Seki, Hikaru; Dannheim, Friederike M.; Willis, Mark J.; Clemens, Graeme; Taylor, Brian A.; Chamberlain, Thomas W.; Bourne, Richard A.Reaction Chemistry & Engineering (2021), 6 (8), 1404-1411CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)We herein report exptl. applications of a novel, automated computational approach to chem. reaction network (CRN) identification. This report shows the first chem. applications of an autonomous tool to identify the kinetic model and parameters of a process, when considering both catalytic species and various integer and non-integer orders in the model's rate laws. This kinetic anal. methodol. requires only the input of the species within the chem. system (starting materials, intermediates, products, etc.) and corresponding time-series concn. data to det. the kinetic information of the chem. of interest. This is performed with minimal human interaction and several case studies were performed to show the wide scope and applicability of this process development tool. The approach described herein can be employed using exptl. data from any source and the code for this methodol. is also provided open-source.
- 26Lawal, M. M.; Govender, T.; Maguire, G. E. M.; Honarparvar, B.; Kruger, H. G. Mechanistic investigation of the uncatalyzed esterification reaction of acetic acid and acid halides with methanol: a DFT study. J. Mol. Model. 2016, 22, 235, DOI: 10.1007/s00894-016-3084-zGoogle Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2szos1artA%253D%253D&md5=3981531b1a7d0967ed1578171575e6e0Mechanistic investigation of the uncatalyzed esterification reaction of acetic acid and acid halides with methanol: a DFT studyLawal Monsurat M; Govender Thavendran; Maguire Glenn E M; Honarparvar Bahareh; Kruger Hendrik G; Maguire Glenn E MJournal of molecular modeling (2016), 22 (10), 235 ISSN:.Implementation of catalysts to drive reactions from reactants to products remains a burden to synthetic and organic chemists. In spite of investigations into the kinetics and mechanism of catalyzed esterification reactions, less effort has been made to explore the possibility of an uncatalyzed esterification process. Therefore, a comprehensive mechanistic perspective for the uncatalyzed mechanism at the molecular level is presented. Herein, we describe the non-catalyzed esterification reaction of acetic acid and its halide derivatives (XAc, where X= OH, F, Cl, Br, I) with methanol (MeOH) through a concerted process. The reaction in vacuum and methanol was performed using the density functional theory (DFT) method at M06-2X level with def2-TZVP basis set after a careful literature survey and computations. Esterification through cyclic 4- or 6-membered transition state structures in one- or two-step concerted mechanisms were investigated. The present study outlines the possible cyclic geometry conformations that may occur during experiments at simple ratio of reactants. The free energy of activation for acetic acid and acetyl chloride are 36 kcal mol(-1) and 21 kcal mol(-1), respectively. These are in good agreement with available experimental results from the literature. The selected quantum chemical descriptors proved to be useful tools in chemical reactivity prediction for the reaction mechanism. This quantum mechanics study can serve as a necessary step towards revisiting uncatalyzed reaction mechanisms in some classical organic reactions.
- 27Pomberger, A.; Pedrina McCarthy, A. A.; Khan, A.; Sung, S.; Taylor, C. J.; Gaunt, M. J.; Colwell, L.; Walz, D.; Lapkin, A. A. The effect of chemical representation on active machine learning towards closed-loop optimization. React. Chem. Eng. 2022, 7, 1368– 1379, DOI: 10.1039/D2RE00008CGoogle Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XmslSntrg%253D&md5=84c1991820916ea1d8ebaf7740d529bdThe effect of chemical representation on active machine learning towards closed-loop optimizationPomberger, A.; Pedrina McCarthy, A. A.; Khan, A.; Sung, S.; Taylor, C. J.; Gaunt, M. J.; Colwell, L.; Walz, D.; Lapkin, A. A.Reaction Chemistry & Engineering (2022), 7 (6), 1368-1379CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Multivariate chem. reaction optimization involving catalytic systems is a non-trivial task due to the high no. of tuneable parameters and discrete choices. Active machine learning (ML) represents a powerful strategy for automating reaction optimization. However, the translation of chem. reaction conditions into a machine-readable format requires the identification of highly informative features which accurately capture the factors which det. reaction success. Herein, we compare the efficacy of different calcd. chem. descriptors for a high throughput experimentation generated dataset to det. the impact on a supervised ML model when predicting reaction yield. Then, the effect of featurization and size of the initial dataset within a closed-loop reaction optimization was examd. Finally, the balance between descriptor complexity and dataset size was considered. Ultimately, tailored descriptors did not outperform simple generic representations, however, a larger initial dataset accelerated reaction optimization.
- 28Taylor, C. J.; Manson, J. A.; Clemens, G.; Taylor, B. A.; Chamberlain, T. W.; Bourne, R. A. Modern advancements in continuous-flow aided kinetic analysis. Reaction Chemistry & Engineering 2022, 7, 1037– 1046, DOI: 10.1039/D1RE00467KGoogle Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XktVOitrk%253D&md5=df25afbfb769c0d2a7028c27b8646020Modern advancements in continuous-flow aided kinetic analysisTaylor, Connor J.; Manson, Jamie A.; Clemens, Graeme; Taylor, Brian A.; Chamberlain, Thomas W.; Bourne, Richard A.Reaction Chemistry & Engineering (2022), 7 (5), 1037-1046CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Although kinetic anal. has traditionally been conducted in a batch vessel, continuous-flow aided kinetic anal. continues to swell in popularity. This can be partly attributed to the favorable characteristics of flow reactors and the growth of flow chem. in general. However, the development of innovative techniques in recent years to obtain more kinetic information using less reaction material, has further accelerated its adoption. These advancements allow faster and more efficient routes to total process understanding, thereby allowing optimum reaction conditions to be identified in process development to maximise product outputs. This minireview documents novel methodologies reported in the recent literature, both to highlight opportunities for their exploitation and to enable further adoption of kinetic anal. in continuous-flow systems in years to come.
- 29Ancheyta-Juárez, J.; López-Isunza, F.; Aguilar-Rodríguez, E.; Moreno-Mayorga, J. C. A Strategy for Kinetic Parameter Estimation in the Fluid Catalytic Cracking Process. Ind. Eng. Chem. Res. 1997, 36, 5170– 5174, DOI: 10.1021/ie970271rGoogle Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXntFKhs7c%253D&md5=34da137cb68f9fa8c87bf5567bd1c572A Strategy for Kinetic Parameter Estimation in the Fluid Catalytic Cracking ProcessAncheyta-Juarez, Jorge; Lopez-Isunza, Felipe; Aguilar-Rodriguez, Enrique; Moreno-Mayorga, Juan C.Industrial & Engineering Chemistry Research (1997), 36 (12), 5170-5174CODEN: IECRED; ISSN:0888-5885. (American Chemical Society)A strategy is proposed to est. lumped kinetic consts. in fluid catalytic cracking (FCC) reactions. This method decreases the no. of simultaneously estd. parameters. The 3-, 4-, and a new 5-lump kinetic model and exptl. data obtained at 480, 500, and 520°C in a microactivity reactor are used to illustrate the procedure. Activation energies for each involved reaction are also reported.
- 30Cox, P. A.; Leach, A. G.; Campbell, A. D.; Lloyd-Jones, G. C. Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH–Rate Profiles, Autocatalysis, and Disproportionation. J. Am. Chem. Soc. 2016, 138, 9145– 9157, DOI: 10.1021/jacs.6b03283Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVyit77I&md5=bba913cb4ed0e5e0084b8872ce95d233Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH-Rate Profiles, Autocatalysis, and DisproportionationCox, Paul A.; Leach, Andrew G.; Campbell, Andrew D.; Lloyd-Jones, Guy C.Journal of the American Chemical Society (2016), 138 (29), 9145-9157CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)PH-rate profiles for aq.-org. protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, and varied substantially between the boronic acids, with rate maxima that varied over 6 orders of magnitude. A mechanistic model contg. five general pathways (k1-k5) has been developed, and together with input of [B]tot, KW, Ka, and KaH, the protodeboronation kinetics can be correlated as a function of pH (1-13) for all 18 species. Cyclopropyl and vinyl boronic acids undergo very slow protodeboronation, as do 3- and 4-pyridyl boronic acids (t0.5 > 1 wk, pH 12, 70 °C). In contrast, 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation (t0.5 ≈ 25-50 s, pH 7, 70 °C), via fragmentation of zwitterionic intermediates. Lewis acid additives (e.g., Cu, Zn salts) can attenuate (2-pyridyl) or accelerate (5-thiazolyl and 5-pyrazolyl) fragmentation. Two addnl. processes compete when the boronic acid and the boronate are present in sufficient proportions (pH = pKa ± 1.6): (i) self-/autocatalysis and (ii) sequential disproportionations of boronic acid to borinic acid and borane.
- 31Cox, P. A.; Reid, M.; Leach, A. G.; Campbell, A. D.; King, E. J.; Lloyd-Jones, G. C. Base-Catalyzed Aryl-B(OH)2 Protodeboronation Revisited: From Concerted Proton Transfer to Liberation of a Transient Aryl Anion. J. Am. Chem. Soc. 2017, 139, 13156– 13165, DOI: 10.1021/jacs.7b07444Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlKhtbvN&md5=f15adb9daf70fa2e0c99b55ec56fe132Base-Catalyzed Aryl-B(OH)2 Protodeboronation Revisited: From Concerted Proton Transfer to Liberation of a Transient Aryl AnionCox, Paul A.; Reid, Marc; Leach, Andrew G.; Campbell, Andrew D.; King, Edward J.; Lloyd-Jones, Guy C.Journal of the American Chemical Society (2017), 139 (37), 13156-13165CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Pioneering studies by Kuivila, published more than 50 years ago, suggested ipso protonation of the boronate as the mechanism for base-catalyzed protodeboronation of arylboronic acids. However, the study was limited to UV spectrophotometric anal. under acidic conditions, and the aq. assocn. consts. (Ka) were estd. By means of NMR, stopped-flow IR, and quenched-flow techniques, the kinetics of base-catalyzed protodeboronation of 30 different arylboronic acids has now been detd. at pH > 13 in aq. dioxane at 70 °C. Included in the study are all 20 isomers of C6HnF(5-n)B(OH)2 with half-lives spanning 9 orders of magnitude: <3 ms to 6.5 mo. In combination with pH-rate profiles, pKa and ΔS⧺ values, kinetic isotope effects (2H, 10B, 13C), linear free-energy relationships, and d. functional theory calcns., we have identified a mechanistic regime involving unimol. heterolysis of the boronate competing with concerted ipso protonation/C-B cleavage. The relative Lewis acidities of arylboronic acids do not correlate with their protodeboronation rates, esp. when ortho substituents are present. Notably, 3,5-dinitrophenylboronic acid is orders of magnitude more stable than tetra- and pentafluorophenylboronic acids but has a similar pKa.
- 32Cox, P. Protodeboronation. Ph.D. thesis, The University of Edinburgh, 2016.Google ScholarThere is no corresponding record for this reference.
- 33van de Vusse, J. G. Plug-flow type reactor versus tank reactor. Chem. Eng. Sci. 1964, 19, 994– 996, DOI: 10.1016/0009-2509(64)85109-5Google ScholarThere is no corresponding record for this reference.
- 34Ridlehoover, G. A.; Seagrave, R. C. Optimization of Van de Vusse Reaction Kinetics Using Semibatch Reactor Operation. Industrial & Engineering Chemistry Fundamentals 1973, 12, 444– 447, DOI: 10.1021/i160048a008Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXltVymt7g%253D&md5=e42bb8f5795e5551cef1f37cf76c1beeOptimization of Van de Vusse reaction kinetics using semibatch reactor operationRidlehoover, G. A.; Seagrave, R. C.Industrial & Engineering Chemistry Fundamentals (1973), 12 (4), 444-7CODEN: IECFA7; ISSN:0196-4313.Methods of semibatch or periodic reactor operation needed to maximize the yield of the desired intermediate species in the Van de Vusse chemical reactions are presented. The operating parameters of the stirred-batch reactor in the kinetic region where semibatch operation is superior to both plug-flow and continuous operation are detd. and are given as a function of the ratios of the assocd. kinetic rate consts. Digital simulation techniques are employed to investigate the range of operating and kinetic conditions likely to be encountered. The methods employed are easily extendable to other reaction schemes.
- 35Sha, Y.; Yu, T. H.; Merinov, B. V.; Goddard, W. A. DFT Prediction of Oxygen Reduction Reaction on Palladium–Copper Alloy Surfaces. ACS Catal. 2014, 4, 1189– 1197, DOI: 10.1021/cs4009623Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtVeqs7Y%253D&md5=3de1f9ce92fe3f29fa59a1744fd1562fDFT Prediction of Oxygen Reduction Reaction on Palladium-Copper Alloy SurfacesSha, Yao; Yu, Ted H.; Merinov, Boris V.; Goddard, William A.ACS Catalysis (2014), 4 (4), 1189-1197CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)The high cost of proton exchange membrane fuel cells (PEMFCs) comes largely from the use of Pt-contg. electrocatalysts. Despite significant progress made the past decade on reducing the Pt catalyst loading in the PEMFC electrodes, further substantial cost redns. require the replacement of Pt with less expensive nonplatinum electrocatalytic materials. PdCu alloys have computationally been studied as possible non-Pt catalysts for O redn. reaction (ORR) in PEMFCs. The authors used d. functional theory (DFT) calcns. to det. the structural preference and ORR activity as a function of the compn. and structure. Five PdCu alloy surface structures, B2, L12, L10, L11-nonlayered, and L11-layered, were considered, and the layered L11 surface structure was found to exhibit significantly improved ORR kinetics compared to that of pure Pd.
- 36Frau, J.; Hernández-Haro, N.; Glossman-Mitnik, D. Computational prediction of the pKas of small peptides through Conceptual DFT descriptors. Chem. Phys. Lett. 2017, 671, 138– 141, DOI: 10.1016/j.cplett.2017.01.038Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlGltro%253D&md5=9c302d02306058cbcad172e7053e9bd6Computational prediction of the pKas of small peptides through Conceptual DFT descriptorsFrau, Juan; Hernandez-Haro, Noemi; Glossman-Mitnik, DanielChemical Physics Letters (2017), 671 (), 138-141CODEN: CHPLBC; ISSN:0009-2614. (Elsevier B.V.)The exptl. pKa of a group of simple amines have been plotted against several Conceptual DFT descriptors calcd. by different d. functionals, basis sets and solvation schemes. The best fits are those that relate the pKa of the amines with the global hardness η through the MN12SX d. functional in connection with the Def2TZVP basis set and the SMD solvation model, using water as a solvent. The parameterized equation resulting from the linear regression anal. has then been used for the prediction of the pKa of small peptides of interest in the study of diabetes and Alzheimer disease. The accuracy of the results is relatively good, with a MAD of 0.36 units of pKa.
- 37Ainley, A. D.; Challenger, F. CCLXXX.─Studies of the boron–carbon linkage. Part I. The oxidation and nitration of phenylboric acid. Journal of the Chemical Society (Resumed) 1930, 0, 2171– 2180, DOI: 10.1039/JR9300002171Google ScholarThere is no corresponding record for this reference.
- 38Kuivila, H. G.; Nahabedian, K. V. Electrophilic Displacement Reactions. X. General Acid Catalysis in the Protodeboronation of Areneboronic Acids1–3. J. Am. Chem. Soc. 1961, 83, 2159– 2163, DOI: 10.1021/ja01470a028Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3MXhtFWrtL0%253D&md5=e553c4d1672e02d4fed59405842d2ee6Electrophilic displacement reactions. X. General acid catalysis in the protodeboronation of areneboronic acidsKuivila, Henry G.; Nahebedian, K. V.Journal of the American Chemical Society (1961), 83 (), 2159-63CODEN: JACSAT; ISSN:0002-7863.cf. CA 52, 5324e. Rate consts. obtained from kinetic studies on the protodeboronation of p-methoxybenzeneboronic acid and 2,6-dimethoxybenzeneboronic acid in aq. H2SO4, H3PO4, HClO4, and HCO2H and phosphate buffer solns. at various temp. were discussed in correlation with acidity function H0. These results indicated that the reaction was generally acid catalyzed.
- 39Kuivila, H. G.; Nahabedian, K. V. Electrophilic Displacement Reactions. XI. Solvent Isotope Effects in the Protodeboronation of Areneboronic Acids1–3. J. Am. Chem. Soc. 1961, 83, 2164– 2166, DOI: 10.1021/ja01470a029Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3MXhtFWrtLo%253D&md5=f6593311ca282524426aa7a53c6bb38fElectrophilic displacement reactions. XI. Solvent isotope effects in the protodeboronation of areneboronic acidsKuivila, Henry G.; Nahebedian, K. V.Journal of the American Chemical Society (1961), 83 (), 2164-6CODEN: JACSAT; ISSN:0002-7863.The effect of solvent hydrogen isotope composition on the rate of protodeboronation of p-methoxybenzeneboronic acid in 6.31M H2SO4 at 25° and of 2,6-dimethoxybenzeneboronic acid in 0.1M HClO4 were detd. In the former case, the kH/kD ratio was 3.7 and a nearly linear dependence of rate const. on the H isotope composition was obtained. In the later case, kH/kD was 1.7 and variation of rate const. with solvent isotope composition was non-linear. The rate behavior obtained was in agreement with a rate determining proton transfer mechanism.
- 40Nahabedian, K. V.; Kuivila, H. G. Electrophilic Displacement Reactions. XII. Substituent Effects in the Protodeboronation of Areneboronic Acids1–3. J. Am. Chem. Soc. 1961, 83, 2167– 2174, DOI: 10.1021/ja01470a030Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3MXhtFWrtLs%253D&md5=52c71c492e978ea6da7f27d9a51257baElectrophilic displacement reactions. XII. Substituent effects in the protodeboronation of areneboronic acidsNahabedian, K. V.; Kuivila, Henry G.Journal of the American Chemical Society (1961), 83 (), 2167-74CODEN: JACSAT; ISSN:0002-7863.Kinetic studies on the hydrolysis of nine areneboronic acids, x-ZC6H4[B(OH)2] (Z = H, m-NO2, p-Br, m-F, p-F, p-Me, p-OMe, m-Cl, and m-CF3) in aq. H2SO4 and H3PO4 were described. Dependence of rate on acidity was examd. in each case, and activation parameters and solvent H isotope effects were detd. in 4 cases (Z = p-Me, p-F, H, and m-F) for activation parameters and in 4 cases (Z = p-Me, p-OMe, p-F, and m-F) for H-isotope effect. Results obtained led to an interpretation of the existence of at least two mechanisms for the reaction.
- 41Kuivila, H. G.; Reuwer, J. F., Jr.; Mangravite, J. A. Electrophilic displacement reactions: xv. kinetics and mechanism of the base-catalyzed protodeboronation of areneboronic acids. Can. J. Chem. 1963, 41, 3081– 3090, DOI: 10.1139/v63-451Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2cXit1Ortw%253D%253D&md5=2d3a684fd4d71447c7ca5bb43a2dab13Electrophilic displacement reactions. XV. Kinetics and mechanism of the base-catalyzed protodeboronation of areneboronic acidsKuivila, Henry G.; Reuwer, Joseph F., Jr.; Mangravite, John A.Canadian Journal of Chemistry (1963), 41 (12), 3081-90CODEN: CJCHAG; ISSN:0008-4042.cf. CA 57, 3465a. An investigation of the kinetics of the protodeboronation of benzeneboronic acid in water in the pH range 2.0 to 6.7 is described. In addn. to the acid-catalyzed reaction studied earlier, a reaction whose rate is independent of pH and one whose rate increases linearly with hydroxide ion concn. have been observed. The effect of malonate buffer concn. at low pH confirms the earlier observations of general acid catalysis. Changes in buffer concn. at pH 6.70 have no effect on rate indicating specific hydroxide ion catalysis. Effect of substituents in the ortho, meta, and para position of the benzene ring on the rate of protodeboronation have been examd. Ortho-para ratios for this reaction are high; possible reasons for this are discussed. The Hammett equation using σ correlates the rates for meta and para substituents.
- 42Brown, R. D.; Buchanan, A. S.; Humffray, A. A. Protodeboronation of thiophenboronic acids. Aust. J. Chem. 1965, 18, 1521– 1525, DOI: 10.1071/CH9651521Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28XhvVGgsg%253D%253D&md5=ef92546d391c4d8444e04bd95cf40107Protodeboronation of thiopheneboronic acidsBrown, R. D.; Buchanan, A. S.; Humffray, A. A.Australian Journal of Chemistry (1965), 18 (10), 1521-5CODEN: AJCHAS; ISSN:0004-9425.The rates of protodeboronation of benzene-, thiophene-2-, and thiophene-3-boronic acids were measured using HClO4 as catalyst. The relative rates at 70° are detd. by the relation between log k and -H0 (acidity function), and correcting the k values to the same -H0 value (-H0 = 0.22, corresponding to M HClO4). The energies and entropies of activation are listed. It is not necessary to make a direct comparison of the entropy values since the very much greater reactivity of thiophene derivs. compared to benzeneboronic acid is evident. The kinetic results are consistent with the A-SE2 mechanism for protodeboronation proposed by Kuivila and Nahebedian (CA 55, 21012a).
- 43Lozada, J.; Liu, Z.; Perrin, D. M. Base-Promoted Protodeboronation of 2,6-Disubstituted Arylboronic Acids. Journal of Organic Chemistry 2014, 79, 5365– 5368, DOI: 10.1021/jo500734zGoogle Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotVagsLY%253D&md5=3573a22c0a2cce004f4a5e0eae6db9e3Base-Promoted Protodeboronation of 2,6-Disubstituted Arylboronic AcidsLozada, Jerome; Liu, Zhibo; Perrin, David M.Journal of Organic Chemistry (2014), 79 (11), 5365-5368CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Facile based promoted deboronation of electron-deficient arylboronate esters was obsd. for arylboronates contg. two ortho electron-withdrawing group (EWG) substituents. Among 30 representative boronates, only the diortho-substituted species underwent facile C-B fission in aq. basic conditions (200 mM hydroxide). These results provide fundamental insight into deboronative mechanisms with implications for cross-coupling reactions, regioselective deuteration/tritiation for isotopic labeling, and the design of new 18F-trifluoroborate radioprosthetics.
- 44Muir, C. W.; Vantourout, J. C.; Isidro-Llobet, A.; Macdonald, S. J. F.; Watson, A. J. B. One-Pot Homologation of Boronic Acids: A Platform for Diversity-Oriented Synthesis. Org. Lett. 2015, 17, 6030– 6033, DOI: 10.1021/acs.orglett.5b03030Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvF2ru7zP&md5=25ef18e5b4cfcdb98a763d4754471e83One-Pot Homologation of Boronic Acids: A Platform for Diversity-Oriented SynthesisMuir, Calum W.; Vantourout, Julien C.; Isidro-Llobet, Albert; Macdonald, Simon J. F.; Watson, Allan J. B.Organic Letters (2015), 17 (24), 6030-6033CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)Formal homologation of sp2-hybridized boronic acids is achieved via cross-coupling of boronic acids with conjunctive haloaryl BMIDA components in the presence of a suitably balanced basic phase. The utility of this approach to provide a platform for diversity-oriented synthesis in discovery medicinal chem. is demonstrated in the context of the synthesis of a series of analogs of a BET bromodomain inhibitor.
- 45Li, Z.; Gelbaum, C.; Heaner, W. L.; Fisk, J.; Jaganathan, A.; Holden, B.; Pollet, P.; Liotta, C. L. Palladium-Catalyzed Suzuki Reactions in Water with No Added Ligand: Effects of Reaction Scale, Temperature, pH of Aqueous Phase, and Substrate Structure. Org. Process Res. Dev. 2016, 20, 1489– 1499, DOI: 10.1021/acs.oprd.6b00180Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVKju77I&md5=e677d8eff9de9e5c95b4f2baf05823b5Palladium-Catalyzed Suzuki Reactions in Water with No Added Ligand: Effects of Reaction Scale, Temperature, pH of Aqueous Phase, and Substrate StructureLi, Zhao; Gelbaum, Carol; Heaner, William L.; Fisk, Jason; Jaganathan, Arvind; Holden, Bruce; Pollet, Pamela; Liotta, Charles L.Organic Process Research & Development (2016), 20 (8), 1489-1499CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The heterogeneous palladium-catalyzed Suzuki reactions between model aryl bromides (4-bromoanisole, 4-bromoaniline, 4-amino-2-bromopyridine, and 2-bromopyridine) and phenylboronic acid have been successfully conducted in water with no added ligand at the 100 mL scale using 20-40 mmol of aryl bromide. The product yields assocd. with these substrates were optimized, and key reaction parameters affecting the yields were identified. The results clearly indicate that the reaction parameters necessary to achieve high yields are substrate-dependent. In addn., it is demonstrated that aq. Suzuki reactions of substrates contg. basic nitrogen centers can produce quant. yields of desired products in the absence of added ligand.
- 46Sander, T.; Freyss, J.; von Korff, M.; Rufener, C. DataWarrior: An Open-Source Program For Chemistry Aware Data Visualization And Analysis. J. Chem. Inf. Model. 2015, 55, 460– 473, DOI: 10.1021/ci500588jGoogle Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXktFWnuw%253D%253D&md5=5c849901b5cb4549d870d81f5eeaca0aDataWarrior: An Open-Source Program For Chemistry Aware Data Visualization And AnalysisSander, Thomas; Freyss, Joel; von Korff, Modest; Rufener, ChristianJournal of Chemical Information and Modeling (2015), 55 (2), 460-473CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)Drug discovery projects in the pharmaceutical industry accumulate thousands of chem. structures and ten-thousands of data points from a dozen or more biol. and pharmacol. assays. A sufficient interpretation of the data requires understanding which mol. families are present, which structural motifs correlate with measured properties, and which tiny structural changes cause large property changes. Data visualization and anal. software with sufficient chem. intelligence to support chemists in this task is rare. In an attempt to contribute to filling the gap, we released our inhouse developed chem. aware data anal. program DataWarrior for free public use. This paper gives an overview of DataWarrior's functionality and architecture. Exemplarily, a new unsupervised, 2-dimensional scaling algorithm is presented, which employs vector-based or nonvector-based descriptors to visualize the chem. or pharmacophore space of even large data sets. DataWarrior uses this method to interactively explore chem. space, activity landscapes, and activity cliffs.
Cited By
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by ACS Publications if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
This article is cited by 2 publications.
- Daniel S. Wigh, Joe Arrowsmith, Alexander Pomberger, Kobi C. Felton, Alexei A. Lapkin. ORDerly: Data Sets and Benchmarks for Chemical Reaction Data. Journal of Chemical Information and Modeling 2024, 64
(9)
, 3790-3798. https://doi.org/10.1021/acs.jcim.4c00292
- Bojana Ranković, Ryan-Rhys Griffiths, Henry B. Moss, Philippe Schwaller. Bayesian optimisation for additive screening and yield improvements – beyond one-hot encoding. Digital Discovery 2024, 3
(4)
, 654-666. https://doi.org/10.1039/D3DD00096F
Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.
Recommended Articles
Abstract
Scheme 1
Scheme 1. General Scheme for Protodeboronation in Aqueous SolutionFigure 1
Figure 1. Example of each of the mechanistic pathways of protodeboronation relevant to the boronic acids considered in this work. (30) A red box encloses the two stages used for calculation of ΔE for each mechanism; k2cat in the fourth row has no red box, since ΔE was calculated using a simplified version of this mechanism (shown in the fifth row). A detailed description of each mechanistic pathway can be found in the Supporting Information.
Figure 2
Figure 2. Heuristics for determining which mechanistic pathways are active for a particular boronic acid (Z = basic nitrogen, X = S, O). (30)
Scheme 2
Scheme 2. Structure of (3,5-Dimethyl-1,2-oxazol-4-yl)boronic Acid (DMOBA)Scheme 3
Scheme 3. Mechanistic Pathway k4 for (3,5-Dimethyl-1,2-oxazol-4-yl)boronic AcidFigure 3
Figure 3. Linear regression of log(k) vs ΔE for the k2 and k4 mechanistic pathways.
Figure 4
Figure 4. Constructing rate curves for each mechanism given the pKa, pKaH, and slope of mechanistic deactivation with pH.
Figure 5
Figure 5. Predicted rate vs measured rate for DMOBA.
Figure 6
Figure 6. Parity plot showing the predictive accuracy of the algorithm. MAE: Mean Absolute Error. MSE: Mean Squared error. R2: Coefficient of Determination.
References
This article references 46 other publications.
- 1Hall, D. G. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2011.There is no corresponding record for this reference.
- 2Bull, S. D.; Davidson, M. G.; van den Elsen, J. M. H.; Fossey, J. S.; Jenkins, A. T. A.; Jiang, Y.-B.; Kubo, Y.; Marken, F.; Sakurai, K.; Zhao, J.; James, T. D. Exploiting the reversible covalent bonding of boronic acids: recognition, sensing, and assembly. Acc. Chem. Res. 2013, 46, 312– 326, DOI: 10.1021/ar300130w2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Knu7bN&md5=5bdc35d91fcf90e3167cd362a9066eafExploiting the Reversible Covalent Bonding of Boronic Acids: Recognition, Sensing, and AssemblyBull, Steven D.; Davidson, Matthew G.; van den Elsen, Jean M. H.; Fossey, John S.; Jenkins, A. Toby A.; Jiang, Yun-Bao; Kubo, Yuji; Marken, Frank; Sakurai, Kazuo; Zhao, Jianzhang; James, Tony D.Accounts of Chemical Research (2013), 46 (2), 312-326CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Boronic acids can interact with Lewis bases to generate boronate anions, and they can also bind with diol units to form cyclic boronate esters. Boronic acid based receptor designs originated when Lorand and Edwards used the pH drop obsd. upon the addn. of saccharides to boronic acids to det. their assocn. consts. The inherent acidity of the boronic acid is enhanced when 1,2-, 1,3-, or 1,4-diols react with boronic acids to form cyclic boronic esters (5, 6, or 7 membered rings) in aq. media, and these interactions form the cornerstone of diol-based receptors used in the construction of sensors and sepn. systems. In addn., the recognition of saccharides through boronic acid complex (or boronic ester) formation often relies on an interaction between a Lewis acidic boronic acid and a Lewis base (proximal tertiary amine or anion). These properties of boronic acids have led to them being exploited in sensing and sepn. systems for anions (Lewis bases) and saccharides (diols). The fast and stable bond formation between boronic acids and diols to form boronate esters can serve as the basis for forming reversible mol. assemblies. In spite of the stability of the boronate esters' covalent B-O bonds, their formation is reversible under certain conditions or under the action of certain external stimuli. The reversibility of boronate ester formation and Lewis acid-base interactions has also resulted in the development and use of boronic acids within multicomponent systems. The dynamic covalent functionality of boronic acids with structure-directing potential has led researchers to develop a variety of self-organizing systems including macrocycles, cages, capsules, and polymers. This Account gives an overview of research published about boronic acids over the last 5 years. We hope that this Account will inspire others to continue the work on boronic acids and reversible covalent chem.
- 3Hirai, M.; Tanaka, N.; Sakai, M.; Yamaguchi, S. Structurally Constrained Boron-, Nitrogen-, Silicon-, and Phosphorus-Centered Polycyclic -Conjugated Systems. Chem. Rev. 2019, 119, 8291– 8331, DOI: 10.1021/acs.chemrev.8b006373https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXksFCnsLs%253D&md5=20577226e3e22e6dfc2957b81fc149b9Structurally constrained boron-, nitrogen-, silicon-, and phosphorus-centered polycyclic π-conjugated systemsHirai, Masato; Tanaka, Naoki; Sakai, Mika; Yamaguchi, ShigehiroChemical Reviews (Washington, DC, United States) (2019), 119 (14), 8291-8331CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Incorporation of main group elements into the π-conjugated frameworks is a sophisticated strategy to alter the fundamental nature of the parent conjugated π-systems, giving rise to attractive electronic and photophys. properties that are otherwise inaccessible with classic carbon- or metal-based materials. Out of all π-conjugated heterocycles, those that are structurally constrained by tethered aryl substituents surrounding the main group center deserve a great deal of attention because not only do they commonly possess the max. efficiency of π-conjugation and intermol. interaction, but they also enjoy remarkable thermal and morphol. stabilities that are esp. crucial for solid-state performances. In certain cases, elucidation of the behavior of such compds. may addnl. provide sufficient perspective toward graphene materials doped with main group elements, which are widely considered as potential next-generation optoelectronic materials. In this Review, we will specifically focus on historical developments of structurally constrained polycyclic π-electron systems particularly of those with boron, nitrogen, silicon or phosphorus atoms annulated directly into the center of π-conjugated systems.
- 4von Grotthuss, E.; John, A.; Kaese, T.; Wagner, M. Doping Polycyclic Aromatics with Boron for Superior Performance in Materials Science and Catalysis. Asian Journal of Organic Chemistry 2018, 7, 37– 53, DOI: 10.1002/ajoc.2017004954https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVKhtbzF&md5=8a327c8561cce8419392356ca3dac1c5Doping Polycyclic Aromatics with Boron for Superior Performance in Materials Science and Catalysisvon Grotthuss, Esther; John, Alexandra; Kaese, Thomas; Wagner, MatthiasAsian Journal of Organic Chemistry (2018), 7 (1), 37-53CODEN: AJOCC7; ISSN:2193-5807. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. B has one valence electron less than a C atom and an available vacant pz orbital. The incorporation of sp2-hybridized B atoms into the host lattice of a polycyclic arom. hydrocarbon (PAH) is formally related to oxidative doping. A B-contg. B-PAH has an energetically low-lying LUMO and a narrow HOMO-LUMO gap, which renders it a strong Lewis acid/electron acceptor and promotes fluorescence in the visible range of the electromagnetic spectrum. Many methods were developed to access B-PAHs that are deliberately designed for specific tasks. Herein, the authors highlight recent breakthroughs in the field of B-PAH synthesis and the scope of their applications, which range from Lewis acid and redox catalysis to device fabrication. The authors will also report on the dynamic covalent chem. of neutral and anionic B-PAHs, as it is a potential limitation in the design of catalyst systems but can also provide a powerful synthetic tool for the prepn. of otherwise inaccessible B-PAHs.
- 5Jäkle, F. Lewis acidic organoboron polymers. Coord. Chem. Rev. 2006, 250, 1107– 1121, DOI: 10.1016/j.ccr.2006.01.007There is no corresponding record for this reference.
- 6Hudson, Z. M.; Wang, S. Impact of Donor-Acceptor Geometry and Metal Chelation on Photophysical Properties and Applications of Triarylboranes. Acc. Chem. Res. 2009, 42, 1584– 1596, DOI: 10.1021/ar900072u6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnslGqtbk%253D&md5=f153c74a8de59beb637d1613f88b4106Impact of Donor-Acceptor Geometry and Metal Chelation on Photophysical Properties and Applications of TriarylboranesHudson, Zachary M.; Wang, SuningAccounts of Chemical Research (2009), 42 (10), 1584-1596CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Three-coordinate organoboron compds. have recently found a wide range of applications in materials chem. as nonlinear optical materials, chem. sensors, and emitters for org. light-emitting diodes (OLEDs). These compds. are excellent electron acceptors due to the empty pπ orbital on the boron center. When accompanied by electron donors such as amines, these mols. possess large electronic dipoles, which promote donor-acceptor charge-transfer upon excitation with light. Because of this, donor-acceptor triarylboranes are often highly luminescent both in the solid state and in soln. In this Account, we describe our research to develop donor-acceptor triarylboranes as efficient blue emitters for OLEDs. Through the use of hole-transporting donor groups such as 1-naphthylphenylamines, we have prepd. multifunctional triarylboranes that can act as the emissive, electron transport, or hole transport layers in OLEDs. We have also examd. donor-acceptor compds. based on 2,2'-dipyridylamine or 7-azaindolyl donors, several of which have fluorescent quantum efficiencies approaching 100%. We are also investigating the chem. of metal-contg. triarylboranes. Our studies show that the electron-deficient boryl group can greatly facilitate metal-to-ligand charge-transfer transitions and phosphorescence. In addn., electroneg. linker groups such as 2,2'-bipyridine can act in synergy with metal chelation to greatly improve the electron-accepting ability and Lewis acidity of triarylboranes. Donor-acceptor triarylboranes developed in our lab. can also serve as a series of "switch-on" sensors for fluoride ions. When the donor and acceptor are linked by rigid naphthyl or nonrigid silane linkers, donor-acceptor conjugation is disrupted and charge transfer occurs primarily through space. The binding of fluoride ions to the boron center disrupts this charge transfer, activating alternative π → π* transitions in the mol. and changing the emission color of the sample. More recently, we have used these nonconjugated linkers to prep. organometallic donor-acceptor triarylboranes in which fluorescence and phosphorescence can simultaneously be obsd. from two different chromophores in the same mol. at ambient temp. These dual emissive mols. remain sensitive to fluoride ions, and give synergistic singlet-triplet emission responses when titrated with F-. Fluoride ions can also act as valuable chem. probes, providing insight into the electronic structure of this new class of optoelectronic materials. We have demonstrated that donor-acceptor triarylboranes are promising materials in anion sensing and electroluminescent device applications. Nonetheless, despite our work and that of other research groups, there is still much to be learned about organometallic and multiply emissive triarylboron systems.
- 7Rao, Y.-L.; Amarne, H.; Wang, S. Photochromic four-coordinate N,C-chelate boron compounds. Coord. Chem. Rev. 2012, 256, 759– 770, DOI: 10.1016/j.ccr.2011.11.0097https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjt1yhtr8%253D&md5=7884ef963aea131457af7c8e66f0243cPhotochromic four-coordinate N,C-chelate boron compoundsRao, Ying-Li; Amarne, Hazem; Wang, SuningCoordination Chemistry Reviews (2012), 256 (5-8), 759-770CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)A review. Four-coordinate organoboron compds. with a N,C-chelate backbone have been found recently to display an unusual photoisomerization phenomenon with a distinct change of color. The photoisomerization process is thermally reversible, enabling the potential use of this class of compds. as a new class of photoresponsive materials. This review provides an account of the authors recent investigation on the effect of substitution, π-conjugation and metal chelation on the photoisomerization process of the N,C-chelate organoboron compds. The photoisomerization phenomenon of azobenzene-based organoboron compds. will also be presented.
- 8Brooks, W. L. A.; Sumerlin, B. S. Synthesis and Applications of Boronic Acid-Containing Polymers: From Materials to Medicine. Chem. Rev. 2016, 116, 1375– 1397, DOI: 10.1021/acs.chemrev.5b003008https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVyktr7K&md5=e2ed1dd3f0a1fe53b62e45bc0ee7955dSynthesis and Applications of Boronic Acid-Containing Polymers: From Materials to MedicineBrooks, William L. A.; Sumerlin, Brent S.Chemical Reviews (Washington, DC, United States) (2016), 116 (3), 1375-1397CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Boronic acid-contg. macromols. have been utilized in a no. of biomedical applications, including use in dynamic covalent materials, dual thermo and saccharide responsive hydrogels, sensors, and nanomaterials, often with the goal of detection and treatment of type-1 diabetes, which requires const. monitoring of blood glucose levels and proactive insulin management. The ability of boronic acids to bind with saccharides and potentially undergo an ionization transition makes the materials ideal for diabetes-related applications. Other biomedical applications of boronic acid contg. macromols. include use as potential HIV barriers, sepns. and chromatog., cell capture and culture, enzymic inhibition, and in site-specific radiation therapy. The review addresses each of these potential and current areas of application, with particular attention to the fundamental chem. involved.
- 9Miyaura, N.; Yamada, K.; Suzuki, A. A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides. Tetrahedron Lett. 1979, 20, 3437– 3440, DOI: 10.1016/S0040-4039(01)95429-2There is no corresponding record for this reference.
- 10Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457– 2483, DOI: 10.1021/cr00039a00710https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXoslGiurg%253D&md5=d127b414a75161652876eebc3ed0c486Palladium-Catalyzed Cross-Coupling Reactions of Organoboron CompoundsMiyaura, Norio; Suzuki, AkiraChemical Reviews (Washington, D. C.) (1995), 95 (7), 2457-83CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review with >250 refs. including title reactions and their mechanisms, prepn. of organoboron reagents, alkoxycarbonylation and dimerization.
- 11Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. New N- and O-arylations with phenylboronic acids and cupric acetate. Tetrahedron Lett. 1998, 39, 2933– 2936, DOI: 10.1016/S0040-4039(98)00503-611https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtVOlu7w%253D&md5=56efb58adc883aba3ca4ab908f6864ecNew N- and O-arylation with phenylboronic acids and cupric acetateChan, Dominic M. T.; Monaco, Kevin L.; Wang, Ru-Ping; Winters, Michael P.Tetrahedron Letters (1998), 39 (19), 2933-2936CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)A new method of arylating N-H and O-H contg. compds. at room temp. with phenylboronic acids and cupric acetate in the presence of a tertiary amine promoter is described. Substrates include phenols, amines, anilines, amides, imides, ureas, carbamates, and sulfonamides.
- 12Evans, D. A.; Katz, J. L.; West, T. R. Synthesis of diaryl ethers through the copper-promoted arylation of phenols with arylboronic acids. An expedient synthesis of thyroxine. Tetrahedron Lett. 1998, 39, 2937– 2940, DOI: 10.1016/S0040-4039(98)00502-412https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtVOlu7o%253D&md5=201a8d8742f73d5249058a91dc2f6309Synthesis of diaryl ethers through the copper-promoted arylation of phenols with arylboronic acids. An expedient synthesis of thyroxineEvans, David A.; Katz, Jeffrey L.; West, Theodore R.Tetrahedron Letters (1998), 39 (19), 2937-2940CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)Diaryl ethers are readily synthesized in high yield at room temp. through the copper(II)-promoted coupling of arylboronic acids and phenols. The reaction is tolerant of a wide range of substituents on both coupling partners. These reaction conditions permit the racemization-free arylation of phenolic amino acids, methodol. that has been applied to an efficient synthesis of thyroxine.
- 13Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid/cupric acetate arylation. Tetrahedron Lett. 1998, 39, 2941– 2944, DOI: 10.1016/S0040-4039(98)00504-813https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtVOlu7k%253D&md5=86155b6f6d3f9765b3270cb3aa9fd509New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid/cupric acetate arylationLam, Patrick Y. S.; Clark, Charles G.; Saubern, Simon; Adams, Jessica; Winters, Michael P.; Chan, Dominic M. T.; Combs, AndrewTetrahedron Letters (1998), 39 (19), 2941-2944CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)A new aryl/heteroaryl C-N bond cross-coupling reaction via the arylboronic acid/cupric acetate arylation of N-H contg. heteroarenes has been discovered. This new methodol. is mild, proceeds at room temp. exposed to air, and works for many heteroarenes and arylboronic acid providing good yields of N-arylated heteroarenes.
- 14Liebeskind, L. S.; Srogl, J. Thiol Ester-Boronic Acid Coupling. A Mechanistically Unprecedented and General Ketone Synthesis. J. Am. Chem. Soc. 2000, 122, 11260– 11261, DOI: 10.1021/ja005613q14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXnsFylsr8%253D&md5=492065027a52db2b2fc18027c5ec6c37Thiol Ester-Boronic Acid Coupling. A Mechanistically Unprecedented and General Ketone SynthesisLiebeskind, Lanny S.; Srogl, JiriJournal of the American Chemical Society (2000), 122 (45), 11260-11261CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A mild and general method for the palladium-catalyzed, copper mediated coupling of thiol esters and boronic acids under base-free conditions was developed. The mechanistic key to this new reaction is the selective activation of a catalytically generated acylpalladium-thiolate in a way that facilitates transmetalation from boron to palladium, while retaining compatibility with the reaction system. The presence of a copper cation and a carboxylate anion was a crit. requirement for the reaction. For example, a mixt. of benzenecarbothioic acid S-[2-(dimethylamino)-2-oxoethyl] ester (thiol ester), phenylboronic acid, Pd2(dba)3-CHCl3, tris(2-furyl)phosphine, 2-thiophenecarboxylic acid copper(1+) salt, and THF was stirred at 50° for 18 h to give, after work-up, 2-methoxybenzophenone in 88% yield.
- 15Cho, C. S.; Uemura, S. Palladium-catalyzed cross-coupling of aryl and alkenyl boronic acids with alkenes via oxidative addition of a carbon-boron bond to palladium(O). J. Organomet. Chem. 1994, 465, 85– 92, DOI: 10.1016/0022-328X(94)87040-315https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXltVyjtLo%253D&md5=622b3a7732473042d4faa47ad32cab40Palladium-catalyzed cross-coupling of aryl and alkenyl boronic acids with alkenes via oxidative addition of a carbon-boron bond to palladium(0)Cho, Chan Sik; Uemura, SakaeJournal of Organometallic Chemistry (1994), 465 (1-2), 85-92CODEN: JORCAI; ISSN:0022-328X.Arylboronic acids, e.g., PhB(OH)2, react with alkenes, e.g., styrene, in HOAc at 25° in the presence of a catalytic amt. of Pd(II) acetate together with NaOAc to give the corresponding aryl-substituted alkenes, e.g., trans-PhCH:CHPh, in high yields. Alkenylboronic acids react with alkenes under similar conditions to give the corresponding conjugated dienes stereospecifically, but the product yields are lower, compared with those from arylboronic acids. Similar treatment of Na tetraphenylborate (NaBPh4) with alkenes also affords the corresponding phenylated alkenes in high yields together with biphenyl and benzene as side products. Oxidative addn. of a C-B bond to palladium(0), formed in situ, to give an organopalladium(II) species is assumed to be the key step of these cross-coupling reactions.
- 16Sakai, M.; Ueda, M.; Miyaura, N. Rhodium-Catalyzed Addition of Organoboronic Acids to Aldehydes. Angew. Chem., Int. Ed. 1998, 37, 3279– 3281, DOI: 10.1002/(SICI)1521-3773(19981217)37:23<3279::AID-ANIE3279>3.0.CO;2-M16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXksVehsQ%253D%253D&md5=a38fdb13e3a145ec7a0b81caf53dac1dRhodium-catalyzed addition of organoboronic acids to aldehydesSakai, Masaaki; Ueda, Masato; Miyaura, NorioAngewandte Chemie, International Edition (1998), 37 (23), 3279-3281CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)The title reaction of RB(OH)2 (R = Ph, p-anisyl, o-, p-tolyl, p-FC6H4, 2,4,6-Me3C6H2, trans-BuCH:CH) with R1CHO (R1 = Ph, p-F3CC6H4, p-NCC6H4, p-AcC6H4, p-BrC6H4, p-tolyl, p-anisyl, 2-furyl, 1-naphthyl, C5H11, C6H11) in the presence of Rh(acac)(CO)2 in aq. DME gave 31-97% 16 R1RCHOH.
- 17Takezawa, A.; Yamaguchi, K.; Ohmura, T.; Yamamoto, Y.; Miyaura, N. Inter- and Intramolecular Additions of 1-Alkenylboronic Acids or Esters to Aldehydes and Ketones Catalyzed by Rhodium(I) Complexes in Basic, Aqueous Solutions. Synlett 2002, 2002, 1733– 1735, DOI: 10.1055/s-2002-34219There is no corresponding record for this reference.
- 18Sakai, M.; Hayashi, H.; Miyaura, N. Rhodium-Catalyzed Conjugate Addition of Aryl- or 1-Alkenylboronic Acids to Enones. Organometallics 1997, 16, 4229– 4231, DOI: 10.1021/om970511318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlvVyhu78%253D&md5=ee6e958f72c00bbd7bca69373c594d65Rhodium-Catalyzed Conjugate Addition of Aryl- or 1-Alkenylboronic Acids to EnonesSakai, Masaaki; Hayashi, Hiroyuki; Miyaura, NorioOrganometallics (1997), 16 (20), 4229-4231CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)The Rh(I)-catalyzed conjugate addn. of aryl- or 1-alkenylboronic acids, R3B(OH)2, to enones, R1CH:CHC(O)R2, was carried out in high yields at 50° in an aq. solvent, giving R1CHR3CH2C(O)R2. A combination of (acac)Rh(CO)2 and dppb was highly effective for the addn. to acyclic and cyclic enones. For example, a 96% yield of 2-phenyl-4-octanone was obtained from PhB(OH)2 and 2-octen-4-one in aq. MeOH in the presence of (acac)Rh(CO)2 and dppb.
- 19Cho, C. S.; Motofusa, S.-i.; Ohe, K.; Uemura, S.; Shim, S. C. A New Catalytic Activity of Antimony(III) Chloride in Palladium(0)-Catalyzed Conjugate Addition of Aromatics to.alpha.,.beta.-Unsaturated Ketones and Aldehydes with Sodium Tetraphenylborate and Arylboronic Acids. Journal of Organic Chemistry 1995, 60, 883– 888, DOI: 10.1021/jo00109a01919https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjs1CntLk%253D&md5=56342ec8d56bce0d91bc1b76ca99edc2A New Catalytic Activity of Antimony(III) Chloride in Palladium(0)-Catalyzed Conjugate Addition of Aromatics to α,β-Unsaturated Ketones and Aldehydes with Sodium Tetraphenylborate and Arylboronic AcidsCho, Chan Sik; Motofusa, Shin-ichi; Ohe, Kouichi; Uemura, Sakae; Shim, Sang ChulJournal of Organic Chemistry (1995), 60 (4), 883-8CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A remarkable catalytic effect of Sb(III) chloride is disclosed in Pd(0)-catalyzed conjugate addn. of aroms. to α,β-unsatd. ketones and aldehydes with Na tetraphenylborate and arylboronic acids in HOAc at 25°. Thus, treating benzalacetone with Na tetraphenylborate in the presence of Pd acetate and Sb(III) chloride gave 92% 4,4-diphenyl-2-butanone. Several other metal chlorides such as AlCl3, SnCl4, AsCl3, TiCl4, FeCl3, MoCl5, and CeCl3 are also effective in some cases, but SbCl3 is the salt of choice. Two key steps are proposed for this reaction: one is the oxidative addn. of a C-B bond to Pd(0) forming an arylpalladium species, and the other is the formation of an Sb enolate derived from the initial coordination of SbCl3 to the carbonyl O of an organopalladium intermediate.
- 20Wigh, D. S.; Goodman, J. M.; Lapkin, A. A. A review of molecular representation in the age of machine learning. WIREs Computational Molecular Science 2022, 12, e1603 DOI: 10.1002/wcms.1603There is no corresponding record for this reference.
- 21Gao, H.; Struble, T. J.; Coley, C. W.; Wang, Y.; Green, W. H.; Jensen, K. F. Using Machine Learning To Predict Suitable Conditions for Organic Reactions. ACS Central Science 2018, 4, 1465– 1476, DOI: 10.1021/acscentsci.8b0035721https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1aru77J&md5=fef56b949b8b8febb5d1403327238f4bUsing Machine Learning To Predict Suitable Conditions for Organic ReactionsGao, Hanyu; Struble, Thomas J.; Coley, Connor W.; Wang, Yuran; Green, William H.; Jensen, Klavs F.ACS Central Science (2018), 4 (11), 1465-1476CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Reaction condition recommendation is an essential element for the realization of computer-assisted synthetic planning. Accurate suggestions of reaction conditions are required for exptl. validation and can have a significant effect on the success or failure of an attempted transformation. However, de novo condition recommendation remains a challenging and under-explored problem and relies heavily on chemists' knowledge and experience. In this work, we develop a neural-network model to predict the chem. context (catalyst(s), solvent(s), reagent(s)), as well as the temp. most suitable for any particular org. reaction. Trained on ∼10 million examples from Reaxys, the model is able to propose conditions where a close match to the recorded catalyst, solvent, and reagent is found within the top-10 predictions 69.6% of the time, with top-10 accuracies for individual species reaching 80-90%. Temp. is accurately predicted within ±20 °C from the recorded temp. in 60-70% of test cases, with higher accuracy for cases with correct chem. context predictions. The utility of the model is illustrated through several examples spanning a range of common reaction classes. We also demonstrate that the model implicitly learns a continuous numerical embedding of solvent and reagent species that captures their functional similarity.
- 22Coley, C. W.; Green, W. H.; Jensen, K. F. Machine Learning in Computer-Aided Synthesis Planning. Acc. Chem. Res. 2018, 51, 1281– 1289, DOI: 10.1021/acs.accounts.8b0008722https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosFKhsb0%253D&md5=a1ea72c55942f3c0f0a99ab080f96899Machine Learning in Computer-Aided Synthesis PlanningColey, Connor W.; Green, William H.; Jensen, Klavs F.Accounts of Chemical Research (2018), 51 (5), 1281-1289CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)Computer-aided synthesis planning (CASP) is focused on the goal of accelerating the process by which chemists decide how to synthesize small mol. compds. The ideal CASP program would take a mol. structure as input and output a sorted list of detailed reaction schemes that each connect that target to purchasable starting materials via a series of chem. feasible reaction steps. Early work in this field relied on expert-crafted reaction rules and heuristics to describe possible retrosynthetic disconnections and selectivity rules but suffered from incompleteness, infeasible suggestions, and human bias. With the relatively recent availability of large reaction corpora (such as the United States Patent and Trademark Office (USPTO), Reaxys, and SciFinder databases), consisting of millions of tabulated reaction examples, it is now possible to construct and validate purely data-driven approaches to synthesis planning. As a result, synthesis planning has been opened to machine learning techniques, and the field is advancing rapidly. In this Account, we focus on two crit. aspects of CASP and recent machine learning approaches to both challenges. First, we discuss the problem of retrosynthetic planning, which requires a recommender system to propose synthetic disconnections starting from a target mol. We describe how the search strategy, necessary to overcome the exponential growth of the search space with increasing no. of reaction steps, can be assisted through a learned synthetic complexity metric. We also describe how the recursive expansion can be performed by a straightforward nearest neighbor model that makes clever use of reaction data to generate high quality retrosynthetic disconnections. Second, we discuss the problem of anticipating the products of chem. reactions, which can be used to validate proposed reactions in a computer-generated synthesis plan (i.e., reduce false positives) to increase the likelihood of exptl. success. While we introduce this task in the context of reaction validation, its utility extends to the prediction of side products and impurities, among other applications. We describe neural network-based approaches that we and others have developed for this forward prediction task that can be trained on previously published exptl. data. Machine learning and artificial intelligence have revolutionized a no. of disciplines, not limited to image recognition, dictation, translation, content recommendation, advertising, and autonomous driving. While there is a rich history of using machine learning for structure-activity models in chem., it is only now that it is being successfully applied more broadly to org. synthesis and synthesis design. As reported in this Account, machine learning is rapidly transforming CASP, but there are several remaining challenges and opportunities, many pertaining to the availability and standardization of both data and evaluation metrics, which must be addressed by the community at large.
- 23Felton, K.; Wigh, D.; Lapkin, A. Multi-task Bayesian Optimization of Chemical Reactions. 34th Conference on Neural Information Processing Systems; NeurIPS, 2020.There is no corresponding record for this reference.
- 24Taylor, C. J.; Booth, M.; Manson, J. A.; Willis, M. J.; Clemens, G.; Taylor, B. A.; Chamberlain, T. W.; Bourne, R. A. Rapid, automated determination of reaction models and kinetic parameters. Chemical Engineering Journal 2021, 413, 127017, DOI: 10.1016/j.cej.2020.12701724https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1ymu7Y%253D&md5=61b266e4d07ffd08b5cb42540313b82cRapid, automated determination of reaction models and kinetic parametersTaylor, Connor J.; Booth, Megan; Manson, Jamie A.; Willis, Mark J.; Clemens, Graeme; Taylor, Brian A.; Chamberlain, Thomas W.; Bourne, Richard A.Chemical Engineering Journal (Amsterdam, Netherlands) (2021), 413 (), 127017CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)A novel kinetic modeling methodol. is reported whereby identification of the correct reaction model and kinetic parameters is conducted by an autonomous framework combined with transient flow measurements to enable comprehensive process understanding with minimal user input. An automated flow chem. platform was employed to initially conduct linear flow-ramp expts. to rapidly map the reaction profile of three processes using transient flow data. Following exptl. data acquisition, a computational approach was utilized to discriminate between all possible reaction models as well as identify the correct kinetic parameters for each process. Species that are known to participate in the process (starting materials, intermediates, products) are initially inputted by the user prior to flow ramp expts., then all possible model candidates are compiled into a model library based on their potential to occur after mass balance assessment. Parallel computational optimization then evaluates each model by algorithmically altering the kinetic parameters of the model to allow convergence of a simulated kinetic curve to the exptl. data provided. Statistical anal. then dets. the most likely reaction model based on model simplicity and agreement with exptl. data. This automated approach to gaining full process understanding, whereby a small no. of data-rich expts. are conducted, and the kinetics are evaluated autonomously, shows significant improvements on current industrial optimization techniques in terms of labor, time and overall cost. The computational approach herein described can be employed using data from any set of expts. and the code is open-source.
- 25Taylor, C. J.; Seki, H.; Dannheim, F. M.; Willis, M. J.; Clemens, G.; Taylor, B. A.; Chamberlain, T. W.; Bourne, R. A. An automated computational approach to kinetic model discrimination and parameter estimation. React. Chem. Eng. 2021, 6, 1404– 1411, DOI: 10.1039/D1RE00098E25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVCqsb%252FN&md5=d5e0cdcf8490b91602000b4cf13b8ce2An automated computational approach to kinetic model discrimination and parameter estimationTaylor, Connor J.; Seki, Hikaru; Dannheim, Friederike M.; Willis, Mark J.; Clemens, Graeme; Taylor, Brian A.; Chamberlain, Thomas W.; Bourne, Richard A.Reaction Chemistry & Engineering (2021), 6 (8), 1404-1411CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)We herein report exptl. applications of a novel, automated computational approach to chem. reaction network (CRN) identification. This report shows the first chem. applications of an autonomous tool to identify the kinetic model and parameters of a process, when considering both catalytic species and various integer and non-integer orders in the model's rate laws. This kinetic anal. methodol. requires only the input of the species within the chem. system (starting materials, intermediates, products, etc.) and corresponding time-series concn. data to det. the kinetic information of the chem. of interest. This is performed with minimal human interaction and several case studies were performed to show the wide scope and applicability of this process development tool. The approach described herein can be employed using exptl. data from any source and the code for this methodol. is also provided open-source.
- 26Lawal, M. M.; Govender, T.; Maguire, G. E. M.; Honarparvar, B.; Kruger, H. G. Mechanistic investigation of the uncatalyzed esterification reaction of acetic acid and acid halides with methanol: a DFT study. J. Mol. Model. 2016, 22, 235, DOI: 10.1007/s00894-016-3084-z26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2szos1artA%253D%253D&md5=3981531b1a7d0967ed1578171575e6e0Mechanistic investigation of the uncatalyzed esterification reaction of acetic acid and acid halides with methanol: a DFT studyLawal Monsurat M; Govender Thavendran; Maguire Glenn E M; Honarparvar Bahareh; Kruger Hendrik G; Maguire Glenn E MJournal of molecular modeling (2016), 22 (10), 235 ISSN:.Implementation of catalysts to drive reactions from reactants to products remains a burden to synthetic and organic chemists. In spite of investigations into the kinetics and mechanism of catalyzed esterification reactions, less effort has been made to explore the possibility of an uncatalyzed esterification process. Therefore, a comprehensive mechanistic perspective for the uncatalyzed mechanism at the molecular level is presented. Herein, we describe the non-catalyzed esterification reaction of acetic acid and its halide derivatives (XAc, where X= OH, F, Cl, Br, I) with methanol (MeOH) through a concerted process. The reaction in vacuum and methanol was performed using the density functional theory (DFT) method at M06-2X level with def2-TZVP basis set after a careful literature survey and computations. Esterification through cyclic 4- or 6-membered transition state structures in one- or two-step concerted mechanisms were investigated. The present study outlines the possible cyclic geometry conformations that may occur during experiments at simple ratio of reactants. The free energy of activation for acetic acid and acetyl chloride are 36 kcal mol(-1) and 21 kcal mol(-1), respectively. These are in good agreement with available experimental results from the literature. The selected quantum chemical descriptors proved to be useful tools in chemical reactivity prediction for the reaction mechanism. This quantum mechanics study can serve as a necessary step towards revisiting uncatalyzed reaction mechanisms in some classical organic reactions.
- 27Pomberger, A.; Pedrina McCarthy, A. A.; Khan, A.; Sung, S.; Taylor, C. J.; Gaunt, M. J.; Colwell, L.; Walz, D.; Lapkin, A. A. The effect of chemical representation on active machine learning towards closed-loop optimization. React. Chem. Eng. 2022, 7, 1368– 1379, DOI: 10.1039/D2RE00008C27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XmslSntrg%253D&md5=84c1991820916ea1d8ebaf7740d529bdThe effect of chemical representation on active machine learning towards closed-loop optimizationPomberger, A.; Pedrina McCarthy, A. A.; Khan, A.; Sung, S.; Taylor, C. J.; Gaunt, M. J.; Colwell, L.; Walz, D.; Lapkin, A. A.Reaction Chemistry & Engineering (2022), 7 (6), 1368-1379CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Multivariate chem. reaction optimization involving catalytic systems is a non-trivial task due to the high no. of tuneable parameters and discrete choices. Active machine learning (ML) represents a powerful strategy for automating reaction optimization. However, the translation of chem. reaction conditions into a machine-readable format requires the identification of highly informative features which accurately capture the factors which det. reaction success. Herein, we compare the efficacy of different calcd. chem. descriptors for a high throughput experimentation generated dataset to det. the impact on a supervised ML model when predicting reaction yield. Then, the effect of featurization and size of the initial dataset within a closed-loop reaction optimization was examd. Finally, the balance between descriptor complexity and dataset size was considered. Ultimately, tailored descriptors did not outperform simple generic representations, however, a larger initial dataset accelerated reaction optimization.
- 28Taylor, C. J.; Manson, J. A.; Clemens, G.; Taylor, B. A.; Chamberlain, T. W.; Bourne, R. A. Modern advancements in continuous-flow aided kinetic analysis. Reaction Chemistry & Engineering 2022, 7, 1037– 1046, DOI: 10.1039/D1RE00467K28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XktVOitrk%253D&md5=df25afbfb769c0d2a7028c27b8646020Modern advancements in continuous-flow aided kinetic analysisTaylor, Connor J.; Manson, Jamie A.; Clemens, Graeme; Taylor, Brian A.; Chamberlain, Thomas W.; Bourne, Richard A.Reaction Chemistry & Engineering (2022), 7 (5), 1037-1046CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Although kinetic anal. has traditionally been conducted in a batch vessel, continuous-flow aided kinetic anal. continues to swell in popularity. This can be partly attributed to the favorable characteristics of flow reactors and the growth of flow chem. in general. However, the development of innovative techniques in recent years to obtain more kinetic information using less reaction material, has further accelerated its adoption. These advancements allow faster and more efficient routes to total process understanding, thereby allowing optimum reaction conditions to be identified in process development to maximise product outputs. This minireview documents novel methodologies reported in the recent literature, both to highlight opportunities for their exploitation and to enable further adoption of kinetic anal. in continuous-flow systems in years to come.
- 29Ancheyta-Juárez, J.; López-Isunza, F.; Aguilar-Rodríguez, E.; Moreno-Mayorga, J. C. A Strategy for Kinetic Parameter Estimation in the Fluid Catalytic Cracking Process. Ind. Eng. Chem. Res. 1997, 36, 5170– 5174, DOI: 10.1021/ie970271r29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXntFKhs7c%253D&md5=34da137cb68f9fa8c87bf5567bd1c572A Strategy for Kinetic Parameter Estimation in the Fluid Catalytic Cracking ProcessAncheyta-Juarez, Jorge; Lopez-Isunza, Felipe; Aguilar-Rodriguez, Enrique; Moreno-Mayorga, Juan C.Industrial & Engineering Chemistry Research (1997), 36 (12), 5170-5174CODEN: IECRED; ISSN:0888-5885. (American Chemical Society)A strategy is proposed to est. lumped kinetic consts. in fluid catalytic cracking (FCC) reactions. This method decreases the no. of simultaneously estd. parameters. The 3-, 4-, and a new 5-lump kinetic model and exptl. data obtained at 480, 500, and 520°C in a microactivity reactor are used to illustrate the procedure. Activation energies for each involved reaction are also reported.
- 30Cox, P. A.; Leach, A. G.; Campbell, A. D.; Lloyd-Jones, G. C. Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH–Rate Profiles, Autocatalysis, and Disproportionation. J. Am. Chem. Soc. 2016, 138, 9145– 9157, DOI: 10.1021/jacs.6b0328330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVyit77I&md5=bba913cb4ed0e5e0084b8872ce95d233Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH-Rate Profiles, Autocatalysis, and DisproportionationCox, Paul A.; Leach, Andrew G.; Campbell, Andrew D.; Lloyd-Jones, Guy C.Journal of the American Chemical Society (2016), 138 (29), 9145-9157CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)PH-rate profiles for aq.-org. protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, and varied substantially between the boronic acids, with rate maxima that varied over 6 orders of magnitude. A mechanistic model contg. five general pathways (k1-k5) has been developed, and together with input of [B]tot, KW, Ka, and KaH, the protodeboronation kinetics can be correlated as a function of pH (1-13) for all 18 species. Cyclopropyl and vinyl boronic acids undergo very slow protodeboronation, as do 3- and 4-pyridyl boronic acids (t0.5 > 1 wk, pH 12, 70 °C). In contrast, 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation (t0.5 ≈ 25-50 s, pH 7, 70 °C), via fragmentation of zwitterionic intermediates. Lewis acid additives (e.g., Cu, Zn salts) can attenuate (2-pyridyl) or accelerate (5-thiazolyl and 5-pyrazolyl) fragmentation. Two addnl. processes compete when the boronic acid and the boronate are present in sufficient proportions (pH = pKa ± 1.6): (i) self-/autocatalysis and (ii) sequential disproportionations of boronic acid to borinic acid and borane.
- 31Cox, P. A.; Reid, M.; Leach, A. G.; Campbell, A. D.; King, E. J.; Lloyd-Jones, G. C. Base-Catalyzed Aryl-B(OH)2 Protodeboronation Revisited: From Concerted Proton Transfer to Liberation of a Transient Aryl Anion. J. Am. Chem. Soc. 2017, 139, 13156– 13165, DOI: 10.1021/jacs.7b0744431https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlKhtbvN&md5=f15adb9daf70fa2e0c99b55ec56fe132Base-Catalyzed Aryl-B(OH)2 Protodeboronation Revisited: From Concerted Proton Transfer to Liberation of a Transient Aryl AnionCox, Paul A.; Reid, Marc; Leach, Andrew G.; Campbell, Andrew D.; King, Edward J.; Lloyd-Jones, Guy C.Journal of the American Chemical Society (2017), 139 (37), 13156-13165CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Pioneering studies by Kuivila, published more than 50 years ago, suggested ipso protonation of the boronate as the mechanism for base-catalyzed protodeboronation of arylboronic acids. However, the study was limited to UV spectrophotometric anal. under acidic conditions, and the aq. assocn. consts. (Ka) were estd. By means of NMR, stopped-flow IR, and quenched-flow techniques, the kinetics of base-catalyzed protodeboronation of 30 different arylboronic acids has now been detd. at pH > 13 in aq. dioxane at 70 °C. Included in the study are all 20 isomers of C6HnF(5-n)B(OH)2 with half-lives spanning 9 orders of magnitude: <3 ms to 6.5 mo. In combination with pH-rate profiles, pKa and ΔS⧺ values, kinetic isotope effects (2H, 10B, 13C), linear free-energy relationships, and d. functional theory calcns., we have identified a mechanistic regime involving unimol. heterolysis of the boronate competing with concerted ipso protonation/C-B cleavage. The relative Lewis acidities of arylboronic acids do not correlate with their protodeboronation rates, esp. when ortho substituents are present. Notably, 3,5-dinitrophenylboronic acid is orders of magnitude more stable than tetra- and pentafluorophenylboronic acids but has a similar pKa.
- 32Cox, P. Protodeboronation. Ph.D. thesis, The University of Edinburgh, 2016.There is no corresponding record for this reference.
- 33van de Vusse, J. G. Plug-flow type reactor versus tank reactor. Chem. Eng. Sci. 1964, 19, 994– 996, DOI: 10.1016/0009-2509(64)85109-5There is no corresponding record for this reference.
- 34Ridlehoover, G. A.; Seagrave, R. C. Optimization of Van de Vusse Reaction Kinetics Using Semibatch Reactor Operation. Industrial & Engineering Chemistry Fundamentals 1973, 12, 444– 447, DOI: 10.1021/i160048a00834https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXltVymt7g%253D&md5=e42bb8f5795e5551cef1f37cf76c1beeOptimization of Van de Vusse reaction kinetics using semibatch reactor operationRidlehoover, G. A.; Seagrave, R. C.Industrial & Engineering Chemistry Fundamentals (1973), 12 (4), 444-7CODEN: IECFA7; ISSN:0196-4313.Methods of semibatch or periodic reactor operation needed to maximize the yield of the desired intermediate species in the Van de Vusse chemical reactions are presented. The operating parameters of the stirred-batch reactor in the kinetic region where semibatch operation is superior to both plug-flow and continuous operation are detd. and are given as a function of the ratios of the assocd. kinetic rate consts. Digital simulation techniques are employed to investigate the range of operating and kinetic conditions likely to be encountered. The methods employed are easily extendable to other reaction schemes.
- 35Sha, Y.; Yu, T. H.; Merinov, B. V.; Goddard, W. A. DFT Prediction of Oxygen Reduction Reaction on Palladium–Copper Alloy Surfaces. ACS Catal. 2014, 4, 1189– 1197, DOI: 10.1021/cs400962335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtVeqs7Y%253D&md5=3de1f9ce92fe3f29fa59a1744fd1562fDFT Prediction of Oxygen Reduction Reaction on Palladium-Copper Alloy SurfacesSha, Yao; Yu, Ted H.; Merinov, Boris V.; Goddard, William A.ACS Catalysis (2014), 4 (4), 1189-1197CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)The high cost of proton exchange membrane fuel cells (PEMFCs) comes largely from the use of Pt-contg. electrocatalysts. Despite significant progress made the past decade on reducing the Pt catalyst loading in the PEMFC electrodes, further substantial cost redns. require the replacement of Pt with less expensive nonplatinum electrocatalytic materials. PdCu alloys have computationally been studied as possible non-Pt catalysts for O redn. reaction (ORR) in PEMFCs. The authors used d. functional theory (DFT) calcns. to det. the structural preference and ORR activity as a function of the compn. and structure. Five PdCu alloy surface structures, B2, L12, L10, L11-nonlayered, and L11-layered, were considered, and the layered L11 surface structure was found to exhibit significantly improved ORR kinetics compared to that of pure Pd.
- 36Frau, J.; Hernández-Haro, N.; Glossman-Mitnik, D. Computational prediction of the pKas of small peptides through Conceptual DFT descriptors. Chem. Phys. Lett. 2017, 671, 138– 141, DOI: 10.1016/j.cplett.2017.01.03836https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlGltro%253D&md5=9c302d02306058cbcad172e7053e9bd6Computational prediction of the pKas of small peptides through Conceptual DFT descriptorsFrau, Juan; Hernandez-Haro, Noemi; Glossman-Mitnik, DanielChemical Physics Letters (2017), 671 (), 138-141CODEN: CHPLBC; ISSN:0009-2614. (Elsevier B.V.)The exptl. pKa of a group of simple amines have been plotted against several Conceptual DFT descriptors calcd. by different d. functionals, basis sets and solvation schemes. The best fits are those that relate the pKa of the amines with the global hardness η through the MN12SX d. functional in connection with the Def2TZVP basis set and the SMD solvation model, using water as a solvent. The parameterized equation resulting from the linear regression anal. has then been used for the prediction of the pKa of small peptides of interest in the study of diabetes and Alzheimer disease. The accuracy of the results is relatively good, with a MAD of 0.36 units of pKa.
- 37Ainley, A. D.; Challenger, F. CCLXXX.─Studies of the boron–carbon linkage. Part I. The oxidation and nitration of phenylboric acid. Journal of the Chemical Society (Resumed) 1930, 0, 2171– 2180, DOI: 10.1039/JR9300002171There is no corresponding record for this reference.
- 38Kuivila, H. G.; Nahabedian, K. V. Electrophilic Displacement Reactions. X. General Acid Catalysis in the Protodeboronation of Areneboronic Acids1–3. J. Am. Chem. Soc. 1961, 83, 2159– 2163, DOI: 10.1021/ja01470a02838https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3MXhtFWrtL0%253D&md5=e553c4d1672e02d4fed59405842d2ee6Electrophilic displacement reactions. X. General acid catalysis in the protodeboronation of areneboronic acidsKuivila, Henry G.; Nahebedian, K. V.Journal of the American Chemical Society (1961), 83 (), 2159-63CODEN: JACSAT; ISSN:0002-7863.cf. CA 52, 5324e. Rate consts. obtained from kinetic studies on the protodeboronation of p-methoxybenzeneboronic acid and 2,6-dimethoxybenzeneboronic acid in aq. H2SO4, H3PO4, HClO4, and HCO2H and phosphate buffer solns. at various temp. were discussed in correlation with acidity function H0. These results indicated that the reaction was generally acid catalyzed.
- 39Kuivila, H. G.; Nahabedian, K. V. Electrophilic Displacement Reactions. XI. Solvent Isotope Effects in the Protodeboronation of Areneboronic Acids1–3. J. Am. Chem. Soc. 1961, 83, 2164– 2166, DOI: 10.1021/ja01470a02939https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3MXhtFWrtLo%253D&md5=f6593311ca282524426aa7a53c6bb38fElectrophilic displacement reactions. XI. Solvent isotope effects in the protodeboronation of areneboronic acidsKuivila, Henry G.; Nahebedian, K. V.Journal of the American Chemical Society (1961), 83 (), 2164-6CODEN: JACSAT; ISSN:0002-7863.The effect of solvent hydrogen isotope composition on the rate of protodeboronation of p-methoxybenzeneboronic acid in 6.31M H2SO4 at 25° and of 2,6-dimethoxybenzeneboronic acid in 0.1M HClO4 were detd. In the former case, the kH/kD ratio was 3.7 and a nearly linear dependence of rate const. on the H isotope composition was obtained. In the later case, kH/kD was 1.7 and variation of rate const. with solvent isotope composition was non-linear. The rate behavior obtained was in agreement with a rate determining proton transfer mechanism.
- 40Nahabedian, K. V.; Kuivila, H. G. Electrophilic Displacement Reactions. XII. Substituent Effects in the Protodeboronation of Areneboronic Acids1–3. J. Am. Chem. Soc. 1961, 83, 2167– 2174, DOI: 10.1021/ja01470a03040https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3MXhtFWrtLs%253D&md5=52c71c492e978ea6da7f27d9a51257baElectrophilic displacement reactions. XII. Substituent effects in the protodeboronation of areneboronic acidsNahabedian, K. V.; Kuivila, Henry G.Journal of the American Chemical Society (1961), 83 (), 2167-74CODEN: JACSAT; ISSN:0002-7863.Kinetic studies on the hydrolysis of nine areneboronic acids, x-ZC6H4[B(OH)2] (Z = H, m-NO2, p-Br, m-F, p-F, p-Me, p-OMe, m-Cl, and m-CF3) in aq. H2SO4 and H3PO4 were described. Dependence of rate on acidity was examd. in each case, and activation parameters and solvent H isotope effects were detd. in 4 cases (Z = p-Me, p-F, H, and m-F) for activation parameters and in 4 cases (Z = p-Me, p-OMe, p-F, and m-F) for H-isotope effect. Results obtained led to an interpretation of the existence of at least two mechanisms for the reaction.
- 41Kuivila, H. G.; Reuwer, J. F., Jr.; Mangravite, J. A. Electrophilic displacement reactions: xv. kinetics and mechanism of the base-catalyzed protodeboronation of areneboronic acids. Can. J. Chem. 1963, 41, 3081– 3090, DOI: 10.1139/v63-45141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2cXit1Ortw%253D%253D&md5=2d3a684fd4d71447c7ca5bb43a2dab13Electrophilic displacement reactions. XV. Kinetics and mechanism of the base-catalyzed protodeboronation of areneboronic acidsKuivila, Henry G.; Reuwer, Joseph F., Jr.; Mangravite, John A.Canadian Journal of Chemistry (1963), 41 (12), 3081-90CODEN: CJCHAG; ISSN:0008-4042.cf. CA 57, 3465a. An investigation of the kinetics of the protodeboronation of benzeneboronic acid in water in the pH range 2.0 to 6.7 is described. In addn. to the acid-catalyzed reaction studied earlier, a reaction whose rate is independent of pH and one whose rate increases linearly with hydroxide ion concn. have been observed. The effect of malonate buffer concn. at low pH confirms the earlier observations of general acid catalysis. Changes in buffer concn. at pH 6.70 have no effect on rate indicating specific hydroxide ion catalysis. Effect of substituents in the ortho, meta, and para position of the benzene ring on the rate of protodeboronation have been examd. Ortho-para ratios for this reaction are high; possible reasons for this are discussed. The Hammett equation using σ correlates the rates for meta and para substituents.
- 42Brown, R. D.; Buchanan, A. S.; Humffray, A. A. Protodeboronation of thiophenboronic acids. Aust. J. Chem. 1965, 18, 1521– 1525, DOI: 10.1071/CH965152142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28XhvVGgsg%253D%253D&md5=ef92546d391c4d8444e04bd95cf40107Protodeboronation of thiopheneboronic acidsBrown, R. D.; Buchanan, A. S.; Humffray, A. A.Australian Journal of Chemistry (1965), 18 (10), 1521-5CODEN: AJCHAS; ISSN:0004-9425.The rates of protodeboronation of benzene-, thiophene-2-, and thiophene-3-boronic acids were measured using HClO4 as catalyst. The relative rates at 70° are detd. by the relation between log k and -H0 (acidity function), and correcting the k values to the same -H0 value (-H0 = 0.22, corresponding to M HClO4). The energies and entropies of activation are listed. It is not necessary to make a direct comparison of the entropy values since the very much greater reactivity of thiophene derivs. compared to benzeneboronic acid is evident. The kinetic results are consistent with the A-SE2 mechanism for protodeboronation proposed by Kuivila and Nahebedian (CA 55, 21012a).
- 43Lozada, J.; Liu, Z.; Perrin, D. M. Base-Promoted Protodeboronation of 2,6-Disubstituted Arylboronic Acids. Journal of Organic Chemistry 2014, 79, 5365– 5368, DOI: 10.1021/jo500734z43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotVagsLY%253D&md5=3573a22c0a2cce004f4a5e0eae6db9e3Base-Promoted Protodeboronation of 2,6-Disubstituted Arylboronic AcidsLozada, Jerome; Liu, Zhibo; Perrin, David M.Journal of Organic Chemistry (2014), 79 (11), 5365-5368CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Facile based promoted deboronation of electron-deficient arylboronate esters was obsd. for arylboronates contg. two ortho electron-withdrawing group (EWG) substituents. Among 30 representative boronates, only the diortho-substituted species underwent facile C-B fission in aq. basic conditions (200 mM hydroxide). These results provide fundamental insight into deboronative mechanisms with implications for cross-coupling reactions, regioselective deuteration/tritiation for isotopic labeling, and the design of new 18F-trifluoroborate radioprosthetics.
- 44Muir, C. W.; Vantourout, J. C.; Isidro-Llobet, A.; Macdonald, S. J. F.; Watson, A. J. B. One-Pot Homologation of Boronic Acids: A Platform for Diversity-Oriented Synthesis. Org. Lett. 2015, 17, 6030– 6033, DOI: 10.1021/acs.orglett.5b0303044https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvF2ru7zP&md5=25ef18e5b4cfcdb98a763d4754471e83One-Pot Homologation of Boronic Acids: A Platform for Diversity-Oriented SynthesisMuir, Calum W.; Vantourout, Julien C.; Isidro-Llobet, Albert; Macdonald, Simon J. F.; Watson, Allan J. B.Organic Letters (2015), 17 (24), 6030-6033CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)Formal homologation of sp2-hybridized boronic acids is achieved via cross-coupling of boronic acids with conjunctive haloaryl BMIDA components in the presence of a suitably balanced basic phase. The utility of this approach to provide a platform for diversity-oriented synthesis in discovery medicinal chem. is demonstrated in the context of the synthesis of a series of analogs of a BET bromodomain inhibitor.
- 45Li, Z.; Gelbaum, C.; Heaner, W. L.; Fisk, J.; Jaganathan, A.; Holden, B.; Pollet, P.; Liotta, C. L. Palladium-Catalyzed Suzuki Reactions in Water with No Added Ligand: Effects of Reaction Scale, Temperature, pH of Aqueous Phase, and Substrate Structure. Org. Process Res. Dev. 2016, 20, 1489– 1499, DOI: 10.1021/acs.oprd.6b0018045https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVKju77I&md5=e677d8eff9de9e5c95b4f2baf05823b5Palladium-Catalyzed Suzuki Reactions in Water with No Added Ligand: Effects of Reaction Scale, Temperature, pH of Aqueous Phase, and Substrate StructureLi, Zhao; Gelbaum, Carol; Heaner, William L.; Fisk, Jason; Jaganathan, Arvind; Holden, Bruce; Pollet, Pamela; Liotta, Charles L.Organic Process Research & Development (2016), 20 (8), 1489-1499CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The heterogeneous palladium-catalyzed Suzuki reactions between model aryl bromides (4-bromoanisole, 4-bromoaniline, 4-amino-2-bromopyridine, and 2-bromopyridine) and phenylboronic acid have been successfully conducted in water with no added ligand at the 100 mL scale using 20-40 mmol of aryl bromide. The product yields assocd. with these substrates were optimized, and key reaction parameters affecting the yields were identified. The results clearly indicate that the reaction parameters necessary to achieve high yields are substrate-dependent. In addn., it is demonstrated that aq. Suzuki reactions of substrates contg. basic nitrogen centers can produce quant. yields of desired products in the absence of added ligand.
- 46Sander, T.; Freyss, J.; von Korff, M.; Rufener, C. DataWarrior: An Open-Source Program For Chemistry Aware Data Visualization And Analysis. J. Chem. Inf. Model. 2015, 55, 460– 473, DOI: 10.1021/ci500588j46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXktFWnuw%253D%253D&md5=5c849901b5cb4549d870d81f5eeaca0aDataWarrior: An Open-Source Program For Chemistry Aware Data Visualization And AnalysisSander, Thomas; Freyss, Joel; von Korff, Modest; Rufener, ChristianJournal of Chemical Information and Modeling (2015), 55 (2), 460-473CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)Drug discovery projects in the pharmaceutical industry accumulate thousands of chem. structures and ten-thousands of data points from a dozen or more biol. and pharmacol. assays. A sufficient interpretation of the data requires understanding which mol. families are present, which structural motifs correlate with measured properties, and which tiny structural changes cause large property changes. Data visualization and anal. software with sufficient chem. intelligence to support chemists in this task is rare. In an attempt to contribute to filling the gap, we released our inhouse developed chem. aware data anal. program DataWarrior for free public use. This paper gives an overview of DataWarrior's functionality and architecture. Exemplarily, a new unsupervised, 2-dimensional scaling algorithm is presented, which employs vector-based or nonvector-based descriptors to visualize the chem. or pharmacophore space of even large data sets. DataWarrior uses this method to interactively explore chem. space, activity landscapes, and activity cliffs.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpca.2c08250.
A detailed explanation of each protodeboronation mechanism, protodeboronation predictions for 50 novel boronic acids, and optimized structures and energies for each relevant mechanism for all 100 molecules (PDF)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.