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Product Citations

Product Citations

Denman, Brylon N ;

Abstract: The highly reactive nature of arynes has been leveraged to make many value-added species. Despite this success, synthetic applications of aryne methodology remain limited by regioselectivity challenges. Additionally, regioselectivity issues can be especially prohibitive in metal-mediated aryne reactions as now additional interactions of the metals, ligands, and substrates contribute to regioinduction. Investigating regioselectivity of metal-bound arynes is crucial to expanding aryne methodology as some transformations can only occur through metal-mediated processes. To induce regioselectivity in metal-catalyzed aryne reactions, we postulated that ligands could be used to control the binding and subsequent functionalization of the aryne. To test this hypothesis, we used a palladium-catalyzed aryne annulation originally developed by Larock and coworkers as a model reaction. We found we can induce regioselectivity by using an unsymmetric (C1) monodentate ligand environment. Bulky monodentate phosphine ligands such as tri-tert-butylphosphine (PtBu3) gave the best combination of regioselectivity and yield. This system was compared to a symmetric (C2) ligand system that Larock and coworkers found optimal. Through these studies we provided the first evidence that ligands can be used to intentionally induce regioselectivity within aryne reactions. To further explore the origins of regioselectivity, we explored the molecular parameters responsible for regioselectivity via linear free energy relationships (LFER) and multivariate linear regression. To study how steric encumbrance influences regioselectivity, we performed Charton analysis on the aryne substituent and the ligand. These results showed that the ligand can amplify steric effects of the aryne substituent to increase regioselectivity. To study electronic effects, Hammett parameters of the aryne substituent were investigated and from these studies it was found that inductive effects influence regioselectivity. Having decoded the contribution of steric and electronic effects on regioselectivity independently, we next sought to create a more comprehensive regioselectivity model via multivariate linear regression. This model shows that both while both steric and electronic effects influence regioselectivity, steric encumbrance is a larger contributor to regioselectivity. Additionally, the mechanism and elementary steps of the catalytic cycle of the palladium-catalyzed annulation were investigated. Kinetic studies show aryne generation is the turnover-limiting step of the catalytic cycle. Upon testing the generality of this regioselectivity inducing approach in other aryne systems, we discovered that two operative pathways can occur to generate carbazoles within a palladium-catalyzed annulation reaction. Additionally, these reaction pathways can be controlled by the identity of the ligand. By using CataCXium® A as ligand, we can force the o-boryaryl triflate substrates to undergo a cross-coupling pathway rather than an aryne pathway.

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Product Details of [ 13319-71-6 ]

CAS No. :13319-71-6
Formula : C7H7BrO
M.W : 187.03
SMILES Code : CC1=CC=CC(Br)=C1O
MDL No. :MFCD09907876
InChI Key :YXZPTVOCJLCMRO-UHFFFAOYSA-N
Pubchem ID :11095329

Safety of [ 13319-71-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 13319-71-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 41.13
TPSA ?

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

20.23 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.11
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

2.86
Log Po/w (WLOGP)?

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

2.46
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.

2.57
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

2.5
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.5

Water Solubility

Log S (ESOL):?

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

-3.29
Solubility 0.0949 mg/ml ; 0.000507 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.

-2.94
Solubility 0.213 mg/ml ; 0.00114 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

-3.06
Solubility 0.162 mg/ml ; 0.000865 mol/l
Class?

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

Soluble

Pharmacokinetics

GI absorption?

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

High
BBB permeant?

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

Yes
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

No
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.

-5.41 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

0.0
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

2.0
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<1.0
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)

1.05

Application In Synthesis of [ 13319-71-6 ]

* 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.

  • Upstream synthesis route of [ 13319-71-6 ]

[ 13319-71-6 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 13319-71-6 ]
  • [ 98-80-6 ]
  • [ 17755-10-1 ]
References: [1] Organic and Biomolecular Chemistry, 2005, vol. 3, # 24, p. 4307 - 4309.
 

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