Using hyperpolarised NMR and DFT to rationalise the unexpected hydrogenation of quinazoline to 3,4-dihydroquinazoline

Richards, Josh E.; Hooper, Alexander J. J.; Bayfield, Oliver W.; Cockett, Martin C. R.; Dear, Gordon J.; Holmes, Amy; John, Richard O.; Mewis, Ryan E.; Pridmore, Natalie E.; Roberts, Andy D.; Whitwood, Adrian C.; Duckett, Simon B.

doi:10.1039/c8cc04826f

“…An iridium centred catalyst is typically employed to propagate polarisation, via J‐coupling, between the para hydrogen derived hydrides and the spin‐

1 / 2

nuclei of the analyte molecule being polarised . The pre‐catalyst, [Ir(IMes)(COD)Cl] (IMes=1,3‐ bis (2,4,6‐trimethylphenyl)imidazole‐2‐ylidene, COD=cyclooctadiene) has been shown to be an excellent catalyst, following activation, in this regard for a number of substrates such as nicotinamide, quinazoline, and niacin . Manipulation of the spin‐reservoir of the substrate, such as deuteration, has been shown to be an effective route by which polarization can be maximized.…”

Section: Introductionmentioning

confidence: 99%

Hyperpolarization of Pyridyl Fentalogues by Signal Amplification By Reversible Exchange (SABRE)

Robertson

¹

,

Antonides

²

,

Gilbert

³

et al. 2019

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Fentanyl, also known as 'jackpot', is a synthetic opiate that is 50-100 times more potent than morphine. Clandestine laboratories produce analogues of fentanyl, known as fentalogues to circumvent legislation regarding its production. Three pyridyl fentalogues were synthesized and then hyperpolarized by signal amplification by reversible exchange (SABRE) to appraise the forensic potential of the technique. A maximum enhancement of -168-fold at 1.4 T was recorded for the ortho pyridyl 1 H nuclei. Studies of the activation parameters for the three fentalogues revealed that the ratio of ligand loss trans to hydride and hydride loss in the complex [Ir(IMes)(L) 3 (H) 2 ] + (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene) ranged from 0.52 to 1.83. The fentalogue possessing the ratio closest to unity produced the largest enhancement subsequent to performing SABRE at earth's magnetic field. It was possible to hyperpolarize a pyridyl fentalogue selectively from a matrix that consisted largely of heroin (97 : 3 heroin:fentalogue) to validate the use of SABRE as a forensic tool.

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“…The presence of 1, 2 and 3 is 37 confirmed by the data presented in the main text. 38 39 2 Pre-catalyst [IrCl(IMes)(COD)] (11 mM) was dissolved in 600 µL of pyridine-d5, yielding a 66 light to dark yellow solution. The solution was exposed to hydrogen in a pressure tube at 10 bar 67 for 2 hours, until it turned into a light yellow liquid.…”

mentioning

confidence: 99%

Indirect Detection of Short-lived Hydride Intermediates of Iridium N-Heterocyclic Carbene Complexes via Chemical Exchange Saturation Transfer (CEST) Spectroscopy

Knecht¹,

Hadjiali²,

Barskiy³

et al. 2019

Preprint

1

0

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For the first time chemical-exchange saturation transfer (CEST) 1H NMR is utilized for the study of short-lived hydride intermediates in the catalytic cycle of the Iridium-based organometallic complex [Ir(IMes)(Py)3(H)2]Cl, which are often not observable by other NMR techniques, since they are low concentrated, and undergo reversible ligand exchange with the main complex. The intermediate complexes [Ir(Cl)(IMes)(Py)2(H)2] and [Ir(CD3OD)(IMes) (Py)2(H)2] are detected, assigned and characterized in situ and at room temperature in solution. Understanding the effects on the spin dynamics induced by these complexes is necessary for enhancing the performance of the nuclear spin hyperpolarization technique SABRE (Signal Amplification By Reversible Exchange). By eliminating [Ir(Cl)(IMes)(Py)2(H)2] and manipulating the spin-system by RF-irradiation, we were able to increase the nuclear spin singlet lifetime of the two protons in the main hydride complex by more than an order of magnitude, from 2.2±0.1 s to 27.2±1.2 s. The presented CEST NMR approach has a large application potential for studying short-lived hydride intermediates in catalytic reactions.

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“…In a previous study 32 , weak peaks with similar chemical shifts were observed at low temperature and were assigned to the solvent-binding complex [Ir(IMes)(Py)2(CD3OD)(H)2] + Cl -. A more recent study 39 , however, reported similar chemical shift values (-22.77 ppm and −23.78 ppm) for the complex…”

mentioning

confidence: 52%

Indirect Detection of Short-lived Hydride Intermediates of Iridium N-Heterocyclic Carbene Complexes via Chemical Exchange Saturation Transfer (CEST) Spectroscopy

Knecht¹,

Hadjiali²,

Barskiy³

et al. 2019

Preprint

0

View full text Add to dashboard Cite

For the first time chemical-exchange saturation transfer (CEST) 1H NMR is utilized for the study of short-lived hydride intermediates in the catalytic cycle of the Iridium-based organometallic complex [Ir(IMes)(Py)3(H)2]Cl, which are often not observable by other NMR techniques, since they are low concentrated, and undergo reversible ligand exchange with the main complex. The intermediate complexes [Ir(Cl)(IMes)(Py)2(H)2] and [Ir(CD3OD)(IMes) (Py)2(H)2] are detected, assigned and characterized in situ and at room temperature in solution. Understanding the effects on the spin dynamics induced by these complexes is necessary for enhancing the performance of the nuclear spin hyperpolarization technique SABRE (Signal Amplification By Reversible Exchange). By eliminating [Ir(Cl)(IMes)(Py)2(H)2] and manipulating the spin-system by RF-irradiation, we were able to increase the nuclear spin singlet lifetime of the two protons in the main hydride complex by more than an order of magnitude, from 2.2±0.1 s to 27.2±1.2 s. The presented CEST NMR approach has a large application potential for studying short-lived hydride intermediates in catalytic reactions.

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Using hyperpolarised NMR and DFT to rationalise the unexpected hydrogenation of quinazoline to 3,4-dihydroquinazoline

Abstract: Hyperpolarised NMR allows the tracking of the DFT-rationalised outer sphere hydrogenation of quinazoline.

Cited by 13 publications

References 60 publications

Hyperpolarization of Pyridyl Fentalogues by Signal Amplification By Reversible Exchange (SABRE)

Hyperpolarization of Pyridyl Fentalogues by Signal Amplification By Reversible Exchange (SABRE)

Indirect Detection of Short-lived Hydride Intermediates of Iridium N-Heterocyclic Carbene Complexes via Chemical Exchange Saturation Transfer (CEST) Spectroscopy

Indirect Detection of Short-lived Hydride Intermediates of Iridium N-Heterocyclic Carbene Complexes via Chemical Exchange Saturation Transfer (CEST) Spectroscopy

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