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Chemical Structure| 142946-79-0

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Michelle Elizabeth Akana ;

Abstract: This dissertation will discuss advancements made toward understanding the intrinsic reactivity of nitrogenous ligands in nickel-catalyzed cross-electrophile coupling, as well as their impacts on reaction selectivities. Chapter 1 will introduce cross-electrophile coupling, highlight the importance of ligands in promoting diverse elementary steps, and discuss strategies to search for, understand, and improve ligand architecture. Chapter 2 describes our initial investigation utilizing descriptors from a diverse set of ligands and ligand-like molecules to predict reaction yield and selectivity. This investigation provided critical insight into experimental design, construction of a training set, and determining project outcomes. The results of these efforts informed our studies that are detailed in successive chapters. Chapter 3 summarizes the application of statistical methods to develop a model for selectivity in bipyridine-nickel-catalyzed cross-electrophile coupling. The resulting model was used to rationalize experimental outcomes, develop mechanistic insight, and design improved ligands in silico. Chapter 4 summarizes initial insights into the relationships between the structure of other classes of heterocycle-based L2 dinitrogen ligands and their corresponding experimental outcomes. These investigations provide a basis for understanding the performance of these ligands and expands on the insights described in Chapter 3. A plan for ongoing research informed by these results is proposed. Chapter 5 describes additional computationally informed projects that were undertaken by the author. These projects utilize computed catalyst structures and energies to rationalize the impact of ligand binding on the reactivity of novel 2,2’-bipyridine-6-carbonitrile ligands, as well as the relationship of ligand structure to selectivity in decarbonylative cross-electrophile coupling.

Purchased from AmBeed: ;

Qiao Lin ; Ethan H. Spielvogel ; Tianning Diao ;

Abstract: The capture of carbon-centered radicals at a nickel(II) center is commonly featured in recent cross-coupling and metallaphotoredox catalytic reactions. Despite its widespread application in catalysis, this fundamental step lacks experimental characterization. This report portrays radical capture at catalytically relevant nickel(II) centers from several aspects, including the structure-activity relationships of the ligands, the mechanism, the kinetics, and the stereoselectivity. Spectroscopic data provide evidence for the formation of a nickel(III) intermediate. Strikingly different reactivity between nickel-aryl and nickel-alkyl complexes implies different rate-determining steps for C(sp3)–C(sp3) and C(sp2)–C(sp3) bond formation. Kinetic data benchmark the capture rates on the scale of 10[7] M−1s−1 and 10[6] M−1s−1 for primary and secondary radicals, respectively. Overall, the activation energy is higher than that of previous computational estimations. Finally, stoichiometric experiments with well-defined chiral nickel complexes demonstrate that the radical trapping step can confer diastereoselectivity and enantioselectivity with a drastic ligand effect.

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Product Details of [ 142946-79-0 ]

CAS No. :142946-79-0
Formula : C12H6F6N2
M.W : 292.18
SMILES Code : FC(C1=CC(C2=NC=CC(C(F)(F)F)=C2)=NC=C1)(F)F
MDL No. :MFCD00233878
InChI Key :FFOMEQIMPYKURW-UHFFFAOYSA-N
Pubchem ID :12058766

Safety of [ 142946-79-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338

Computational Chemistry of [ 142946-79-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 20
Num. arom. heavy atoms 12
Fraction Csp3 0.17
Num. rotatable bonds 3
Num. H-bond acceptors 8.0
Num. H-bond donors 0.0
Molar Refractivity 57.47
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

25.78 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.7
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

3.25
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

6.49
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.81
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

4.46
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.94

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.95
Solubility 0.0332 mg/ml ; 0.000113 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-3.47
Solubility 0.1 mg/ml ; 0.000343 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-5.93
Solubility 0.000339 mg/ml ; 0.00000116 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

Low
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

Yes
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.77 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

1.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.22

Application In Synthesis of [ 142946-79-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 142946-79-0 ]

[ 142946-79-0 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 175205-81-9 ]
  • [ 142946-79-0 ]
YieldReaction ConditionsOperation in experiment
56% With palladium diacetate; potassium carbonate; at 120℃; for 48h;Inert atmosphere; General procedure: 2-Iodopyrazine (5.00 g, 24.3 mmol), PdII(OAc)2 (34 mg, 0.151 mmol), K2CO3 (3.4 g, 24.6 mmol) and poly(ethylene glycol) (Mw 4000, 24.0 g) were combined in an argon-purged flask. The mixture was gradually heated to 120 C and the temperature maintained for 48 h with stirring. The mixture was cooled to ca. 80 C and warm water (30 mL) was added to prevent solidification. On cooling to room temperature, further water (100 mL) was added and the suspension exhaustively extracted with ethyl acetate. The combined extracts were washed once with saturated aqueous Na2S2O3 and then thrice with brine. The organic layer was dried over MgSO4 and solvent removed under vacuum. The residue was triturated with n-pentane and the white crystalline solid filtered off, washed with n-pentane and dried. Yield: 1.35 g (70%).
52% 2.2 Synthesis of 4,4'-bis(trifluoromethyl)-2,2'-bipyridine 2-Bromo-4-trifluoromethyl pyridine (1.2 g, 5.31 mmol) was placed in a round bottom flask with 7.14 g of activated copper bronze. The reaction flask was then flushed with N2 and a reflux condenser was affixed. The reaction was then heated to 190 C for 16 h. The reaction was then cooled to room temperature and the ligand extracted with acetone and chloroform (?100 mL). The organic fraction was then extracted with 1.2 N HCl. Once the aq. fraction turned blue, the organic fraction was extracted then evaporated to afford a yellow oil. The ligand was then purified by vacuum sublimation (52% yield). Spectroscopic data matched literature values [12] .
 

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