N-(Hydroxymethyl)phthalimide

N-(Hydroxymethyl)phthalimide Property

Melting point:

147-149 °C (lit.)

Boiling point:

309.06°C (rough estimate)

Density 

1.3312 (rough estimate)

refractive index 

1.5200 (estimate)

storage temp. 

Store below +30°C.

pka

13.17±0.10(Predicted)

form 

Fine Crystalline Powder

color 

White

BRN 

140946

InChI

InChI=1S/C9H7NO3/c11-5-10-8(12)6-3-1-2-4-7(6)9(10)13/h1-4,11H,5H2

InChIKey

MNSGOOCAMMSKGI-UHFFFAOYSA-N

SMILES

C1(=O)C2=C(C=CC=C2)C(=O)N1CO

CAS DataBase Reference

118-29-6(CAS DataBase Reference)

NIST Chemistry Reference

1H-isoindole-1,3(2h)-dione, 2-(hydroxymethyl)-(118-29-6)

EPA Substance Registry System

N-(Hydroxymethyl)phthalimide (118-29-6)

Safety

Safety Statements 

22-24/25

WGK Germany 

3

RTECS 

TI5270000

TSCA 

Yes

HS Code 

29251995

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P304+P340IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P405Store locked up.

N-(Hydroxymethyl)phthalimide Chemical Properties,Usage,Production

Chemical Properties

white crystalline powder

Uses

N-(Hydroxymethyl)phthalimide is used as a reactant in the synthesis of 5-[(3-aralkyl amido/imidoalkyl)phenyl]-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines as antiviral agents.

Uses

For amidomethylation of aromatics in triflic acid.

Preparation

To a flask equipped with a mechanical stirrer and condenser is added 511 gm (3.47 moles) of phthalimide, 260 ml of 40% formalin (3.47 moles), and 1750 ml of water. The mixture is refluxed for about 5-10 min or until a clear solution results (if any insoluble material remains, it is first filtered). Then the mixture is cooled for several hours. The resulting product is filtered with suction, washed with cold water, and air-dried to afford 594 gm (96%), m.p. 137-141°C.
NOTE: The product should not be oven-dried since it decomposes with the loss of formaldehyde. Recrystallization of the product from ethanol affords 94% recovery of the original material with the same melting point range.

Definition

ChEBI: A primary alcohol comprising phthalimide carrying an N-hydroxymethyl substituent.

Synthesis Reference(s)

Journal of the American Chemical Society, 77, p. 1913, 1955 DOI: 10.1021/ja01612a068

Synthesis

1. 3-Hydroxy-1H-isoindol-1-one (41.14 g, 0.30 mol) was stirred with distilled water (100 mL) for 10 minutes at room temperature. Subsequently, 40% formaldehyde solution (27 mL, 0.36 mol) was added and the mixture was refluxed for 1.5 hours. After completion of the reaction, it was cooled to 0-5 °C, the precipitate was collected by filtration, washed with cold water (0-5 °C, 200 mL) and dried in air to give N-hydroxymethylphthalimide (51.01 g, 96% yield). 2. In another reaction, a solution of thionyl chloride (23.0 mL, 37.7 g, 0.32 mol) in dichloromethane (50 mL) was slowly added to a mixture of N-hydroxymethylphthalimide, dichloromethane (550 mL) and N,N-dimethylformamide (350 mL). After stirring for 30 minutes at room temperature, stirring was continued for 2 hours. Cooled to 0 °C, water (200 mL) was slowly added and neutralized with saturated aqueous NaHCO3 to pH 6.7-7.0. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was washed with n-hexane (100 mL) to afford N-chloromethylphthalimide (51.4 g, 93% yield). 3. N-Chloromethylphthalimide (51.0 g, 0.26 mol) was dissolved in acetone (500 mL), and potassium O-ethylxanthate (43.9 g, 274 mmol) was added in batches under cooling in an ice-water bath. After stirring at room temperature for 10 hours, the solvent was removed and the residue was dissolved in dichloromethane, washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure to give a light yellow solid, which was recrystallized from ethyl acetate to give the target product (67.2 g, 92% yield) with a melting point of 99-100 °C. 1H NMR (CDCl3, 400 MHz) δ: 1.47 (t, J = 7.1 Hz, 3H, CH3), 4.68 (q, J = 7.1 Hz, 2H, CH2), 5.34 (s, 2H, CH2), 7.75 (dd, J = 5.5, 3.1 Hz, 2H, ArH), 7.88 (dd, J = 5.5, 3.1 Hz. 2H, ArH). 13C NMR (CDCl3, 100 MHz) δ: 13.7, 41.2, 70.5, 123.6, 131.8, 134.4, 166.6, 210.2.

References

[1] Chemistry - A European Journal, 2012, vol. 18, # 11, p. 3241 - 3247
[2] Synthetic Communications, 2000, vol. 30, # 20, p. 3801 - 3807
[3] Tetrahedron, 2013, vol. 69, # 3, p. 1050 - 1056
[4] Chinese Chemical Letters, 2011, vol. 22, # 10, p. 1159 - 1162
[5] Journal of Medicinal Chemistry, 2011, vol. 54, # 16, p. 5811 - 5819