Rationalizing and Adapting Water-Accelerated Reactions for Sustainable Flow Organic ProcessesClick to copy article linkArticle link copied!
- Katarzyna A. MaltbyKatarzyna A. MaltbyInstitute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.More by Katarzyna A. Maltby
- Krishna SharmaKrishna SharmaInstitute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.More by Krishna Sharma
- Marc A. S. ShortMarc A. S. ShortInstitute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.More by Marc A. S. Short
- Sannia FarooqueSannia FarooqueInstitute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.More by Sannia Farooque
- Rosalie HamillRosalie HamillInstitute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.More by Rosalie Hamill
- A. John BlackerA. John BlackerInstitute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.More by A. John Blacker
- Nikil KapurNikil KapurSchool of Mechanical Engineering, University of Leeds, Leeds LS2 9JT, U.K.More by Nikil Kapur
- Charlotte E. WillansCharlotte E. WillansInstitute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.More by Charlotte E. Willans
- Bao N. Nguyen*Bao N. Nguyen*Email: [email protected]Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.More by Bao N. Nguyen
Abstract
![](/cms/10.1021/acssuschemeng.3c02164/asset/images/medium/sc3c02164_0010.gif)
Water-accelerated reactions, wherein at least one organic reactant is not soluble in water, are an important class of organic reactions, with a potentially pivotal impact on sustainability of chemical manufacturing processes. However, mechanistic understanding of the factors controlling the acceleration effect has been limited, due to the complex and varied physical and chemical nature of these processes. In this study, a theoretical framework has been established to calculate the rate acceleration of known water-accelerated reactions, giving computational estimations of the change to ΔG‡ which correlate with experimental data. In-depth study of a Henry reaction between N-methylisatin and nitromethane using our framework led to rationalization of the reaction kinetics, its lack of dependence on mixing, kinetic isotope effect, and different salt effects with NaCl and Na2SO4. Based on these findings, a multiphase flow process which includes continuous phase separation and recycling of the aqueous phase was developed, and its superior green metrics (PMI-reaction = 4 and STY = 0.64 kg L–1 h–1) were demonstrated. These findings form the essential basis for further in silico discovery and development of water-accelerated reactions for sustainable manufacturing.
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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
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Synopsis
A theoretical and practical framework for predicting, rationalizing, and adapting water-accelerated reactions into holistically sustainable flow processes has been demonstrated.
1. Introduction
Figure 1
![](/cms/10.1021/acssuschemeng.3c02164/asset/images/medium/sc3c02164_0002.gif)
Figure 1. Simplified phase complexity scenarios of water-accelerated reactions: (a) all reactants are insoluble in water; (b) one reactant is partially soluble in water; (c) reactants are phase-separated; and (d) one reactant is activated at the aqueous–organic interface.
2. Experimental Section
2.1. Materials
2.2. Standard Protocol for Henry Reaction
2.3. Reactions in the Presence of Different Salts
2.4. Recycling of the Aqueous Phase in Batch
2.5. Flow Experiments
2.6. Characterization
3. Results and Discussion
no. | solvent/mediuma | reaction time (h) | yield (%, 1H NMR) |
---|---|---|---|
1 | none | 8 | 0 |
2 | 1,2-dichloroethane | 18 | 0 |
3 | EtOH | 18 | 0 |
4 | EtOH/H2O 9:1 | 18 | 0 |
5 | H2O (pH 7) | 3 | 98 |
Typical reaction conditions: N-methylisatin (0.317 mmol), nitromethane (7.925 mmol, 25 equiv), solvent (3 mL), 70 °C, and 800 rpm stirring rate with a BRAND crosshead magnetic stirrer (10 mm span), in sealed 14 mL dram vials (OD 22 mm) and custom aluminum heating blocks (see the Supporting Information).
Measured with a pH probe.
Scheme 1
![](/cms/10.1021/acssuschemeng.3c02164/asset/images/medium/sc3c02164_0009.gif)
Figure 2
![](/cms/10.1021/acssuschemeng.3c02164/asset/images/medium/sc3c02164_0003.gif)
Figure 2. Dependence of the water-accelerated Henry reaction on reaction conditions: (a) kinetic isotope effect; (b) salt effects by NaCl 1 M, LiCl 1 M, Bu4NCl 1 M, Na2SO4 1 M (70 °C), and phosphate buffer 0.1 M at pH 7 (22 °C), error bars are excluded for clarity; and (c) effect of temperature (color), stirring rate (dot size), excess nitromethane, and amount of 1 on reaction yield at 1 h.
3.1. Comparison of Computational Methods for Water-Accelerated Reactions
3.2. Computational Studies of Water-Accelerated Henry Reaction
Figure 3
![](/cms/10.1021/acssuschemeng.3c02164/asset/images/medium/sc3c02164_0004.gif)
Figure 3. Energy profile of Henry reaction under (a) water-accelerated conditions, or in ethanol, and (b) in the presence of HSO4–.
Figure 4
![](/cms/10.1021/acssuschemeng.3c02164/asset/images/medium/sc3c02164_0005.gif)
Figure 4. Natural bond orbital (NBO) charge distribution analysis of the transition states TS1w, TS2w, TS1HSO4, and TS2HSO4.
3.3. Sustainable Flow Process for Water-Accelerated Henry Reaction
method | 1 (g) | MeNO2 (mL) | aqueous phase (mL)b | reaction time (min) | PMI/PMI-reaction |
---|---|---|---|---|---|
A | 0.081 | 0.11 | 3c | 30 | 33 |
B | 0.225 | 2.1 | 3c,d | 180c/10d | 17c,e/16d,e |
C | 0.051 | 0.42 | 0.42d | 10 | 14 |
D | 18.7 | 155 | 12d | 10 | 10 |
E | 16.6 | 50 | 13d | 20 | 4 |
Method A: literature batch protocol at room temperature; (35) method B: DoE-optimized batch protocol with recycling of the aqueous phase; method C: batch protocol using a 1:1 phase ratio at 40 °C, no recycling; method D: flow protocol using 25 equiv of nitromethane at 40 °C with continuous aqueous phase recycling (13 cycles); and method E: flow protocol using 9 equiv of nitromethane at 40 °C with continuous aqueous phase recycling (4 cycles).
Including top-up water/buffer solution.
Using water.
Using 0.1 M phosphate buffer pH 7.
Calculated for batch protocols with recycling of water (at 70 °C) or 0.1 M phosphate buffer (25 °C), 5 cycles.
Figure 5
![](/cms/10.1021/acssuschemeng.3c02164/asset/images/medium/sc3c02164_0006.gif)
Figure 5. (a) Reaction yields with recycling of the aqueous phase in batch, orange bar depicting yield with water as the aqueous phase and green bar depicting yield with 0.1 M phosphate buffer pH 7 as the aqueous phase. Reaction conditions: 51 mg of 1, 0.42 mL of nitromethane, 3 mL of aqueous phase recycled up to 5 times, 850 rpm, 70 °C (water), 25 °C (phosphate buffer), 3 h (water), 10 min (phosphate buffer). (b) Kinetic profile of Henry reaction in batch at a 1:1 phase ratio using 25 equiv (●) or 9 equiv (■) of nitromethane. Reaction conditions: 0.42 mL solution of 1 in nitromethane with 5 mol % trimethoxybenzene as an internal standard [(●) 0.121 g 1/1 mL; (■) 0.331 g 1/1 mL], 0.42 mL of 0.1 M phosphate buffer, 40 °C, 850 rpm, 0–25 min.
Figure 6
![](/cms/10.1021/acssuschemeng.3c02164/asset/images/medium/sc3c02164_0007.gif)
Figure 6. Flow process diagram including the continuous recycling of the aqueous phase.
Figure 7
![](/cms/10.1021/acssuschemeng.3c02164/asset/images/medium/sc3c02164_0008.gif)
Figure 7. Yields and mass balance of flow processes with continuous aqueous phase recycling using (a) 0.121 g of 1 per 1 mL CH3NO2 and (b) 0.3331 g of 1 per 1 mL CH3NO2. (▲) Molar fraction of 1; (■) molar fraction of product 2; (●) molar fraction of side product 3; and (▼) total mass balance.
4. Conclusions
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acssuschemeng.3c02164.
Experimental procedures and calculations of green metrics and DFT computational details (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 was undertaken on ARC3 and ARC4, part of the High-Performance Computing facilities at the University of Leeds, UK. R.H. thanks AstraZeneca and the EPSRC for her CASE studentship. M.S. thanks the CCDC for its support in his studentship. K.S., K.A.M., S.F., A.J.B., N.K., and B.N.N. thank the EPSRC for its support through grant number EP/S013768/1.
PMI | process mass intensity |
RDS | rate-determining step |
DFT | density functional theory |
CSTR | continuous stirred tank reactor |
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- 15González-Cruz, D.; Tejedor, D.; de Armas, P.; Morales, E. Q.; García-Tellado, F. Organocatalysis “on Water”. Regioselective [3 + 2]-Cycloaddition of Nitrones and Allenolates. Chem. Commun. 2006, 26, 2798– 2800, DOI: 10.1039/B606096JGoogle ScholarThere is no corresponding record for this reference.
- 16Pirrung, M. C.; Sarma, K. D. Aqueous Medium Effects on Multi-Component Reactions. Tetrahedron 2005, 61, 11456– 11472, DOI: 10.1016/j.tet.2005.08.068Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFOrs7vO&md5=15f2ea96a82f64e87b966ac23e852058Aqueous medium effects on multi-component reactionsPirrung, Michael C.; Das Sarma, KoushikTetrahedron (2005), 61 (48), 11456-11472CODEN: TETRAB; ISSN:0040-4020. (Elsevier B.V.)The effect of aq. media on many org. reactions has been studied, and often those reactions exhibiting pressure acceleration are also accelerated in water. Because some specific examples of the Ugi and Passerini reactions that are inefficient under conventional conditions have been accelerated by pressure, we examd. Ugi and Passerini reactions in aq. solns., where significant increases in efficiency were obsd. These effects were correlated to the cohesive energy d. of aq. solns.
- 17Azizi, N.; Saidi, M. R. Highly Chemoselective Addition of Amines to Epoxides in Water. Org. Lett. 2005, 7, 3649– 3651, DOI: 10.1021/ol051220qGoogle Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsFGgtbg%253D&md5=3518bba9a17bdbd6ebb7f997db601ae0Highly Chemoselective Addition of Amines to Epoxides in WaterAzizi, Najmodin; Saidi, Mohammad R.Organic Letters (2005), 7 (17), 3649-3651CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)Aminolysis of a variety of epoxides by aliph. and arom. amines in water, in the absence of any catalyst with high yields, is reported. β-Amino alcs. were formed under mild conditions with high selectivity and in excellent yields.
- 18Hajra, S.; Singha Roy, S.; Aziz, S. M.; Das, D. Catalyst-Free “On-Water” Regio- and Stereospecific Ring-Opening of Spiroaziridine Oxindole: Enantiopure Synthesis of Unsymmetrical 3,3′-Bisindoles. Org. Lett. 2017, 19, 4082– 4085, DOI: 10.1021/acs.orglett.7b01833Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOks7nL&md5=f35ba40ca090f1dc858093642ec7516dCatalyst-Free "On-Water" Regio- and Stereospecific Ring-Opening of Spiroaziridine Oxindole: Enantiopure Synthesis of Unsymmetrical 3,3'-BisindolesHajra, Saumen; Singha Roy, Somnath; Aziz, Sk Mohammad; Das, DhirajOrganic Letters (2017), 19 (15), 4082-4085CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A catalyst-free water-mediated regio- and stereospecific ring-opening reaction of nonracemic spiroaziridine oxindoles and indoles has been developed with retention of configuration. This method provides direct access to enantiopure 3,3'-mixed bisindoles with excellent yield and enantioselectivity (up to 98% ee).
- 19Kitanosono, T.; Kobayashi, S. Toward Chemistry-Based Design of the Simplest Metalloenzyme-Like Catalyst That Works Efficiently in Water. Chem.─Asian J. 2015, 10, 133– 138, DOI: 10.1002/asia.201403004Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFamsL3L&md5=a3d82e7efb95f8a40a52b2261263ac33Toward Chemistry-Based Design of the Simplest Metalloenzyme-Like Catalyst That Works Efficiently in WaterKitanosono, Taku; Kobayashi, ShuChemistry - An Asian Journal (2015), 10 (1), 133-138CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)The authors describe the design of small mols. that act as the simplest metalloenzyme-like catalysts that can function in water without mimicking enzyme structures. These artificial catalysts, e.g., Sc(OTf)3 and I, efficiently promoted enantioselective direct-type aldol reactions using aq. formaldehyde. The reactions followed Michaelis-Menten kinetics; and heat-resistant asym. environments were constructed in water.
- 20Du, Z.-H.; Da, C. S.; Yuan, M.; Tao, B. X.; Ding, T. Y. Efficient Catalyst-Free Henry Reaction between Nitroalkanes and Aldehydes or Trifluoromethyl Ketones Promoted by Tap Water. Synthesis 2022, 54, 5461– 5470, DOI: 10.1055/a-1933-3709Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XisFWisbvJ&md5=32793b71c71c6cc2abe0db5fde153002Efficient Catalyst-Free Henry Reaction between Nitroalkanes and Aldehydes or Trifluoromethyl Ketones Promoted by Tap WaterDu, Zhi-Hong; Yuan, Meng; Tao, Bao-Xiu; Ding, Tie-Ying; Da, Chao-ShanSynthesis (2022), 54 (24), 5461-5470CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)The first examples of highly effective Henry reactions between nitroalkanes and aldehydes or trifluoromethyl ketones that proceed under catalyst-free and additive-free conditions, in a recyclable tap water medium, and at room temp. was reported. This process tolerated a broad range of aldehydes and trifluoromethyl ketones to give a series of β-nitro alc. products in excellent yields. Such products are widely used in the syntheses of pharmaceutical intermediates and natural products. This protocol can be successfully scaled up to a 50-mmol scale without a redn. in yield. Tap water from different locations in China exhibited pH values ranging from 7.5 to 8.1, but the varying pH had no effect on the yield and the processes were successfully reproduced. Finally, the tap water was effectively recovered and reused without any post processing, even when the reaction substrates were different.
- 21Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F. Organocatalytic Direct Asymmetric Aldol Reactions in Water. J. Am. Chem. Soc. 2006, 37, 734, DOI: 10.1002/chin.200624079Google ScholarThere is no corresponding record for this reference.
- 22Butler, R. N.; Coyne, A. G. Understanding “On-Water” Catalysis of Organic Reactions. Effects of H+ and Li+ Ions in the Aqueous Phase and Nonreacting Competitor H-Bond Acceptors in the Organic Phase: On H2O versus on D2O for Huisgen Cycloadditions. J. Org. Chem. 2015, 80, 1809– 1817, DOI: 10.1021/jo502732yGoogle Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVWnt7s%253D&md5=38f54811e8e45ccb0515f9d67d8ebb5eUnderstanding "On-Water" Catalysis of Organic Reactions. Effects of H+ and Li+ Ions in the Aqueous Phase and Nonreacting Competitor H-Bond Acceptors in the Organic Phase: On H2O versus on D2O for Huisgen CycloadditionsButler, Richard N.; Coyne, Anthony G.Journal of Organic Chemistry (2015), 80 (3), 1809-1817CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)For a typical Huisgen cycloaddn., carried out on water, the behavior of water mols. at the oil-water interface depended on the properties of the reactants. With weakly basic reactants, a small quantity of added H+ (HClO4, 0.0001-0.01 M) present in the aq. phase had negligible effects, but larger quantities of H+ (HClO4, 0.1-3.0 M) increased the catalytic effect and caused protons to cross the water-org. interface and affect the products. Added Li+ ions (LiClO4, 0.1-3.0 M) had no effect for on-water reactions but enhanced the rates and endo products for in-water reactions. For these cycloaddn. reactions, the product endo:exo ratios, when compared to those in org. solvents, can be used to distinguish between the on-water and in-water modes. Comparisons of org. reactions on H2O and on D2O indicate that on-water catalysis ranges from weak to strong trans-phase H-bonding for reactants with basic pKa < ca. -6 and to interfacial proton transfer for reactants with higher basic pKa > ca. 2 (pKa of conjugate acid). Water shows a chameleon-type response to org. mols. at hydrophobic surfaces.
- 23Tiwari, S.; Kumar, A. Unusual Temperature Dependence of Salt Effects for “on Water” Wittig Reaction: Hydrophobicity at the Interface. Chem. Commun. 2008, 37, 4445– 4447, DOI: 10.1039/B809127GGoogle ScholarThere is no corresponding record for this reference.
- 24Bae, H. Y.; Song, C. E. Unprecedented Hydrophobic Amplification in Noncovalent Organocatalysis “on Water”: Hydrophobic Chiral Squaramide Catalyzed Michael Addition of Malonates to Nitroalkenes. ACS Catal. 2015, 5, 3613– 3619, DOI: 10.1021/acscatal.5b00685Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnsFOgtro%253D&md5=b8521d563a8d5cd0ce85e9376912f2abUnprecedented Hydrophobic Amplification in Noncovalent Organocatalysis "on Water": Hydrophobic Chiral Squaramide Catalyzed Michael Addition of Malonates to NitroalkenesBae, Han Yong; Song, Choong EuiACS Catalysis (2015), 5 (6), 3613-3619CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)In this study, water was demonstrated to be an exceptionally efficient reaction medium for the noncovalent, hydrogen-bonding-promoted enantioselective Michael addn. of malonates to diverse nitroolefins using cinchona-based squaramide catalysts. A significant increase in the reaction rate was obsd. when the reaction was performed "on water" rather than in the conventional org. solvents, because of the hydrophobic hydration effect. This hydrophobic amplification was significantly dependent upon the hydrophobicity of the C3-substituent (vinyl or ethyl) of cinchona-based catalysts. Thus, the use of more hydrophobic catalyst with an Et group at the C3-position, even a highly challenging Michael donor such as di-Me methylmalonate was also smoothly converted to the desired adduct. Furthermore, because of the remarkable rate acceleration under "on water" conditions, the catalyst loading also significantly decreased. Thus, in the case of β-ketoesters, even 0.01 mol % of catalyst loading was enough to complete the reaction at room temp., affording the corresponding Michael adducts with perfect diastereo- and enantioselectivity (up to >99:1 d.r., up to 99% ee). The developed "on water" protocol was successfully applied for the scalable syntheses of an antidepressant (S)-rolipram and an anticonvulsant (S)-pregabalin.
- 25Butler, R. N.; Coyne, A. G. Organic Synthesis Reactions On-Water at the Organic-Liquid Water Interface. Org. Biomol. Chem. 2016, 14, 9945– 9960, DOI: 10.1039/C6OB01724JGoogle Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1SisL3I&md5=2035e37b25c4628ec99455e3bc139e33Organic synthesis reactions on-water at the organic-liquid water interfaceButler, Richard N.; Coyne, Anthony G.Organic & Biomolecular Chemistry (2016), 14 (42), 9945-9960CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Org. reactions that occur at the water interface for water-insol. compds., and reactions in water soln. for water sol. compds., has added a powerful dimension to prospects for org. synthesis under more beneficial economic and environmental conditions. Many org. mols. are partially sol. in water and reactions that appear as heterogeneous mixts. and suspensions may involve on-water and in-water reaction modes occurring simultaneously. The behavior of water mols. and org. mols. at this interface is discussed in the light of reported theor. and exptl. studies. The on-water catalytic effect, relative to neat reactions or org. solvents, ranges from factors of several hundred times to 1-2 times and it depends on the properties of reactant compds. In some cases when on-water reactions produce quant. yields of water-insol. products they can reach ideal synthetic aspirations.
- 26Kleiner, C. M.; Schreiner, P. R. Hydrophobic Amplification of Noncovalent Organocatalysis. Chem. Commun. 2006, 41, 4315– 4317, DOI: 10.1039/B605850GGoogle ScholarThere is no corresponding record for this reference.
- 27Gajewski, J. J. A Semitheoretical Multiparameter Approach to Correlate Solvent Effects on Reactions and Equilibria. J. Org. Chem. 1992, 57, 5500– 5506, DOI: 10.1021/jo00046a036Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XlsFSnur8%253D&md5=39f659fd1e7769954e40593771c7659eA semitheoretical multiparameter approach to correlate solvent effects on reactions and equilibriaGajewski, Joseph J.Journal of Organic Chemistry (1992), 57 (20), 5500-6CODEN: JOCEAH; ISSN:0022-3263.A solvent rate effect equation which uses four phys. properties of the solvent for parameters has been applied with good success to solvolysis reactions, solvent Et values, Claisen rearrangements, Diels-Alder reactions, endo-exo ratios in Diels-Alder reactions, azo-Cope rearrangements, and enol-ketone equil. of the dimedone and pyridone variety. The coeffs. of the parameters, which are the Kirkwood-Onsager function, the solvent cohesive energy d., the specific solvation of chloride ion, and the specific solvation of potassium ion, lead to differences in dipole moments, in vols. between initial and final states, and in the extent of specific solvation of anionic and cationic sites relative to the solvation of chloride ion and potassium ion, resp.
- 28García, J. I.; Martínez-Merino, V.; Mayoral, J. A.; Salvatella, L. Density Functional Theory Study of a Lewis Acid Catalyzed Diels–Alder Reaction. The Butadiene + Acrolein Paradigm. J. Am. Chem. Soc. 1998, 120, 2415– 2420, DOI: 10.1021/ja9722279Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXhtlWnu7k%253D&md5=c62bc1d2484c3d3a82411e3c194bb0faDensity Functional Theory Study of a Lewis Acid Catalyzed Diels-Alder Reaction. The Butadiene + Acrolein ParadigmGarcia, J. I.; Martinez-Merino, V.; Mayoral, J. A.; Salvatella, L.Journal of the American Chemical Society (1998), 120 (10), 2415-2420CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The four transition structures (TS's) of the reaction between butadiene and acrolein, both uncatalyzed and catalyzed by BF3, have been theor. studied taking into account electron correlation effects by means of DFT (B3LYP) calcns. In both the uncatalyzed and catalyzed reactions, the endo s-cis is the most stable of the four possible transition structures. In the case of the catalyzed reaction, the inclusion of electron correlation in the search for this transition structure indicates the classical [4+2] reaction path, instead of that corresponding to a [2+4] inverse electron, demands hetero-Diels-Alder reaction, as happens when the Hartree-Fock level of theory is used. The B3LYP/6-31G(d) calcns. lead to activation energy values close to those exptl. found. The origin of the endo/exo selectivity, both in the presence and in the absence of the catalyst, is discussed.
- 29Manna, A.; Kumar, A. Why Does Water Accelerate Organic Reactions under Heterogeneous Condition?. J. Phys. Chem. A 2013, 117, 2446– 2454, DOI: 10.1021/jp4002934Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFars7s%253D&md5=771c6256cdfeec35f4aa65a8c13bfa19Why Does Water Accelerate Organic Reactions under Heterogeneous Condition?Manna, Arpan; Kumar, AnilJournal of Physical Chemistry A (2013), 117 (12), 2446-2454CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)A kinetic anal. has been carried out to elucidate the role of the oil-water interface in guiding "on water org. reaction" mechanism. The preferential solvation of polarizable ions at the water surface was shown. Exptl. methods were developed to control the mol. structure of oil-water interface in situ. Temp.-dependent analyses allowing one to understand the enthalpic and entropic modifications of the interfacial water mols. during a heterogeneous reaction are given. The kinetic and the thermodn. outcomes established that the hydrogen bond ability of the surface water mols. played a crit. role in the on-water org. reaction mechanism.
- 30Guo, D.; Zhu, D.; Zhou, X.; Zheng, B. Accelerating the “On Water” Reaction: By Organic-Water Interface or By Hydrodynamic Effects?. Langmuir 2015, 31, 13759– 13763, DOI: 10.1021/acs.langmuir.5b04031Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFWrt7zP&md5=63cd1810876fed248c3cfc7893f0bfb7Accelerating the "On Water" Reaction: By Organic-Water Interface or By Hydrodynamic Effects?Guo, Dameng; Zhu, Deyong; Zhou, Xiaohu; Zheng, BoLangmuir (2015), 31 (51), 13759-13763CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)A series of org. reactions proceed dramatically faster in a heterogeneous mixt. of the reactants and water than in a homogeneous mixt. Currently it is unclear whether the rate acceleration is due to the free OH groups at the org.-water interface, or due to the hydrodynamic effects caused by vigorous stirring, vortexing, or ultrasonication. The authors produced static droplets in microfluidic devices to answer this question. A series of org. droplets contg. di-Et azodicarboxylate (DEAD) and quadricyclane surrounded by water were produced, which were transferred to and confined in glass capillaries to minimize the hydrodynamic effects. The cycloaddn. process of DEAD with quadricyclane was recorded by a CCD camera. The results showed the reaction proceeded in three steps, and the org.-water interface alone was catalytically efficient enough to enhance the reaction rate to the same level as in the bulk emulsion reaction, indicating that the hydrodynamic effects were negligible.
- 31Jung, Y.; Marcus, R. A. On the Theory of Organic Catalysis “on Water. J. Am. Chem. Soc. 2007, 129, 5492– 5502, DOI: 10.1021/ja068120fGoogle Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVOrs70%253D&md5=2442ced8c33009e4bf5dfa8278791761On the Theory of Organic Catalysis "on Water"Jung, Yousung; Marcus, R. A.Journal of the American Chemical Society (2007), 129 (17), 5492-5502CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A mol. origin of the striking rate increase obsd. in a reaction on water is studied theor. A key aspect of the on-water rate phenomenon is the chem. between water and reactants that occurs at an oil-water phase boundary. In particular, the structure of water at the oil-water interface of an oil emulsion, in which approx. one in every four interfacial water mols. has a free (dangling) OH group that protrudes into the org. phase, plays a key role in catalyzing reactions via the formation of hydrogen bonds. Catalysis is expected when these OH's form stronger hydrogen bonds with the transition state than with the reactants. In expts. more than a 5 orders of magnitude enhancement in rate const. was found in a chosen reaction. The structural arrangement at the oil-water interface is in contrast to the structure of water mols. around a small hydrophobic solute in homogeneous soln., where the water mols. are tangentially oriented. The latter implies that a breaking of an existing hydrogen-bond network in homogeneous soln. is needed to permit a catalytic effect of hydrogen bonds, but not for the on-water reaction. Thereby, the reaction in homogeneous aq. soln. is intrinsically slower than the surface reaction, as obsd. exptl. The proposed mechanism of rate acceleration is discussed in light of other on-water reactions that showed smaller accelerations in rates. To interpret the results in different media, a method is given for comparing the rate consts. of different rate processes, homogeneous, neat and on-water, all of which have different units, by introducing models that reduce them to the same units. The obsd. deuterium kinetic isotope effect is discussed briefly, and some expts. are suggested that can test the present interpretation and increase understanding of the on-water catalysis.
- 32Jorgensen, W. L.; Blake, J. F.; Lim, D.; Severance, D. L. Investigation of Solvent Effects on Pericyclic Reactions by Computer Simulations. J. Chem. Soc., Faraday Trans. 1994, 90, 1727– 1732, DOI: 10.1039/FT9949001727Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXksFKqtrw%253D&md5=541eec3ff02bbfbf414ca37d679d5fc9Investigation of solvent effects on pericyclic reactions by computer simulationsJorgensen, William L.; Blake, James F.; Lim, Dongchul; Severance, Daniel L.Journal of the Chemical Society, Faraday Transactions (1994), 90 (12), 1727-32CODEN: JCFTEV; ISSN:0956-5000.A combination of quantum and statistical mechanics is being used to probe the origins of solvent effects on the kinetics of org. reactions. Ab initio MO calcns. provide gas-phase reaction paths and partial charges for the reacting systems. The reaction paths are then followed by Monte Carlo simulations in periodic cells contg. hundreds of solvent mols., and the changes in Gibbs free energies of solvation are obtained. Results are provided for several prototypical pericyclic reactions: Diels-Alder cycloaddns. for Me vinyl ketone with cyclopentadiene and the dimerization of cyclopentadiene, the Claisen rearrangement of allyl vinyl ether, and the electrocyclic ring opening of cyclopropanones to oxyallyls. Detailed insights are obtained on issues such as the acceleration of the Diels-Alder reactions and Claisen rearrangement in water, and the electronic nature of oxyallyls.
- 33Blake, J. F.; Jorgensen, W. L. Solvent Effects on a Diels-Alder Reaction from Computer Simulations. J. Am. Chem. Soc. 1991, 113, 7430– 7432, DOI: 10.1021/ja00019a055Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXltlGhurw%253D&md5=6fe84d721287fef1b1026de66b8d009eSolvent effects on a Diels-Alder reaction from computer simulationsBlake, James F.; Jorgensen, William L.Journal of the American Chemical Society (1991), 113 (19), 7430-2CODEN: JACSAT; ISSN:0002-7863.Free energy of solvation profiles for the Diels-Alder reaction of cyclopentadiene and Me vinyl ketone have been obtained from Monte Carlo statistical mechanics simulations in liq. propane, methanol, and water. The gas-phase min.-energy reaction path through the endo-cis transition state was detd. from ab initio MO calcns. and was followed in periodic cells contg. 260-500 solvent mols. Statistical perturbation theory yielded the changes in free energies of solvation along the reaction path. Essentially no solvent effect on the energetics was found in liq. propane. However, in water, the dramatic rate acceleration obsd. by Rideout and Breslow (1980) is mirrored in the computed results. The free energy of solvation of the transition state is computed to be 4.2±0.4 kcal/mol lower relative to the reactants in water than in propane, while the exptl. data show a lowering of the free energy of activation in water by 3.8 kcal/mol relative to an alkane solvent. The corresponding figures for methanol relative to the alkane solvent are 2.4±0.3 kcal/mol from the simulations and 1.5 kcal/mol exptl. Further analyses indicate that the rate acceleration in water results both from a hydrophobic effect and from enhanced H bonding to the carbonyl group in the more polar transition state than in reactants or product.
- 34Furlani, T. R.; Gao, J. Hydrophobic and Hydrogen-Bonding Effects on the Rate of Diels–Alder Reactions in Aqueous Solution. J. Org. Chem. 1996, 61, 5492– 5497, DOI: 10.1021/jo9518011Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XksVSlurc%253D&md5=201b821e5c34d5e836694d29cc5a8e22Hydrophobic and Hydrogen-Bonding Effects on the Rate of Diels-Alder Reactions in Aqueous SolutionFurlani, Thomas R.; Gao, JialiJournal of Organic Chemistry (1996), 61 (16), 5492-5497CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Using a combined quantum mech. and mol. mech. (QM/MM) potential, we have carried out Monte Carlo simulations to investigate the hydrophobic and hydrogen-bonding effects on Diels-Alder reactions in aq. soln. Two prototypical systems were considered, including the reaction of cyclopentadiene (CP) with Me vinyl ketone (MVK) and the reaction of cyclopentadiene with isoprene. Anal. of the simulation results revealed that the hydrophobic effect is significant in both reactions. Since hydrogen bonding interactions are not involved in the reaction of CP and isoprene, the entire transition-state stabilization (4.6 ± 0.3 kcal/mol) can be attributed to the hydrophobic effect. In the reaction of CP and MVK, enhanced hydrogen-bonding interaction and the hydrophobic effect contribute equally to the transition state stabilization (-3.5 ± 0.4 kcal/mol). These findings are compared with the exptl. results and predictions from previous theor. studies.
- 35SaiPrathima, P.; Srinivas, K.; Mohan Rao, M. On Water” Catalysis: An Expeditious Approach for the Synthesis of Quaternary Centered 3-Hydroxy-3-(Nitromethyl)Indolin-2-One Derivatives. Green Chem. 2015, 17, 2339– 2343, DOI: 10.1039/C4GC02203CGoogle Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitlaisbs%253D&md5=1e330dc03c370e47b2643fad9c474c49"On water" catalysis: an expeditious approach for the synthesis of quaternary centered 3-hydroxy-3-(nitromethyl)indolin-2-one derivativesSaiPrathima, Parvathaneni; Srinivas, Keesara; Mohan Rao, MandapatiGreen Chemistry (2015), 17 (4), 2339-2343CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)A novel, efficient, eco-friendly "on water" method was developed for the Henry reaction of isatins with nitromethane to afford 3-hydroxy-3-nitromethylindolin-2-ones. An enhancement in reaction rate was obsd. "on water" under mild and catalyst-free conditions. This reaction tolerated a wide range of substrates with good to excellent product yields and is even applicable at large scales. Moreover, this method is environmentally friendly as it reduces the waste generated using toxic solvents.
- 36Hyde, A. M.; Zultanski, S. L.; Waldman, J. H.; Zhong, Y.-L.; Shevlin, M.; Peng, F. General Principles and Strategies for Salting-Out Informed by the Hofmeister Series. Org. Process Res. Dev. 2017, 21, 1355– 1370, DOI: 10.1021/acs.oprd.7b00197Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlWmtb%252FF&md5=85f3b59968b6f942f1a948f8b0782f91General Principles and Strategies for Salting-Out Informed by the Hofmeister SeriesHyde, Alan M.; Zultanski, Susan L.; Waldman, Jacob H.; Zhong, Yong-Li; Shevlin, Michael; Peng, FengOrganic Process Research & Development (2017), 21 (9), 1355-1370CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Overarching principles for salting-out extn. are long-established but poorly disseminated. We highlight the opportunity for more widespread application of this technique using the Hofmeister series as a foundational basis for choosing the right salt. The power of this approach is exemplified by the aq. workup of a highly water-sol. nucleoside in which the use of sodium sulfate allowed for high recoveries without relying on back extn.
- 37Bora, P. P.; Bez, G. Henry Reaction in Aqueous Media at Neutral PH. Eur. J. Org. Chem. 2013, 2013, 2922– 2929, DOI: 10.1002/ejoc.201201682Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXksFejtLg%253D&md5=01e5515b721491ad4ad70a75e9f7a4ddHenry Reaction in Aqueous Media at Neutral pHBora, Pranjal P.; Bez, GhanashyamEuropean Journal of Organic Chemistry (2013), 2013 (14), 2922-2929CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)An efficient method for the synthesis of β-nitro alcs. from nitro alkanes and aldehydes in aq. phosphate buffer under neutral pH conditions at room temp. is reported. In the case of higher nitro alkanes, the reaction showed very good diastereoselectivity to give syn β-nitro alcs. in preference to their anti products.
- 38Zhang, L.; Yuan, P.; Chen, J.; Huang, Y. Enantioselective Cooperative Proton-Transfer Catalysis Using Chiral Ammonium Phosphates. Chem. Commun. 2018, 54, 1473– 1476, DOI: 10.1039/C7CC09549JGoogle Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosVKnsg%253D%253D&md5=1df2f079e98ad05893db83d53b927d89Enantioselective cooperative proton-transfer catalysis using chiral ammonium phosphatesZhang, Linrui; Yuan, Pengfei; Chen, Jiean; Huang, YongChemical Communications (Cambridge, United Kingdom) (2018), 54 (12), 1473-1476CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Chiral phosphorate anions are shown to be highly enantioselective templates for proton-transfer catalysis. A salt generated in situ from a bridgehead amine and a BINOL-derived chiral phosphoric acid serves as an effective proton-shuttle that exhibits remarkable enantioselectivity in a bioinspired, triple co-operative catalysis involving an achiral NHC. Thioesters with a β-chiral center can be prepd. in a single step from substituted cinnamaldehyde derivs., with up to 99% yield and 99% ee. Heteroaryl groups are well tolerated in these reactions, despite the presence of basic sites.
- 39Vilčiauskas, L.; Tuckerman, M. E.; Bester, G.; Paddison, S. J.; Kreuer, K.-D. The Mechanism of Proton Conduction in Phosphoric Acid. Nat. Chem. 2012, 4, 461– 466, DOI: 10.1038/nchem.1329Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlvVKmt7o%253D&md5=1a33fce24b92b02a36a2442b2690128dThe mechanism of proton conduction in phosphoric acidVilciauskas, Linas; Tuckerman, Mark E.; Bester, Gabriel; Paddison, Stephen J.; Kreuer, Klaus-DieterNature Chemistry (2012), 4 (6), 461-466CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)Neat liq. H3PO4 has the highest intrinsic proton cond. of any known substance and is a useful model for understanding proton transport in other phosphate-based systems in biol. and clean energy technologies. Here, the authors present an ab initio mol. dynamics study that reveals, for the 1st time, the microscopic mechanism of this high proton cond. Anomalously fast proton transport in H-bonded systems involves a structural diffusion mechanism in which intramol. proton transfer is driven by specific H bond rearrangements in the surrounding environment. Aq. media transport excess charge defects through local H bond rearrangements that drive individual proton transfer reactions. But strong, polarizable H bonds in H3PO4 produce coupled proton motion and a pronounced protic dielec. response of the medium, giving extended, polarized H-bonded chains. The interplay between these chains and a frustrated H-bond network gives rise to the high proton cond.
- 40Sela, T.; Vigalok, A. Salt-Controlled Selectivity in “on Water” and “in Water” Passerini-Type Multicomponent Reactions. Adv. Synth. Catal. 2012, 354, 2407– 2411, DOI: 10.1002/adsc.201200448Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1Gks77N&md5=5351fdc2a1606348a50124dd97ac124eSalt-controlled selectivity in "on water" and "in water" Passerini-type multicomponent reactionsSela, Tal; Vigalok, ArkadiAdvanced Synthesis & Catalysis (2012), 354 (13), 2407-2411, S2407/1-S2407/21CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)Simple sodium salts completely reversed the product ratios of the Passerini reaction in aq. media. Furthermore, the use of the "salting-in" salt and a small excess of the nucleophile gives significantly higher yields than the use of the satd. soln. of the nucleophile alone. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
- 41Mellouli, S.; Bousekkine, L.; Theberge, A. B.; Huck, W. T. S. Investigation of “On Water” Conditions Using a Biphasic Fluidic Platform. Angew. Chem., Int. Ed. 2012, 51, 7981– 7984, DOI: 10.1002/anie.201200575Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsV2lurk%253D&md5=00362d7b062f581e98a937653bb4ea92Investigation of "On Water" Conditions Using a Biphasic Fluidic PlatformMellouli, Sonia; Bousekkine, Lise; Theberge, Ashleigh B.; Huck, Wilhelm T. S.Angewandte Chemie, International Edition (2012), 51 (32), 7981-7984, S7981/1-S7981/8CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We have demonstrated how biphasic flow can be used to study interfacial reactions on a macroscopic scale. Total flow rate, residence times, and most importantly, the interfacial area between the water and the org. phase can be precisely known and controlled in a (micro)fluidic system, which is not possible in bulk emulsions. We have used this technique to quantify the "on water" effect for the first time. We suggest as a possible mechanism the model based on the stabilization of the transition state by hydrogen bonding proposed by Jung and Marcus. But it is also quite apparent that the magnitude of the "on water" effect can be rather modest and even if the reaction is accelerated initially, the effect becomes less pronounced with longer reaction times. The interfacial nature of the reaction can greatly influence the overall reaction rates as product mols. might become pinned at the interface. These factors strongly counteract the favorable redn. in activation energy. Our method allows for rapid examn. of the key features of "on water" conditions, which could reduce the use of org. solvents.
- 42Champagne, P. A.; Pomarole, J.; Thérien, M.-È.; Benhassine, Y.; Beaulieu, S.; Legault, C. Y.; Paquin, J.-F. Enabling Nucleophilic Substitution Reactions of Activated Alkyl Fluorides through Hydrogen Bonding. Org. Lett. 2013, 15, 2210– 2213, DOI: 10.1021/ol400765aGoogle Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXms1Wisrw%253D&md5=f3a55eb15516e129876c65a0b13b4061Enabling Nucleophilic Substitution Reactions of Activated Alkyl Fluorides through Hydrogen BondingChampagne, Pier Alexandre; Pomarole, Julien; Therien, Marie-Eve; Benhassine, Yasmine; Beaulieu, Samuel; Legault, Claude Y.; Paquin, Jean-FrancoisOrganic Letters (2013), 15 (9), 2210-2213CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)It was discovered that the presence of water as a cosolvent enables the reaction of activated alkyl fluorides for bimol. nucleophilic substitution reactions. DFT calcns. show that activation proceeds through stabilization of the transition structure by a stronger F···H2O interaction and diminishing C-F bond elongation, and not simple transition state electrostatic stabilization. Overall, the findings put forward a distinct strategy for C-F bond activation through H-bonding.
- 43Dhameliya, T. M.; Chourasiya, S. S.; Mishra, E.; Jadhavar, P. S.; Bharatam, P. V.; Chakraborti, A. K. Rationalization of Benzazole-2-Carboxylate versus Benzazine-3-One/Benzazine-2,3-Dione Selectivity Switch during Cyclocondensation of 2-Aminothiophenols/Phenols/Anilines with 1,2-Biselectrophiles in Aqueous Medium. J. Org. Chem. 2017, 82, 10077– 10091, DOI: 10.1021/acs.joc.7b01548Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtl2lsb7K&md5=184a39f822a75ed481609f594f0b379dRationalization of Benzazole-2-carboxylate versus Benzazine-3-one/Benzazine-2,3-dione Selectivity Switch during Cyclocondensation of 2-Aminothiophenols/Phenols/Anilines with 1,2-Biselectrophiles in Aqueous MediumDhameliya, Tejas M.; Chourasiya, Sumit S.; Mishra, Eshan; Jadhavar, Pradeep S.; Bharatam, Prasad V.; Chakraborti, Asit K.Journal of Organic Chemistry (2017), 82 (19), 10077-10091CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The cyclocondensation reaction of 2-aminothiophenols with 1,2-biselectrophiles such as Et glyoxalate and di-Et oxalate in aq. medium leads to the formation of benzothiazole-2-carboxylates via the 5-endo-trig process contrary to Baldwin's rule. The reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via the 6-exo-trig process in compliance with Baldwin's rule. The mechanistic insights of these cyclocondensation reactions using the hard-soft acid-base principle, quantum chem. calcns. (d. functional theory), and orbital interaction studies rationalize the selectivity switch of benzothiazole-2-carboxylates vs. benzazine-3-ones/benzazine-2,3-diones. The presence of water facilitates these cyclocondensation reactions by lowering of the energy barrier.
- 44Acevedo, O.; Armacost, K. Claisen Rearrangements: Insight into Solvent Effects and “on Water” Reactivity from QM/MM Simulations. J. Am. Chem. Soc. 2010, 132, 1966– 1975, DOI: 10.1021/ja908680cGoogle Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvFWguw%253D%253D&md5=ec0a669be1259236c40794eab4c6da61Claisen Rearrangements: Insight into Solvent Effects and "on Water" Reactivity from QM/MM SimulationsAcevedo, Orlando; Armacost, KiraJournal of the American Chemical Society (2010), 132 (6), 1966-1975CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)An "on water" environment, defined by the absence of water soly. of the reactants, has been reported to provide increased rate accelerations, yields, and specificity for several types of org. reaction classes compared to org. solvents. The arom. Claisen rearrangements of allyl p-R-Ph ethers (R = CH3, Br, and OCH3) and allyl naphthyl ether have been investigated to det. the origin of the on water effect using QM/MM Monte Carlo calcns. and free-energy perturbation theory. The simulations indicate that on water rate enhancements for the rearrangements are derived from the ability of the interfacial waters to stabilize the polar transition state via enhanced hydrogen bonding at the oil/water interface. The position and orientation of the arom. ethers at the interface are crucial factors affecting solvent accessibility during the reaction pathway; computed solute-solvent energy pair distributions and radial distribution functions showed that hydrophobic substituents on the solute provided a more polar solvent environment than hydrophilic substituents by tilting the reacting oxygen toward the water surface. Calcns. in 16 different solvents accurately reproduced the exptl. trend of increased rates correlated to increasing solvent polarity. Hydrophobic effects did not provide a substantial contribution to the lowering of the free energy activation barrier (<0.5 kcal/mol), and solvent polarizability via a polarizable force field was also found to be negligible in the obsd. rate accelerations. New insight into solvent effects for the Claisen rearrangement is presented herein, and a QM/MM approach for computing reactions on a liq. surface is highlighted.
- 45Grieco, P. A.; Brandes, E. B.; McCann, S.; Clark, J. D. Water as a Solvent for the Claisen Rearrangement: Practical Implications for Synthetic Organic Chemistry. J. Org. Chem. 1989, 54, 5849– 5851, DOI: 10.1021/jo00286a010Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXmtlWntr4%253D&md5=472b2db05dce60987216401c8dc82827Water as a solvent for the Claisen rearrangement: practical implications for synthetic organic chemistryGrieco, Paul A.; Brandes, Ellen B.; McCann, Stephen; Clark, Jerry D.Journal of Organic Chemistry (1989), 54 (25), 5849-51CODEN: JOCEAH; ISSN:0022-3263.The accelerating influence of water as a solvent on the rate of the Claisen rearrangement has been demonstrated on several substrates, thus illustrating the enormous potential it holds for those engaged in the synthesis of natural and unnatural products. Claisen rearrangement products which hitherto were inaccessible due to decompn. at high temps. or elimination can now be realized through the agency of water.
- 46Moncrieff, D.; Wilson, S. Computational Linear Dependence in Molecular Electronic Structure Calculations Using Universal Basis Sets. Int. J. Quantum Chem. 2005, 101, 363– 371, DOI: 10.1002/qua.20275Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVSgsr8%253D&md5=655f910b2c01b9c3db4f280c9ed69155Computational linear dependence in molecular electronic structure calculations using universal basis setsMoncrieff, D.; Wilson, S.International Journal of Quantum Chemistry (2005), 101 (4), 363-371CODEN: IJQCB2; ISSN:0020-7608. (John Wiley & Sons, Inc.)A review. In this article, we compare the mol. calcns. reported by Jorge and coworkers with our previous studies.
- 47Witte, J.; Neaton, J. B.; Head-Gordon, M. Push It to the Limit: Characterizing the Convergence of Common Sequences of Basis Sets for Intermolecular Interactions as Described by Density Functional Theory. J. Chem. Phys. 2016, 144, 194306, DOI: 10.1063/1.4949536Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xot1Glu7o%253D&md5=9ae77edd84e1d02e4eef2bdea9744f37Push it to the limit: Characterizing the convergence of common sequences of basis sets for intermolecular interactions as described by density functional theoryWitte, Jonathon; Neaton, Jeffrey B.; Head-Gordon, MartinJournal of Chemical Physics (2016), 144 (19), 194306/1-194306/12CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)With the aim of systematically characterizing the convergence of common families of basis sets such that general recommendations for basis sets can be made, we have tested a wide variety of basis sets against complete-basis binding energies across the S22 set of intermol. interactions-noncovalent interactions of small and medium-sized mols. consisting of first- and second-row atoms-with three distinct d. functional approxns.: SPW92, a form of local-d. approxn.; B3LYP, a global hybrid generalized gradient approxn.; and B97M-V, a meta-generalized gradient approxn. with nonlocal correlation. We have found that it is remarkably difficult to reach the basis set limit; for the methods and systems examd., the most complete basis is Jensen's pc-4. The Dunning correlation-consistent sequence of basis sets converges slowly relative to the Jensen sequence. The Karlsruhe basis sets are quite cost effective, particularly when a correction for basis set superposition error is applied: counterpoise-cor. def2-SVPD binding energies are better than corresponding energies computed in comparably sized Dunning and Jensen bases, and on par with uncorrected results in basis sets 3-4 times larger. These trends are exhibited regardless of the level of d. functional approxn. employed. A sense of the magnitude of the intrinsic incompleteness error of each basis set not only provides a foundation for guiding basis set choice in future studies but also facilitates quant. comparison of existing studies on similar types of systems. (c) 2016 American Institute of Physics.
- 48Finneran, I. A.; Carroll, P. B.; Allodi, M. A.; Blake, G. A. Hydrogen Bonding in the Ethanol–Water Dimer. Phys. Chem. Chem. Phys. 2015, 17, 24210– 24214, DOI: 10.1039/C5CP03589AGoogle Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVahtb7O&md5=812c0632f255d6007495752f3d5694b2Hydrogen bonding in the ethanol-water dimerFinneran, Ian A.; Carroll, P. Brandon; Allodi, Marco A.; Blake, Geoffrey A.Physical Chemistry Chemical Physics (2015), 17 (37), 24210-24214CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)We report the first rotational spectrum of the ground state of the isolated ethanol-water dimer using chirped-pulse Fourier transform microwave spectroscopy between 8-18 GHz. With the aid of isotopic substitutions, and ab initio calcns., we identify the measured conformer as a water-donor/ethanol-acceptor structure. Ethanol is found to be in the gauche conformation, while the monomer distances and orientations likely reflect a cooperation between the strong (O-H···O) and weak (C-H···O) hydrogen bonds that stabilizes the measured conformer. No other conformers were assigned in an argon expansion, confirming that this is the ground-state structure. This result is consistent with previous vibrationally-resolved Raman and IR work, but sheds addnl. light on the structure, due to the specificity of rotational spectroscopy.
- 49PubChem Annotation Record for Sulfuric Acid. Hazardous Substances Data Bank (HSDB); National Center for Biotechnology Information, 2021.Google ScholarThere is no corresponding record for this reference.
- 50Köckinger, M.; Hanselmann, P.; Roberge, D. M.; Geotti-Bianchini, P.; Kappe, C. O.; Cantillo, D. Sustainable Electrochemical Decarboxylative Acetoxylation of Aminoacids in Batch and Continuous Flow. Green Chem. 2021, 23, 2382– 2390, DOI: 10.1039/D1GC00201EGoogle ScholarThere is no corresponding record for this reference.
- 51Steiner, A.; Williams, J. D.; de Frutos, O.; Rincón, J. A.; Mateos, C.; Kappe, C. O. Continuous Photochemical Benzylic Bromination Using in Situ Generated Br2: Process Intensification towards Optimal PMI and Throughput. Green Chem. 2020, 22, 448– 454, DOI: 10.1039/C9GC03662HGoogle Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlGhurvP&md5=e5c553cd71cc781f93e033b74e373a8aContinuous photochemical benzylic bromination using in situ generated Br2: process intensification towards optimal PMI and throughputSteiner, Alexander; Williams, Jason D.; de Frutos, Oscar; Rincon, Juan A.; Mateos, Carlos; Kappe, C. OliverGreen Chemistry (2020), 22 (2), 448-454CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)The detailed development of photochem. benzylic brominations using a NaBrO3/HBr bromine generator in continuous flow mode is reported. Optimization of the bromine generator enables highly efficient mass utilization by HBr recycling, coupled with fast interphase transfer within a microstructured photochem. reactor (405 nm LEDs). Intensification of the reaction system, including complete removal of org. solvent, allowed a redn. in PMI from 13.25 to just 4.33. The photochem. transformation achieved exceptionally high throughput, providing complete conversion in residence times as low as 15 s. The org. solvent-free prepn. of two pharmaceutically relevant building blocks was demonstrated with outstanding mass efficiency, by monobromination (1.17 kg scale in 230 min, PMI = 3.08) or dibromination (15 g scale in 20 min, PMI = 3.64).
- 52Prieschl, M.; García-Lacuna, J.; Munday, R.; Leslie, K.; O’Kearney-McMullan, A.; Hone, C. A.; Kappe, C. O. Optimization and Sustainability Assessment of a Continuous Flow Ru-Catalyzed Ester Hydrogenation for an Important Precursor of a Β2-Adrenergic Receptor Agonist. Green Chem. 2020, 22, 5762– 5770, DOI: 10.1039/D0GC02225JGoogle Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFKksr%252FJ&md5=8bcd00e8bdbf6c016c9b5c82e79e05c7Optimization and sustainability assessment of a continuous flow Ru-catalyzed ester hydrogenation for an important precursor of a β2-adrenergic receptor agonistPrieschl, Michael; Garcia-Lacuna, Jorge; Munday, Rachel; Leslie, Kevin; O'Kearney-McMullan, Anne; Hone, Christopher A.; Kappe, C. OliverGreen Chemistry (2020), 22 (17), 5762-5770CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H2) gas is reported. The reaction was utilized for the redn. of an important precursor in the synthesis of abediterol, a β2-adrenoceptor agonist that has undergone phase IIa clin. trials for the treatment of asthma and chronic obstructive pulmonary disorder. The reaction was investigated within a batch autoclave by using a design of expts. (DoE) approach to identify important parameter effects. The optimized flow process was successfully operated over 6 h with inline benchtop 19F NMR spectroscopy for reaction monitoring. The protocol is shown to be high yielding (98% yield, 3.7 g h-1) with very low catalyst loading (0.065 mol%). The environmental impact of the Ru-catalyzed hydrogenation was assessed and compared to an existing stoichiometric lithium aluminum hydride (LAH) redn. and sodium borohydride (NaBH4) redn. The process mass intensity (PMI) for the Ru-catalyzed hydrogenation (14) compared favorably to a LAH redn. (52) and NaBH4 redn. (133).
- 53Adamo, A.; Heider, P. L.; Weeranoppanant, N.; Jensen, K. F. Membrane-Based, Liquid–Liquid Separator with Integrated Pressure Control. Ind. Eng. Chem. Res. 2013, 52, 10802– 10808, DOI: 10.1021/ie401180tGoogle Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVCrsrzM&md5=d01e4234f23bde47c3cdeaf79a153a8aMembrane-based, liquid-liquid separator with integrated pressure controlAdamo, Andrea; Heider, Patrick L.; Weeranoppanant, Nopphon; Jensen, Klavs F.Industrial & Engineering Chemistry Research (2013), 52 (31), 10802-10808CODEN: IECRED; ISSN:0888-5885. (American Chemical Society)We describe the development and application of an improved, membrane-based, liq.-liq. separator. Membrane-based sepn. relies on the exploitation of surface forces and the use of a membrane wetted by one of the phases; however, successful sepn. requires accurate control of pressures, making the operation and implementation cumbersome. Here we present an improved separator design that integrates a pressure control element to ensure that adequate operating conditions are always maintained. Addnl., the integrated pressure control decouples the separator from downstream unit operations. A detailed examn. of the controlling phys. equations shows how to design the device to allow operation across a wide range of conditions. Easy to implement, multistage sepns. such as solvent swaps and countercurrent extns. are demonstrated. The presented design significantly simplifies applications ranging from multistep synthesis to complex multistage sepns.
- 54Chapman, M. R.; Kwan, M. H. T.; King, G.; Jolley, K. E.; Hussain, M.; Hussain, S.; Salama, I. E.; González Nino, C.; Thompson, L. A.; Bayana, M. E.; Clayton, A. D.; Nguyen, B. N.; Turner, N. J.; Kapur, N.; Blacker, A. J. Simple and Versatile Laboratory Scale CSTR for Multiphasic Continuous-Flow Chemistry and Long Residence Times. Org. Process Res. Dev. 2017, 21, 1294– 1301, DOI: 10.1021/acs.oprd.7b00173Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVOntrvO&md5=c89c9bf886fcd92bd1f78b9aa7dd292bSimple and Versatile Laboratory Scale CSTR for Multiphasic Continuous-Flow Chemistry and Long Residence TimesChapman, Michael R.; Kwan, Maria H. T.; King, Georgina; Jolley, Katherine E.; Hussain, Mariam; Hussain, Shahed; Salama, Ibrahim E.; Gonzalez Nino, Carlos; Thompson, Lisa A.; Bayana, Mary E.; Clayton, Adam D.; Nguyen, Bao N.; Turner, Nicholas J.; Kapur, Nikil; Blacker, A. JohnOrganic Process Research & Development (2017), 21 (9), 1294-1301CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A universal multi-stage cascade CSTR has been developed which is suitable for a wide range of continuous-flow processes. Coined by authors group the 'Freactor' (free-to-access reactor), the new reactor integrates the efficiency of pipe-flow processing with the advanced mixing of a CSTR, delivering a general 'plug-and-play' reactor platform which is well-suited to multiphasic continuous-flow chem. Importantly, the reactor geometry is easily customized to accommodate reactions requiring long residence times (≥ 3 h tested).
- 55Becker, J.; Manske, C.; Randl, S. Green Chemistry and Sustainability Metrics in the Pharmaceutical Manufacturing Sector. Curr. Opin. Green Sustainable Chem. 2022, 33, 100562, DOI: 10.1016/j.cogsc.2021.100562Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsVOiur7L&md5=15ca54e8fff23975206484d7eb479094Green chemistry and sustainability metrics in the pharmaceutical manufacturing sectorBecker, Jochen; Manske, Carolin; Randl, StefanCurrent Opinion in Green and Sustainable Chemistry (2022), 33 (), 100562CODEN: COGSC4; ISSN:2452-2236. (Elsevier B.V.)This review article summarizes recent developments of green chem. and sustainability metrics with a focus on the pharmaceutical industry. We discuss synergies and discrepancies of the green chem. principles with regulatory guidelines in the field of pharmaceutical process development and manufg. under Good Manufg. Practices (GMP). This review captures selected views and publications on green chem. and sustainability metrics. It discusses two recent process development highlights from the pharmaceutical industry which use different approaches to optimize the process mass intensity (PMI) of small-mol. active pharmaceutical ingredient (API) manufg. processes. The first example is the development of green process conditions by switching reaction media from org. solvents to micellar catalysis in water in the Takeda process of the API TAK-954. The second example features process intensifications accomplished by the application of innovative technologies in pharmaceutical processing in the Merck process of the API MK-7264.
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Abstract
Figure 1
Figure 1. Simplified phase complexity scenarios of water-accelerated reactions: (a) all reactants are insoluble in water; (b) one reactant is partially soluble in water; (c) reactants are phase-separated; and (d) one reactant is activated at the aqueous–organic interface.
Scheme 1
Figure 2
Figure 2. Dependence of the water-accelerated Henry reaction on reaction conditions: (a) kinetic isotope effect; (b) salt effects by NaCl 1 M, LiCl 1 M, Bu4NCl 1 M, Na2SO4 1 M (70 °C), and phosphate buffer 0.1 M at pH 7 (22 °C), error bars are excluded for clarity; and (c) effect of temperature (color), stirring rate (dot size), excess nitromethane, and amount of 1 on reaction yield at 1 h.
Figure 3
Figure 3. Energy profile of Henry reaction under (a) water-accelerated conditions, or in ethanol, and (b) in the presence of HSO4–.
Figure 4
Figure 4. Natural bond orbital (NBO) charge distribution analysis of the transition states TS1w, TS2w, TS1HSO4, and TS2HSO4.
Figure 5
Figure 5. (a) Reaction yields with recycling of the aqueous phase in batch, orange bar depicting yield with water as the aqueous phase and green bar depicting yield with 0.1 M phosphate buffer pH 7 as the aqueous phase. Reaction conditions: 51 mg of 1, 0.42 mL of nitromethane, 3 mL of aqueous phase recycled up to 5 times, 850 rpm, 70 °C (water), 25 °C (phosphate buffer), 3 h (water), 10 min (phosphate buffer). (b) Kinetic profile of Henry reaction in batch at a 1:1 phase ratio using 25 equiv (●) or 9 equiv (■) of nitromethane. Reaction conditions: 0.42 mL solution of 1 in nitromethane with 5 mol % trimethoxybenzene as an internal standard [(●) 0.121 g 1/1 mL; (■) 0.331 g 1/1 mL], 0.42 mL of 0.1 M phosphate buffer, 40 °C, 850 rpm, 0–25 min.
Figure 6
Figure 6. Flow process diagram including the continuous recycling of the aqueous phase.
Figure 7
Figure 7. Yields and mass balance of flow processes with continuous aqueous phase recycling using (a) 0.121 g of 1 per 1 mL CH3NO2 and (b) 0.3331 g of 1 per 1 mL CH3NO2. (▲) Molar fraction of 1; (■) molar fraction of product 2; (●) molar fraction of side product 3; and (▼) total mass balance.
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- 20Du, Z.-H.; Da, C. S.; Yuan, M.; Tao, B. X.; Ding, T. Y. Efficient Catalyst-Free Henry Reaction between Nitroalkanes and Aldehydes or Trifluoromethyl Ketones Promoted by Tap Water. Synthesis 2022, 54, 5461– 5470, DOI: 10.1055/a-1933-370920https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XisFWisbvJ&md5=32793b71c71c6cc2abe0db5fde153002Efficient Catalyst-Free Henry Reaction between Nitroalkanes and Aldehydes or Trifluoromethyl Ketones Promoted by Tap WaterDu, Zhi-Hong; Yuan, Meng; Tao, Bao-Xiu; Ding, Tie-Ying; Da, Chao-ShanSynthesis (2022), 54 (24), 5461-5470CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)The first examples of highly effective Henry reactions between nitroalkanes and aldehydes or trifluoromethyl ketones that proceed under catalyst-free and additive-free conditions, in a recyclable tap water medium, and at room temp. was reported. This process tolerated a broad range of aldehydes and trifluoromethyl ketones to give a series of β-nitro alc. products in excellent yields. Such products are widely used in the syntheses of pharmaceutical intermediates and natural products. This protocol can be successfully scaled up to a 50-mmol scale without a redn. in yield. Tap water from different locations in China exhibited pH values ranging from 7.5 to 8.1, but the varying pH had no effect on the yield and the processes were successfully reproduced. Finally, the tap water was effectively recovered and reused without any post processing, even when the reaction substrates were different.
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- 22Butler, R. N.; Coyne, A. G. Understanding “On-Water” Catalysis of Organic Reactions. Effects of H+ and Li+ Ions in the Aqueous Phase and Nonreacting Competitor H-Bond Acceptors in the Organic Phase: On H2O versus on D2O for Huisgen Cycloadditions. J. Org. Chem. 2015, 80, 1809– 1817, DOI: 10.1021/jo502732y22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVWnt7s%253D&md5=38f54811e8e45ccb0515f9d67d8ebb5eUnderstanding "On-Water" Catalysis of Organic Reactions. Effects of H+ and Li+ Ions in the Aqueous Phase and Nonreacting Competitor H-Bond Acceptors in the Organic Phase: On H2O versus on D2O for Huisgen CycloadditionsButler, Richard N.; Coyne, Anthony G.Journal of Organic Chemistry (2015), 80 (3), 1809-1817CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)For a typical Huisgen cycloaddn., carried out on water, the behavior of water mols. at the oil-water interface depended on the properties of the reactants. With weakly basic reactants, a small quantity of added H+ (HClO4, 0.0001-0.01 M) present in the aq. phase had negligible effects, but larger quantities of H+ (HClO4, 0.1-3.0 M) increased the catalytic effect and caused protons to cross the water-org. interface and affect the products. Added Li+ ions (LiClO4, 0.1-3.0 M) had no effect for on-water reactions but enhanced the rates and endo products for in-water reactions. For these cycloaddn. reactions, the product endo:exo ratios, when compared to those in org. solvents, can be used to distinguish between the on-water and in-water modes. Comparisons of org. reactions on H2O and on D2O indicate that on-water catalysis ranges from weak to strong trans-phase H-bonding for reactants with basic pKa < ca. -6 and to interfacial proton transfer for reactants with higher basic pKa > ca. 2 (pKa of conjugate acid). Water shows a chameleon-type response to org. mols. at hydrophobic surfaces.
- 23Tiwari, S.; Kumar, A. Unusual Temperature Dependence of Salt Effects for “on Water” Wittig Reaction: Hydrophobicity at the Interface. Chem. Commun. 2008, 37, 4445– 4447, DOI: 10.1039/B809127GThere is no corresponding record for this reference.
- 24Bae, H. Y.; Song, C. E. Unprecedented Hydrophobic Amplification in Noncovalent Organocatalysis “on Water”: Hydrophobic Chiral Squaramide Catalyzed Michael Addition of Malonates to Nitroalkenes. ACS Catal. 2015, 5, 3613– 3619, DOI: 10.1021/acscatal.5b0068524https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnsFOgtro%253D&md5=b8521d563a8d5cd0ce85e9376912f2abUnprecedented Hydrophobic Amplification in Noncovalent Organocatalysis "on Water": Hydrophobic Chiral Squaramide Catalyzed Michael Addition of Malonates to NitroalkenesBae, Han Yong; Song, Choong EuiACS Catalysis (2015), 5 (6), 3613-3619CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)In this study, water was demonstrated to be an exceptionally efficient reaction medium for the noncovalent, hydrogen-bonding-promoted enantioselective Michael addn. of malonates to diverse nitroolefins using cinchona-based squaramide catalysts. A significant increase in the reaction rate was obsd. when the reaction was performed "on water" rather than in the conventional org. solvents, because of the hydrophobic hydration effect. This hydrophobic amplification was significantly dependent upon the hydrophobicity of the C3-substituent (vinyl or ethyl) of cinchona-based catalysts. Thus, the use of more hydrophobic catalyst with an Et group at the C3-position, even a highly challenging Michael donor such as di-Me methylmalonate was also smoothly converted to the desired adduct. Furthermore, because of the remarkable rate acceleration under "on water" conditions, the catalyst loading also significantly decreased. Thus, in the case of β-ketoesters, even 0.01 mol % of catalyst loading was enough to complete the reaction at room temp., affording the corresponding Michael adducts with perfect diastereo- and enantioselectivity (up to >99:1 d.r., up to 99% ee). The developed "on water" protocol was successfully applied for the scalable syntheses of an antidepressant (S)-rolipram and an anticonvulsant (S)-pregabalin.
- 25Butler, R. N.; Coyne, A. G. Organic Synthesis Reactions On-Water at the Organic-Liquid Water Interface. Org. Biomol. Chem. 2016, 14, 9945– 9960, DOI: 10.1039/C6OB01724J25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1SisL3I&md5=2035e37b25c4628ec99455e3bc139e33Organic synthesis reactions on-water at the organic-liquid water interfaceButler, Richard N.; Coyne, Anthony G.Organic & Biomolecular Chemistry (2016), 14 (42), 9945-9960CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Org. reactions that occur at the water interface for water-insol. compds., and reactions in water soln. for water sol. compds., has added a powerful dimension to prospects for org. synthesis under more beneficial economic and environmental conditions. Many org. mols. are partially sol. in water and reactions that appear as heterogeneous mixts. and suspensions may involve on-water and in-water reaction modes occurring simultaneously. The behavior of water mols. and org. mols. at this interface is discussed in the light of reported theor. and exptl. studies. The on-water catalytic effect, relative to neat reactions or org. solvents, ranges from factors of several hundred times to 1-2 times and it depends on the properties of reactant compds. In some cases when on-water reactions produce quant. yields of water-insol. products they can reach ideal synthetic aspirations.
- 26Kleiner, C. M.; Schreiner, P. R. Hydrophobic Amplification of Noncovalent Organocatalysis. Chem. Commun. 2006, 41, 4315– 4317, DOI: 10.1039/B605850GThere is no corresponding record for this reference.
- 27Gajewski, J. J. A Semitheoretical Multiparameter Approach to Correlate Solvent Effects on Reactions and Equilibria. J. Org. Chem. 1992, 57, 5500– 5506, DOI: 10.1021/jo00046a03627https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XlsFSnur8%253D&md5=39f659fd1e7769954e40593771c7659eA semitheoretical multiparameter approach to correlate solvent effects on reactions and equilibriaGajewski, Joseph J.Journal of Organic Chemistry (1992), 57 (20), 5500-6CODEN: JOCEAH; ISSN:0022-3263.A solvent rate effect equation which uses four phys. properties of the solvent for parameters has been applied with good success to solvolysis reactions, solvent Et values, Claisen rearrangements, Diels-Alder reactions, endo-exo ratios in Diels-Alder reactions, azo-Cope rearrangements, and enol-ketone equil. of the dimedone and pyridone variety. The coeffs. of the parameters, which are the Kirkwood-Onsager function, the solvent cohesive energy d., the specific solvation of chloride ion, and the specific solvation of potassium ion, lead to differences in dipole moments, in vols. between initial and final states, and in the extent of specific solvation of anionic and cationic sites relative to the solvation of chloride ion and potassium ion, resp.
- 28García, J. I.; Martínez-Merino, V.; Mayoral, J. A.; Salvatella, L. Density Functional Theory Study of a Lewis Acid Catalyzed Diels–Alder Reaction. The Butadiene + Acrolein Paradigm. J. Am. Chem. Soc. 1998, 120, 2415– 2420, DOI: 10.1021/ja972227928https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXhtlWnu7k%253D&md5=c62bc1d2484c3d3a82411e3c194bb0faDensity Functional Theory Study of a Lewis Acid Catalyzed Diels-Alder Reaction. The Butadiene + Acrolein ParadigmGarcia, J. I.; Martinez-Merino, V.; Mayoral, J. A.; Salvatella, L.Journal of the American Chemical Society (1998), 120 (10), 2415-2420CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The four transition structures (TS's) of the reaction between butadiene and acrolein, both uncatalyzed and catalyzed by BF3, have been theor. studied taking into account electron correlation effects by means of DFT (B3LYP) calcns. In both the uncatalyzed and catalyzed reactions, the endo s-cis is the most stable of the four possible transition structures. In the case of the catalyzed reaction, the inclusion of electron correlation in the search for this transition structure indicates the classical [4+2] reaction path, instead of that corresponding to a [2+4] inverse electron, demands hetero-Diels-Alder reaction, as happens when the Hartree-Fock level of theory is used. The B3LYP/6-31G(d) calcns. lead to activation energy values close to those exptl. found. The origin of the endo/exo selectivity, both in the presence and in the absence of the catalyst, is discussed.
- 29Manna, A.; Kumar, A. Why Does Water Accelerate Organic Reactions under Heterogeneous Condition?. J. Phys. Chem. A 2013, 117, 2446– 2454, DOI: 10.1021/jp400293429https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFars7s%253D&md5=771c6256cdfeec35f4aa65a8c13bfa19Why Does Water Accelerate Organic Reactions under Heterogeneous Condition?Manna, Arpan; Kumar, AnilJournal of Physical Chemistry A (2013), 117 (12), 2446-2454CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)A kinetic anal. has been carried out to elucidate the role of the oil-water interface in guiding "on water org. reaction" mechanism. The preferential solvation of polarizable ions at the water surface was shown. Exptl. methods were developed to control the mol. structure of oil-water interface in situ. Temp.-dependent analyses allowing one to understand the enthalpic and entropic modifications of the interfacial water mols. during a heterogeneous reaction are given. The kinetic and the thermodn. outcomes established that the hydrogen bond ability of the surface water mols. played a crit. role in the on-water org. reaction mechanism.
- 30Guo, D.; Zhu, D.; Zhou, X.; Zheng, B. Accelerating the “On Water” Reaction: By Organic-Water Interface or By Hydrodynamic Effects?. Langmuir 2015, 31, 13759– 13763, DOI: 10.1021/acs.langmuir.5b0403130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFWrt7zP&md5=63cd1810876fed248c3cfc7893f0bfb7Accelerating the "On Water" Reaction: By Organic-Water Interface or By Hydrodynamic Effects?Guo, Dameng; Zhu, Deyong; Zhou, Xiaohu; Zheng, BoLangmuir (2015), 31 (51), 13759-13763CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)A series of org. reactions proceed dramatically faster in a heterogeneous mixt. of the reactants and water than in a homogeneous mixt. Currently it is unclear whether the rate acceleration is due to the free OH groups at the org.-water interface, or due to the hydrodynamic effects caused by vigorous stirring, vortexing, or ultrasonication. The authors produced static droplets in microfluidic devices to answer this question. A series of org. droplets contg. di-Et azodicarboxylate (DEAD) and quadricyclane surrounded by water were produced, which were transferred to and confined in glass capillaries to minimize the hydrodynamic effects. The cycloaddn. process of DEAD with quadricyclane was recorded by a CCD camera. The results showed the reaction proceeded in three steps, and the org.-water interface alone was catalytically efficient enough to enhance the reaction rate to the same level as in the bulk emulsion reaction, indicating that the hydrodynamic effects were negligible.
- 31Jung, Y.; Marcus, R. A. On the Theory of Organic Catalysis “on Water. J. Am. Chem. Soc. 2007, 129, 5492– 5502, DOI: 10.1021/ja068120f31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVOrs70%253D&md5=2442ced8c33009e4bf5dfa8278791761On the Theory of Organic Catalysis "on Water"Jung, Yousung; Marcus, R. A.Journal of the American Chemical Society (2007), 129 (17), 5492-5502CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A mol. origin of the striking rate increase obsd. in a reaction on water is studied theor. A key aspect of the on-water rate phenomenon is the chem. between water and reactants that occurs at an oil-water phase boundary. In particular, the structure of water at the oil-water interface of an oil emulsion, in which approx. one in every four interfacial water mols. has a free (dangling) OH group that protrudes into the org. phase, plays a key role in catalyzing reactions via the formation of hydrogen bonds. Catalysis is expected when these OH's form stronger hydrogen bonds with the transition state than with the reactants. In expts. more than a 5 orders of magnitude enhancement in rate const. was found in a chosen reaction. The structural arrangement at the oil-water interface is in contrast to the structure of water mols. around a small hydrophobic solute in homogeneous soln., where the water mols. are tangentially oriented. The latter implies that a breaking of an existing hydrogen-bond network in homogeneous soln. is needed to permit a catalytic effect of hydrogen bonds, but not for the on-water reaction. Thereby, the reaction in homogeneous aq. soln. is intrinsically slower than the surface reaction, as obsd. exptl. The proposed mechanism of rate acceleration is discussed in light of other on-water reactions that showed smaller accelerations in rates. To interpret the results in different media, a method is given for comparing the rate consts. of different rate processes, homogeneous, neat and on-water, all of which have different units, by introducing models that reduce them to the same units. The obsd. deuterium kinetic isotope effect is discussed briefly, and some expts. are suggested that can test the present interpretation and increase understanding of the on-water catalysis.
- 32Jorgensen, W. L.; Blake, J. F.; Lim, D.; Severance, D. L. Investigation of Solvent Effects on Pericyclic Reactions by Computer Simulations. J. Chem. Soc., Faraday Trans. 1994, 90, 1727– 1732, DOI: 10.1039/FT994900172732https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXksFKqtrw%253D&md5=541eec3ff02bbfbf414ca37d679d5fc9Investigation of solvent effects on pericyclic reactions by computer simulationsJorgensen, William L.; Blake, James F.; Lim, Dongchul; Severance, Daniel L.Journal of the Chemical Society, Faraday Transactions (1994), 90 (12), 1727-32CODEN: JCFTEV; ISSN:0956-5000.A combination of quantum and statistical mechanics is being used to probe the origins of solvent effects on the kinetics of org. reactions. Ab initio MO calcns. provide gas-phase reaction paths and partial charges for the reacting systems. The reaction paths are then followed by Monte Carlo simulations in periodic cells contg. hundreds of solvent mols., and the changes in Gibbs free energies of solvation are obtained. Results are provided for several prototypical pericyclic reactions: Diels-Alder cycloaddns. for Me vinyl ketone with cyclopentadiene and the dimerization of cyclopentadiene, the Claisen rearrangement of allyl vinyl ether, and the electrocyclic ring opening of cyclopropanones to oxyallyls. Detailed insights are obtained on issues such as the acceleration of the Diels-Alder reactions and Claisen rearrangement in water, and the electronic nature of oxyallyls.
- 33Blake, J. F.; Jorgensen, W. L. Solvent Effects on a Diels-Alder Reaction from Computer Simulations. J. Am. Chem. Soc. 1991, 113, 7430– 7432, DOI: 10.1021/ja00019a05533https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXltlGhurw%253D&md5=6fe84d721287fef1b1026de66b8d009eSolvent effects on a Diels-Alder reaction from computer simulationsBlake, James F.; Jorgensen, William L.Journal of the American Chemical Society (1991), 113 (19), 7430-2CODEN: JACSAT; ISSN:0002-7863.Free energy of solvation profiles for the Diels-Alder reaction of cyclopentadiene and Me vinyl ketone have been obtained from Monte Carlo statistical mechanics simulations in liq. propane, methanol, and water. The gas-phase min.-energy reaction path through the endo-cis transition state was detd. from ab initio MO calcns. and was followed in periodic cells contg. 260-500 solvent mols. Statistical perturbation theory yielded the changes in free energies of solvation along the reaction path. Essentially no solvent effect on the energetics was found in liq. propane. However, in water, the dramatic rate acceleration obsd. by Rideout and Breslow (1980) is mirrored in the computed results. The free energy of solvation of the transition state is computed to be 4.2±0.4 kcal/mol lower relative to the reactants in water than in propane, while the exptl. data show a lowering of the free energy of activation in water by 3.8 kcal/mol relative to an alkane solvent. The corresponding figures for methanol relative to the alkane solvent are 2.4±0.3 kcal/mol from the simulations and 1.5 kcal/mol exptl. Further analyses indicate that the rate acceleration in water results both from a hydrophobic effect and from enhanced H bonding to the carbonyl group in the more polar transition state than in reactants or product.
- 34Furlani, T. R.; Gao, J. Hydrophobic and Hydrogen-Bonding Effects on the Rate of Diels–Alder Reactions in Aqueous Solution. J. Org. Chem. 1996, 61, 5492– 5497, DOI: 10.1021/jo951801134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XksVSlurc%253D&md5=201b821e5c34d5e836694d29cc5a8e22Hydrophobic and Hydrogen-Bonding Effects on the Rate of Diels-Alder Reactions in Aqueous SolutionFurlani, Thomas R.; Gao, JialiJournal of Organic Chemistry (1996), 61 (16), 5492-5497CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Using a combined quantum mech. and mol. mech. (QM/MM) potential, we have carried out Monte Carlo simulations to investigate the hydrophobic and hydrogen-bonding effects on Diels-Alder reactions in aq. soln. Two prototypical systems were considered, including the reaction of cyclopentadiene (CP) with Me vinyl ketone (MVK) and the reaction of cyclopentadiene with isoprene. Anal. of the simulation results revealed that the hydrophobic effect is significant in both reactions. Since hydrogen bonding interactions are not involved in the reaction of CP and isoprene, the entire transition-state stabilization (4.6 ± 0.3 kcal/mol) can be attributed to the hydrophobic effect. In the reaction of CP and MVK, enhanced hydrogen-bonding interaction and the hydrophobic effect contribute equally to the transition state stabilization (-3.5 ± 0.4 kcal/mol). These findings are compared with the exptl. results and predictions from previous theor. studies.
- 35SaiPrathima, P.; Srinivas, K.; Mohan Rao, M. On Water” Catalysis: An Expeditious Approach for the Synthesis of Quaternary Centered 3-Hydroxy-3-(Nitromethyl)Indolin-2-One Derivatives. Green Chem. 2015, 17, 2339– 2343, DOI: 10.1039/C4GC02203C35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitlaisbs%253D&md5=1e330dc03c370e47b2643fad9c474c49"On water" catalysis: an expeditious approach for the synthesis of quaternary centered 3-hydroxy-3-(nitromethyl)indolin-2-one derivativesSaiPrathima, Parvathaneni; Srinivas, Keesara; Mohan Rao, MandapatiGreen Chemistry (2015), 17 (4), 2339-2343CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)A novel, efficient, eco-friendly "on water" method was developed for the Henry reaction of isatins with nitromethane to afford 3-hydroxy-3-nitromethylindolin-2-ones. An enhancement in reaction rate was obsd. "on water" under mild and catalyst-free conditions. This reaction tolerated a wide range of substrates with good to excellent product yields and is even applicable at large scales. Moreover, this method is environmentally friendly as it reduces the waste generated using toxic solvents.
- 36Hyde, A. M.; Zultanski, S. L.; Waldman, J. H.; Zhong, Y.-L.; Shevlin, M.; Peng, F. General Principles and Strategies for Salting-Out Informed by the Hofmeister Series. Org. Process Res. Dev. 2017, 21, 1355– 1370, DOI: 10.1021/acs.oprd.7b0019736https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlWmtb%252FF&md5=85f3b59968b6f942f1a948f8b0782f91General Principles and Strategies for Salting-Out Informed by the Hofmeister SeriesHyde, Alan M.; Zultanski, Susan L.; Waldman, Jacob H.; Zhong, Yong-Li; Shevlin, Michael; Peng, FengOrganic Process Research & Development (2017), 21 (9), 1355-1370CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Overarching principles for salting-out extn. are long-established but poorly disseminated. We highlight the opportunity for more widespread application of this technique using the Hofmeister series as a foundational basis for choosing the right salt. The power of this approach is exemplified by the aq. workup of a highly water-sol. nucleoside in which the use of sodium sulfate allowed for high recoveries without relying on back extn.
- 37Bora, P. P.; Bez, G. Henry Reaction in Aqueous Media at Neutral PH. Eur. J. Org. Chem. 2013, 2013, 2922– 2929, DOI: 10.1002/ejoc.20120168237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXksFejtLg%253D&md5=01e5515b721491ad4ad70a75e9f7a4ddHenry Reaction in Aqueous Media at Neutral pHBora, Pranjal P.; Bez, GhanashyamEuropean Journal of Organic Chemistry (2013), 2013 (14), 2922-2929CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)An efficient method for the synthesis of β-nitro alcs. from nitro alkanes and aldehydes in aq. phosphate buffer under neutral pH conditions at room temp. is reported. In the case of higher nitro alkanes, the reaction showed very good diastereoselectivity to give syn β-nitro alcs. in preference to their anti products.
- 38Zhang, L.; Yuan, P.; Chen, J.; Huang, Y. Enantioselective Cooperative Proton-Transfer Catalysis Using Chiral Ammonium Phosphates. Chem. Commun. 2018, 54, 1473– 1476, DOI: 10.1039/C7CC09549J38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosVKnsg%253D%253D&md5=1df2f079e98ad05893db83d53b927d89Enantioselective cooperative proton-transfer catalysis using chiral ammonium phosphatesZhang, Linrui; Yuan, Pengfei; Chen, Jiean; Huang, YongChemical Communications (Cambridge, United Kingdom) (2018), 54 (12), 1473-1476CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Chiral phosphorate anions are shown to be highly enantioselective templates for proton-transfer catalysis. A salt generated in situ from a bridgehead amine and a BINOL-derived chiral phosphoric acid serves as an effective proton-shuttle that exhibits remarkable enantioselectivity in a bioinspired, triple co-operative catalysis involving an achiral NHC. Thioesters with a β-chiral center can be prepd. in a single step from substituted cinnamaldehyde derivs., with up to 99% yield and 99% ee. Heteroaryl groups are well tolerated in these reactions, despite the presence of basic sites.
- 39Vilčiauskas, L.; Tuckerman, M. E.; Bester, G.; Paddison, S. J.; Kreuer, K.-D. The Mechanism of Proton Conduction in Phosphoric Acid. Nat. Chem. 2012, 4, 461– 466, DOI: 10.1038/nchem.132939https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlvVKmt7o%253D&md5=1a33fce24b92b02a36a2442b2690128dThe mechanism of proton conduction in phosphoric acidVilciauskas, Linas; Tuckerman, Mark E.; Bester, Gabriel; Paddison, Stephen J.; Kreuer, Klaus-DieterNature Chemistry (2012), 4 (6), 461-466CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)Neat liq. H3PO4 has the highest intrinsic proton cond. of any known substance and is a useful model for understanding proton transport in other phosphate-based systems in biol. and clean energy technologies. Here, the authors present an ab initio mol. dynamics study that reveals, for the 1st time, the microscopic mechanism of this high proton cond. Anomalously fast proton transport in H-bonded systems involves a structural diffusion mechanism in which intramol. proton transfer is driven by specific H bond rearrangements in the surrounding environment. Aq. media transport excess charge defects through local H bond rearrangements that drive individual proton transfer reactions. But strong, polarizable H bonds in H3PO4 produce coupled proton motion and a pronounced protic dielec. response of the medium, giving extended, polarized H-bonded chains. The interplay between these chains and a frustrated H-bond network gives rise to the high proton cond.
- 40Sela, T.; Vigalok, A. Salt-Controlled Selectivity in “on Water” and “in Water” Passerini-Type Multicomponent Reactions. Adv. Synth. Catal. 2012, 354, 2407– 2411, DOI: 10.1002/adsc.20120044840https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1Gks77N&md5=5351fdc2a1606348a50124dd97ac124eSalt-controlled selectivity in "on water" and "in water" Passerini-type multicomponent reactionsSela, Tal; Vigalok, ArkadiAdvanced Synthesis & Catalysis (2012), 354 (13), 2407-2411, S2407/1-S2407/21CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)Simple sodium salts completely reversed the product ratios of the Passerini reaction in aq. media. Furthermore, the use of the "salting-in" salt and a small excess of the nucleophile gives significantly higher yields than the use of the satd. soln. of the nucleophile alone. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
- 41Mellouli, S.; Bousekkine, L.; Theberge, A. B.; Huck, W. T. S. Investigation of “On Water” Conditions Using a Biphasic Fluidic Platform. Angew. Chem., Int. Ed. 2012, 51, 7981– 7984, DOI: 10.1002/anie.20120057541https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsV2lurk%253D&md5=00362d7b062f581e98a937653bb4ea92Investigation of "On Water" Conditions Using a Biphasic Fluidic PlatformMellouli, Sonia; Bousekkine, Lise; Theberge, Ashleigh B.; Huck, Wilhelm T. S.Angewandte Chemie, International Edition (2012), 51 (32), 7981-7984, S7981/1-S7981/8CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We have demonstrated how biphasic flow can be used to study interfacial reactions on a macroscopic scale. Total flow rate, residence times, and most importantly, the interfacial area between the water and the org. phase can be precisely known and controlled in a (micro)fluidic system, which is not possible in bulk emulsions. We have used this technique to quantify the "on water" effect for the first time. We suggest as a possible mechanism the model based on the stabilization of the transition state by hydrogen bonding proposed by Jung and Marcus. But it is also quite apparent that the magnitude of the "on water" effect can be rather modest and even if the reaction is accelerated initially, the effect becomes less pronounced with longer reaction times. The interfacial nature of the reaction can greatly influence the overall reaction rates as product mols. might become pinned at the interface. These factors strongly counteract the favorable redn. in activation energy. Our method allows for rapid examn. of the key features of "on water" conditions, which could reduce the use of org. solvents.
- 42Champagne, P. A.; Pomarole, J.; Thérien, M.-È.; Benhassine, Y.; Beaulieu, S.; Legault, C. Y.; Paquin, J.-F. Enabling Nucleophilic Substitution Reactions of Activated Alkyl Fluorides through Hydrogen Bonding. Org. Lett. 2013, 15, 2210– 2213, DOI: 10.1021/ol400765a42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXms1Wisrw%253D&md5=f3a55eb15516e129876c65a0b13b4061Enabling Nucleophilic Substitution Reactions of Activated Alkyl Fluorides through Hydrogen BondingChampagne, Pier Alexandre; Pomarole, Julien; Therien, Marie-Eve; Benhassine, Yasmine; Beaulieu, Samuel; Legault, Claude Y.; Paquin, Jean-FrancoisOrganic Letters (2013), 15 (9), 2210-2213CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)It was discovered that the presence of water as a cosolvent enables the reaction of activated alkyl fluorides for bimol. nucleophilic substitution reactions. DFT calcns. show that activation proceeds through stabilization of the transition structure by a stronger F···H2O interaction and diminishing C-F bond elongation, and not simple transition state electrostatic stabilization. Overall, the findings put forward a distinct strategy for C-F bond activation through H-bonding.
- 43Dhameliya, T. M.; Chourasiya, S. S.; Mishra, E.; Jadhavar, P. S.; Bharatam, P. V.; Chakraborti, A. K. Rationalization of Benzazole-2-Carboxylate versus Benzazine-3-One/Benzazine-2,3-Dione Selectivity Switch during Cyclocondensation of 2-Aminothiophenols/Phenols/Anilines with 1,2-Biselectrophiles in Aqueous Medium. J. Org. Chem. 2017, 82, 10077– 10091, DOI: 10.1021/acs.joc.7b0154843https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtl2lsb7K&md5=184a39f822a75ed481609f594f0b379dRationalization of Benzazole-2-carboxylate versus Benzazine-3-one/Benzazine-2,3-dione Selectivity Switch during Cyclocondensation of 2-Aminothiophenols/Phenols/Anilines with 1,2-Biselectrophiles in Aqueous MediumDhameliya, Tejas M.; Chourasiya, Sumit S.; Mishra, Eshan; Jadhavar, Pradeep S.; Bharatam, Prasad V.; Chakraborti, Asit K.Journal of Organic Chemistry (2017), 82 (19), 10077-10091CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The cyclocondensation reaction of 2-aminothiophenols with 1,2-biselectrophiles such as Et glyoxalate and di-Et oxalate in aq. medium leads to the formation of benzothiazole-2-carboxylates via the 5-endo-trig process contrary to Baldwin's rule. The reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via the 6-exo-trig process in compliance with Baldwin's rule. The mechanistic insights of these cyclocondensation reactions using the hard-soft acid-base principle, quantum chem. calcns. (d. functional theory), and orbital interaction studies rationalize the selectivity switch of benzothiazole-2-carboxylates vs. benzazine-3-ones/benzazine-2,3-diones. The presence of water facilitates these cyclocondensation reactions by lowering of the energy barrier.
- 44Acevedo, O.; Armacost, K. Claisen Rearrangements: Insight into Solvent Effects and “on Water” Reactivity from QM/MM Simulations. J. Am. Chem. Soc. 2010, 132, 1966– 1975, DOI: 10.1021/ja908680c44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvFWguw%253D%253D&md5=ec0a669be1259236c40794eab4c6da61Claisen Rearrangements: Insight into Solvent Effects and "on Water" Reactivity from QM/MM SimulationsAcevedo, Orlando; Armacost, KiraJournal of the American Chemical Society (2010), 132 (6), 1966-1975CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)An "on water" environment, defined by the absence of water soly. of the reactants, has been reported to provide increased rate accelerations, yields, and specificity for several types of org. reaction classes compared to org. solvents. The arom. Claisen rearrangements of allyl p-R-Ph ethers (R = CH3, Br, and OCH3) and allyl naphthyl ether have been investigated to det. the origin of the on water effect using QM/MM Monte Carlo calcns. and free-energy perturbation theory. The simulations indicate that on water rate enhancements for the rearrangements are derived from the ability of the interfacial waters to stabilize the polar transition state via enhanced hydrogen bonding at the oil/water interface. The position and orientation of the arom. ethers at the interface are crucial factors affecting solvent accessibility during the reaction pathway; computed solute-solvent energy pair distributions and radial distribution functions showed that hydrophobic substituents on the solute provided a more polar solvent environment than hydrophilic substituents by tilting the reacting oxygen toward the water surface. Calcns. in 16 different solvents accurately reproduced the exptl. trend of increased rates correlated to increasing solvent polarity. Hydrophobic effects did not provide a substantial contribution to the lowering of the free energy activation barrier (<0.5 kcal/mol), and solvent polarizability via a polarizable force field was also found to be negligible in the obsd. rate accelerations. New insight into solvent effects for the Claisen rearrangement is presented herein, and a QM/MM approach for computing reactions on a liq. surface is highlighted.
- 45Grieco, P. A.; Brandes, E. B.; McCann, S.; Clark, J. D. Water as a Solvent for the Claisen Rearrangement: Practical Implications for Synthetic Organic Chemistry. J. Org. Chem. 1989, 54, 5849– 5851, DOI: 10.1021/jo00286a01045https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXmtlWntr4%253D&md5=472b2db05dce60987216401c8dc82827Water as a solvent for the Claisen rearrangement: practical implications for synthetic organic chemistryGrieco, Paul A.; Brandes, Ellen B.; McCann, Stephen; Clark, Jerry D.Journal of Organic Chemistry (1989), 54 (25), 5849-51CODEN: JOCEAH; ISSN:0022-3263.The accelerating influence of water as a solvent on the rate of the Claisen rearrangement has been demonstrated on several substrates, thus illustrating the enormous potential it holds for those engaged in the synthesis of natural and unnatural products. Claisen rearrangement products which hitherto were inaccessible due to decompn. at high temps. or elimination can now be realized through the agency of water.
- 46Moncrieff, D.; Wilson, S. Computational Linear Dependence in Molecular Electronic Structure Calculations Using Universal Basis Sets. Int. J. Quantum Chem. 2005, 101, 363– 371, DOI: 10.1002/qua.2027546https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVSgsr8%253D&md5=655f910b2c01b9c3db4f280c9ed69155Computational linear dependence in molecular electronic structure calculations using universal basis setsMoncrieff, D.; Wilson, S.International Journal of Quantum Chemistry (2005), 101 (4), 363-371CODEN: IJQCB2; ISSN:0020-7608. (John Wiley & Sons, Inc.)A review. In this article, we compare the mol. calcns. reported by Jorge and coworkers with our previous studies.
- 47Witte, J.; Neaton, J. B.; Head-Gordon, M. Push It to the Limit: Characterizing the Convergence of Common Sequences of Basis Sets for Intermolecular Interactions as Described by Density Functional Theory. J. Chem. Phys. 2016, 144, 194306, DOI: 10.1063/1.494953647https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xot1Glu7o%253D&md5=9ae77edd84e1d02e4eef2bdea9744f37Push it to the limit: Characterizing the convergence of common sequences of basis sets for intermolecular interactions as described by density functional theoryWitte, Jonathon; Neaton, Jeffrey B.; Head-Gordon, MartinJournal of Chemical Physics (2016), 144 (19), 194306/1-194306/12CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)With the aim of systematically characterizing the convergence of common families of basis sets such that general recommendations for basis sets can be made, we have tested a wide variety of basis sets against complete-basis binding energies across the S22 set of intermol. interactions-noncovalent interactions of small and medium-sized mols. consisting of first- and second-row atoms-with three distinct d. functional approxns.: SPW92, a form of local-d. approxn.; B3LYP, a global hybrid generalized gradient approxn.; and B97M-V, a meta-generalized gradient approxn. with nonlocal correlation. We have found that it is remarkably difficult to reach the basis set limit; for the methods and systems examd., the most complete basis is Jensen's pc-4. The Dunning correlation-consistent sequence of basis sets converges slowly relative to the Jensen sequence. The Karlsruhe basis sets are quite cost effective, particularly when a correction for basis set superposition error is applied: counterpoise-cor. def2-SVPD binding energies are better than corresponding energies computed in comparably sized Dunning and Jensen bases, and on par with uncorrected results in basis sets 3-4 times larger. These trends are exhibited regardless of the level of d. functional approxn. employed. A sense of the magnitude of the intrinsic incompleteness error of each basis set not only provides a foundation for guiding basis set choice in future studies but also facilitates quant. comparison of existing studies on similar types of systems. (c) 2016 American Institute of Physics.
- 48Finneran, I. A.; Carroll, P. B.; Allodi, M. A.; Blake, G. A. Hydrogen Bonding in the Ethanol–Water Dimer. Phys. Chem. Chem. Phys. 2015, 17, 24210– 24214, DOI: 10.1039/C5CP03589A48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVahtb7O&md5=812c0632f255d6007495752f3d5694b2Hydrogen bonding in the ethanol-water dimerFinneran, Ian A.; Carroll, P. Brandon; Allodi, Marco A.; Blake, Geoffrey A.Physical Chemistry Chemical Physics (2015), 17 (37), 24210-24214CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)We report the first rotational spectrum of the ground state of the isolated ethanol-water dimer using chirped-pulse Fourier transform microwave spectroscopy between 8-18 GHz. With the aid of isotopic substitutions, and ab initio calcns., we identify the measured conformer as a water-donor/ethanol-acceptor structure. Ethanol is found to be in the gauche conformation, while the monomer distances and orientations likely reflect a cooperation between the strong (O-H···O) and weak (C-H···O) hydrogen bonds that stabilizes the measured conformer. No other conformers were assigned in an argon expansion, confirming that this is the ground-state structure. This result is consistent with previous vibrationally-resolved Raman and IR work, but sheds addnl. light on the structure, due to the specificity of rotational spectroscopy.
- 49PubChem Annotation Record for Sulfuric Acid. Hazardous Substances Data Bank (HSDB); National Center for Biotechnology Information, 2021.There is no corresponding record for this reference.
- 50Köckinger, M.; Hanselmann, P.; Roberge, D. M.; Geotti-Bianchini, P.; Kappe, C. O.; Cantillo, D. Sustainable Electrochemical Decarboxylative Acetoxylation of Aminoacids in Batch and Continuous Flow. Green Chem. 2021, 23, 2382– 2390, DOI: 10.1039/D1GC00201EThere is no corresponding record for this reference.
- 51Steiner, A.; Williams, J. D.; de Frutos, O.; Rincón, J. A.; Mateos, C.; Kappe, C. O. Continuous Photochemical Benzylic Bromination Using in Situ Generated Br2: Process Intensification towards Optimal PMI and Throughput. Green Chem. 2020, 22, 448– 454, DOI: 10.1039/C9GC03662H51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlGhurvP&md5=e5c553cd71cc781f93e033b74e373a8aContinuous photochemical benzylic bromination using in situ generated Br2: process intensification towards optimal PMI and throughputSteiner, Alexander; Williams, Jason D.; de Frutos, Oscar; Rincon, Juan A.; Mateos, Carlos; Kappe, C. OliverGreen Chemistry (2020), 22 (2), 448-454CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)The detailed development of photochem. benzylic brominations using a NaBrO3/HBr bromine generator in continuous flow mode is reported. Optimization of the bromine generator enables highly efficient mass utilization by HBr recycling, coupled with fast interphase transfer within a microstructured photochem. reactor (405 nm LEDs). Intensification of the reaction system, including complete removal of org. solvent, allowed a redn. in PMI from 13.25 to just 4.33. The photochem. transformation achieved exceptionally high throughput, providing complete conversion in residence times as low as 15 s. The org. solvent-free prepn. of two pharmaceutically relevant building blocks was demonstrated with outstanding mass efficiency, by monobromination (1.17 kg scale in 230 min, PMI = 3.08) or dibromination (15 g scale in 20 min, PMI = 3.64).
- 52Prieschl, M.; García-Lacuna, J.; Munday, R.; Leslie, K.; O’Kearney-McMullan, A.; Hone, C. A.; Kappe, C. O. Optimization and Sustainability Assessment of a Continuous Flow Ru-Catalyzed Ester Hydrogenation for an Important Precursor of a Β2-Adrenergic Receptor Agonist. Green Chem. 2020, 22, 5762– 5770, DOI: 10.1039/D0GC02225J52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFKksr%252FJ&md5=8bcd00e8bdbf6c016c9b5c82e79e05c7Optimization and sustainability assessment of a continuous flow Ru-catalyzed ester hydrogenation for an important precursor of a β2-adrenergic receptor agonistPrieschl, Michael; Garcia-Lacuna, Jorge; Munday, Rachel; Leslie, Kevin; O'Kearney-McMullan, Anne; Hone, Christopher A.; Kappe, C. OliverGreen Chemistry (2020), 22 (17), 5762-5770CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H2) gas is reported. The reaction was utilized for the redn. of an important precursor in the synthesis of abediterol, a β2-adrenoceptor agonist that has undergone phase IIa clin. trials for the treatment of asthma and chronic obstructive pulmonary disorder. The reaction was investigated within a batch autoclave by using a design of expts. (DoE) approach to identify important parameter effects. The optimized flow process was successfully operated over 6 h with inline benchtop 19F NMR spectroscopy for reaction monitoring. The protocol is shown to be high yielding (98% yield, 3.7 g h-1) with very low catalyst loading (0.065 mol%). The environmental impact of the Ru-catalyzed hydrogenation was assessed and compared to an existing stoichiometric lithium aluminum hydride (LAH) redn. and sodium borohydride (NaBH4) redn. The process mass intensity (PMI) for the Ru-catalyzed hydrogenation (14) compared favorably to a LAH redn. (52) and NaBH4 redn. (133).
- 53Adamo, A.; Heider, P. L.; Weeranoppanant, N.; Jensen, K. F. Membrane-Based, Liquid–Liquid Separator with Integrated Pressure Control. Ind. Eng. Chem. Res. 2013, 52, 10802– 10808, DOI: 10.1021/ie401180t53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVCrsrzM&md5=d01e4234f23bde47c3cdeaf79a153a8aMembrane-based, liquid-liquid separator with integrated pressure controlAdamo, Andrea; Heider, Patrick L.; Weeranoppanant, Nopphon; Jensen, Klavs F.Industrial & Engineering Chemistry Research (2013), 52 (31), 10802-10808CODEN: IECRED; ISSN:0888-5885. (American Chemical Society)We describe the development and application of an improved, membrane-based, liq.-liq. separator. Membrane-based sepn. relies on the exploitation of surface forces and the use of a membrane wetted by one of the phases; however, successful sepn. requires accurate control of pressures, making the operation and implementation cumbersome. Here we present an improved separator design that integrates a pressure control element to ensure that adequate operating conditions are always maintained. Addnl., the integrated pressure control decouples the separator from downstream unit operations. A detailed examn. of the controlling phys. equations shows how to design the device to allow operation across a wide range of conditions. Easy to implement, multistage sepns. such as solvent swaps and countercurrent extns. are demonstrated. The presented design significantly simplifies applications ranging from multistep synthesis to complex multistage sepns.
- 54Chapman, M. R.; Kwan, M. H. T.; King, G.; Jolley, K. E.; Hussain, M.; Hussain, S.; Salama, I. E.; González Nino, C.; Thompson, L. A.; Bayana, M. E.; Clayton, A. D.; Nguyen, B. N.; Turner, N. J.; Kapur, N.; Blacker, A. J. Simple and Versatile Laboratory Scale CSTR for Multiphasic Continuous-Flow Chemistry and Long Residence Times. Org. Process Res. Dev. 2017, 21, 1294– 1301, DOI: 10.1021/acs.oprd.7b0017354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVOntrvO&md5=c89c9bf886fcd92bd1f78b9aa7dd292bSimple and Versatile Laboratory Scale CSTR for Multiphasic Continuous-Flow Chemistry and Long Residence TimesChapman, Michael R.; Kwan, Maria H. T.; King, Georgina; Jolley, Katherine E.; Hussain, Mariam; Hussain, Shahed; Salama, Ibrahim E.; Gonzalez Nino, Carlos; Thompson, Lisa A.; Bayana, Mary E.; Clayton, Adam D.; Nguyen, Bao N.; Turner, Nicholas J.; Kapur, Nikil; Blacker, A. JohnOrganic Process Research & Development (2017), 21 (9), 1294-1301CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A universal multi-stage cascade CSTR has been developed which is suitable for a wide range of continuous-flow processes. Coined by authors group the 'Freactor' (free-to-access reactor), the new reactor integrates the efficiency of pipe-flow processing with the advanced mixing of a CSTR, delivering a general 'plug-and-play' reactor platform which is well-suited to multiphasic continuous-flow chem. Importantly, the reactor geometry is easily customized to accommodate reactions requiring long residence times (≥ 3 h tested).
- 55Becker, J.; Manske, C.; Randl, S. Green Chemistry and Sustainability Metrics in the Pharmaceutical Manufacturing Sector. Curr. Opin. Green Sustainable Chem. 2022, 33, 100562, DOI: 10.1016/j.cogsc.2021.10056255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsVOiur7L&md5=15ca54e8fff23975206484d7eb479094Green chemistry and sustainability metrics in the pharmaceutical manufacturing sectorBecker, Jochen; Manske, Carolin; Randl, StefanCurrent Opinion in Green and Sustainable Chemistry (2022), 33 (), 100562CODEN: COGSC4; ISSN:2452-2236. (Elsevier B.V.)This review article summarizes recent developments of green chem. and sustainability metrics with a focus on the pharmaceutical industry. We discuss synergies and discrepancies of the green chem. principles with regulatory guidelines in the field of pharmaceutical process development and manufg. under Good Manufg. Practices (GMP). This review captures selected views and publications on green chem. and sustainability metrics. It discusses two recent process development highlights from the pharmaceutical industry which use different approaches to optimize the process mass intensity (PMI) of small-mol. active pharmaceutical ingredient (API) manufg. processes. The first example is the development of green process conditions by switching reaction media from org. solvents to micellar catalysis in water in the Takeda process of the API TAK-954. The second example features process intensifications accomplished by the application of innovative technologies in pharmaceutical processing in the Merck process of the API MK-7264.
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