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Chemical Structure| 1208-52-2 Chemical Structure| 1208-52-2

Structure of 1208-52-2

Chemical Structure| 1208-52-2

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Product Citations

Product Citations

Maria Hoppe ; Margit Gmeiner ; Petra Schmid ;

Abstract: Primary aromatic amines (PAAs) may be found in food contact materials and can potentially migrate from packaging material into the packed foodstuffs. Certain members of this substance class are of particular concern due to their toxicological properties. Legislators and authorities require a risk assessment regarding the transfer of PAAs into food. The evaluation of PAAs’ migration into food relies on migration or extraction tests using aqueous and acidic food simulants or solvents. However, PAAs exhibit stability issues in acidic media, which could lead to an underestimation of migration. Therefore, a systematic stability study was conducted for 28 PAAs in 3% acetic acid and water at different storage conditions. Standard solutions of 2 and 10 ng/ml of the amines in these media were prepared and stored under the following conditions: 2 h at 40 °C, 70 °C, and 100 °C, and 10 days at − 20 °C, 4 °C, 20 °C, 40° C, and 60 °C. The test solutions were analyzed using liquid chromatography coupled to mass spectrometry, and recovery was calculated against freshly prepared standard solutions. It was found that several PAAs undergo a loss of recovery under the investigated conditions; 7 of the substances were identified to be the most unstable: 3,3ʹ-dimethoxybenzidine, 3,3ʹ-dimethylbenzidine, 6-methoxy-m-toluidine, 4-methoxy-m-phenylendiamine, 2,6-toluenediamine, benzidine and 2,4-toluenediamine. It was concluded that both time and storage temperature play a pivotal role in the stability of PAAs. The experiments also demonstrated that PAAs exhibit greater stability in water than in 3% acetic acid.

Keywords: Primary aromatic amines ; Food contact materials ; Migration and extraction testing ; PAA stability

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Product Details of [ 1208-52-2 ]

CAS No. :1208-52-2
Formula : C13H14N2
M.W : 198.26
SMILES Code : NC1=CC=C(CC2=C(N)C=CC=C2)C=C1
MDL No. :MFCD01670227
InChI Key :UTNMPUFESIRPQP-UHFFFAOYSA-N
Pubchem ID :14580

Safety of [ 1208-52-2 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H301+H311+H331-H317-H319-H341-H410
Precautionary Statements:P261-P273-P280-P301+P310-P305+P351+P338
Class:6.1
UN#:2811
Packing Group:

Computational Chemistry of [ 1208-52-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 12
Fraction Csp3 0.08
Num. rotatable bonds 2
Num. H-bond acceptors 0.0
Num. H-bond donors 2.0
Molar Refractivity 64.7
TPSA ?

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

52.04 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.73
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

2.18
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.

2.69
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

2.42
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.29

Water Solubility

Log S (ESOL):?

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

-2.9
Solubility 0.248 mg/ml ; 0.00125 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.

-2.91
Solubility 0.246 mg/ml ; 0.00124 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

-4.61
Solubility 0.00492 mg/ml ; 0.0000248 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

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

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

Yes
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.

-5.96 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

1.0
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.

1.0 alert
Brenk?

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

1.0 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)

1.48

Application In Synthesis of [ 1208-52-2 ]

* 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 [ 1208-52-2 ]
  • Downstream synthetic route of [ 1208-52-2 ]

[ 1208-52-2 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 50-00-0 ]
  • [ 62-53-3 ]
  • [ 1208-52-2 ]
  • [ 6582-52-1 ]
  • [ 101-77-9 ]
YieldReaction ConditionsOperation in experiment
44.5%
Stage #1: at 25 - 80℃;
Stage #2: at 45 - 140℃; for 2.5 - 2.83333 h;
Stage #3: With sodium hydroxide In water at 100℃;
Example 1 a) Preparation of the polyamine mixture: In a stirred vessel, 2600 g of aniline were intimately mixed at 25°C with 1000 g of formalin (30 wt.percent aqueous solution), with stirring until the mixture warmed up to 60°C. The stirrer was stopped and the upper, aqueous phase was separated off. 68 g of 30 wt.percent aqueous hydrochloric acid were then admixed, with renewed stirring and cooling. The temperature was kept at 45°C. After stirring for a further 15 min at this temperature, the cooling was replaced by heating and the mixture was heated uniformly to 140°C over 120 min under 5 bar pressure and then kept at this temperature for 15 min. The mixture was then cooled to 100°C, let down to normal pressure and neutralized by adding 54 g of 50 wt.percent aqueous sodium hydroxide solution, with stirring. After the stirrer had been stopped, the phases were left to settle and the lower, aqueous phase was siphoned off. Excess aniline with residual water was then distilled off, initially under normal pressure, and the aniline residues were removed by distilling the resulting polyamine mixture at 100 mbar and 250°C. This yielded 1900 g of a polyamine mixture having the following composition: 4,4'-MDA: 60.1 wt.percent2,4'-MDA: 6.0 wt.percent2,2'-MDA: 0.2 wt.percenthigher-molecular polyamines: 33.7 wt.percent; Example 2 a) Preparation of the polyamine mixture: In a stirred vessel, 1800 g of aniline were intimately mixed at 30°C with 1000 g of formalin (30 wt.percent aqueous solution), with stirring. The mixture was warmed up to 80°C. The stirrer was stopped and the upper, aqueous phase was separated off. 23 g of 30 wt.percent aqueous hydrochloric acid were then admixed, with renewed stirring and cooling. The temperature was kept at 45°C. After stirring for a further 15 min at this temperature, the cooling was replaced by heating and the mixture was heated uniformly to 140°C over 150 min under 5 bar pressure and then kept at this temperature for 20 min. The mixture was then cooled to 100°C, let down to normal pressure and neutralized by adding 18 g of 50 wt.percent aqueous sodium hydroxide solution, with stirring. After the stirrer had been stopped, the phases were left to settle and the lower, aqueous phase was siphoned off. Excess aniline with residual water was then distilled off, initially under normal pressure, and the aniline residues were removed by distilling the resulting polyamine mixture at 100 mbar and 250°C. This gave 1880 g of a polyamine mixture having the following composition: 4,4'-MDA: 44.5 wt.percent2,4'-MDA: 7.3 wt.percent2,2'-MDA: 0.5 wt.percenthigher-molecular polyamines: 47.7 wt.percent
References: [1] Patent: EP1734035, 2006, A1, . Location in patent: Page/Page column 5-6.
  • 2
  • [ 50-00-0 ]
  • [ 62-53-3 ]
  • [ 1208-52-2 ]
  • [ 6582-52-1 ]
  • [ 101-77-9 ]
References: [1] Patent: US2007/117997, 2007, A1, . Location in patent: Page/Page column 3; 4.
[2] Patent: US2007/265465, 2007, A1, . Location in patent: Page/Page column 4.
[3] Applied Catalysis A: General, 2011, vol. 398, # 1-2, p. 143 - 149.
  • 3
  • [ 50-00-0 ]
  • [ 98-95-3 ]
  • [ 62-53-3 ]
  • [ 1208-52-2 ]
  • [ 6582-52-1 ]
  • [ 101-77-9 ]
References: [1] Patent: US2006/183938, 2006, A1, . Location in patent: Page/Page column 4.
  • 4
  • [ 50-00-0 ]
  • [ 142-04-1 ]
  • [ 1208-52-2 ]
  • [ 6582-52-1 ]
  • [ 101-77-9 ]
YieldReaction ConditionsOperation in experiment
66.75 %Chromat.
Stage #1: at 38 - 90℃;
Stage #2: With sodium hydroxide In water
Example 1:; Hydrochloric acid (a concentration percentage by weight is 30.8percent, this hydrochloric acid is a by-product from MDI apparatus) from storage tank 2 and aniline from storage tank 3 are fed into venturi mixer 5 by a pump 6 with a molar ratio of hydrochloric acid/anilin=0.36:1, for mixing and reacting with each other to produce aniline hydrochloride which is then pumped into circulation pipes and mixed with a circulation solution coming from a condensation stirred vessel 1 to obtain a mixed solution. The obtained mixed solution is introduced into a heat exchanger 7 to remove the reaction heat, and the mixed solution, which is cooled to 38°C and left the heat exchanger 7, is introduced into a feeding port of the high gravity rotating bed reactor 8 of rotating packed bed type. Formaldehyde solution (a concentration percentage by weight is 37 wtpercent) stream from storage tank 4 is fed through another feeding port of the high gravity rotating bed reactor 8, the ratio of formaldehyde to aniline is controlled at 0.40:1. The formaldehyde solution is mixed sufficiently with the previously mixed solution phase and conducted a pre-condensation reaction in the high gravity rotating bed reactor 8, the reaction temperature is controlled at 35°C, the reaction time is 0.5 sec, and the rotation speed of the rotor of high gravity rotating bed reactor is 1000rpm. Then the mixed reaction solution flows into the condensation reaction vessel 1 to proceed with the pre-condensation reaction, the temperature of reaction solution is controlled at 42°C, the stirring speed is about 110rpm, and the reaction residence time is about 20 min. Then the temperature of reaction solution is elevated to over 90°C to conduct a molecular rearrangement reaction, the residence time for molecular rearrangement reaction is about 2 hours. Finally a solution of diphenylmethylene diamine hydrochloride and polymethylene polyphenyl polyamines hydrochloride is obtained. 92 vol percent of the reaction mixture from the condensation reaction vessel 1 returns to the circulation pipes, as circulation solution, and flows to heat exchanger 7, the other 8 vol percent of the reaction mixture is discharged and neutralized with a sodium hydroxide solution at a concentration of 42 wtpercent. The salt water phase is separated from the polyamine organic phase, and the polyamines are washed with water and purified to finally obtain a mixture of diphenylmethylene diamine and polymethylene polyphenyl polyamines. The composition of products is listed in table 2.
References: [1] Patent: EP2145874, 2010, A1, . Location in patent: Page/Page column 6.
  • 5
  • [ 1208-52-2 ]
  • [ 6582-52-1 ]
  • [ 101-77-9 ]
References: [1] Tetrahedron Letters, 1986, vol. 27, # 17, p. 1887 - 1890.
  • 6
  • [ 101-77-9 ]
  • [ 1208-52-2 ]
  • [ 6582-52-1 ]
References: [1] Tetrahedron Letters, 1986, vol. 27, # 17, p. 1887 - 1890.
  • 7
  • [ 50-00-0 ]
  • [ 62-53-3 ]
  • [ 1208-52-2 ]
  • [ 6582-52-1 ]
  • [ 26628-67-1 ]
  • [ 101-77-9 ]
References: [1] Journal fuer Praktische Chemie (Leipzig), 1986, vol. 328, # 1, p. 142 - 148.
 

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