593-56-6

Basic information

• Product Name: Methoxyammonium chloride
• Synonyms: Methoxyamine Hydrochloride, O-Methylhydroxylamine hydrochloride, Methoxylamine hydrochloride;Methoxylamine hydrochloride solution 25-30 wt. % in H2O;Hydroxylamine, O-methyl-, hydrochloride (1:1);O-Methylhydroxylammonium chloride for synthesis;O-METHYLHYDROXYAMINE HYDROCHLORIDE;O-METHYLHYDROXYLAMINE HCL;O-METHYLHYDROXYLAMINE HYDROCHLORIDE;O-METHYLHYDROXYLAMMONIUM CHLORIDE
• CAS NO: 593-56-6
• Molecular Formula: CH₆NO*Cl
• Molecular Weight: 83.52
• EINECS: 209-798-7
• Product Categories: Amines and Anilines;API intermediates;Amination;Hydroxylamines;Hydroxylamines (O-Substituted);Synthetic Organic Chemistry;Amine Salts;Amino Alcohols;Building Blocks;Chemical Synthesis;Nitrogen Compounds;Organic Building Blocks;Oxygen Compounds
• Mol File: 593-56-6.mol
• Article Data: 26

Chemical Properties

• Melting Point: 151-154 °C(lit.)
• Boiling Point: 105-110°C
• Flash Point: 18.2 °C
• Appearance: White to very faint yellow/Crystalline Powder
• Density: 1.1 g/mL at 25 °C
• Vapor Pressure: 298mmHg at 25°C
• Refractive Index: n20/D 1.4021
• Storage Temp.: Store below +30°C.
• Solubility: alcohol: soluble(lit.)
• Water Solubility: SOLUBLE
• Sensitive: Hygroscopic
• Merck: 14,5989
• BRN: 3589723
• CAS DataBase Reference: Methoxyammonium chloride(CAS DataBase Reference)
• NIST Chemistry Reference: Methoxyammonium chloride(593-56-6)
• EPA Substance Registry System: Methoxyammonium chloride(593-56-6)

Safety Data

• Hazard Codes: C,Xi,N
• Statements: 34-36/37/38-50-43-20/21/22-37-35
• Safety Statements: 3-24-26-36/37/39-45-61-24/25-27
• RIDADR: UN 3265 8/PG 2
• WGK Germany: 3
• RTECS: NC3980000
• F: 3-10
• TSCA: Yes
• HazardClass: 8
• PackingGroup: III
• Hazardous Substances Data: 593-56-6(Hazardous Substances Data)

Usage

Methoxyamine hydrochloride

Methoxyamine hydrochloride (also known as O-methylhydroxylamine hydrochloride; Methoxyamine; Methoxyamine hydrochloride (OMHA), is an important medicine, pesticide intermediates. Its major applications are as follows: it can be used for color photography and film printing. it is used as a reducing agent in organic synthesis industry for preparation of oximes. the field of medicine: it can be used for the synthesis of second-generation cephalosporins antibiotics cefuroxime (ester), neopropene, norethindine and hydroxyurea. the field of pesticides: the synthesis of new efficient, low-toxicity bactericidal metominostrobin. It is mainly produced by sodium nitrite method in our country. The similar compound of methoxyamine hydrochloride, the ethoxylamine hydrochloride is mainly used for the production of herbicides, oxycarbazone, diltiazem and other herbicides.

Application

Used as a methoxyamine reagent, also used in the production of the side chain of Cefuroxime and other new drugs Used for pesticide synthesis. Use for pharmaceuticals production Used for the preparation of O-methyloxime together with aldehydes or ketones.

Chemical Properties

White to very faintly yellow crystalline powder

Uses

Different sources of media describe the Uses of 593-56-6 differently. You can refer to the following data:
1. antineoplastic, hydroxymethyltransferase inhibitor
2. Methoxylamine is a methoxime derivative used as internal standard for Prostaglandin assays by gas chromatography-mass spectrometry
3. Methoxylamine hydrochloride is used as a reagent in the preparation of O-methyl oximes from aldehydes. It is orally bioavailable small molecule inhibitor with potential adjuvant activity. It is also used as internal standard for prostaglandin assays by gas chromatography-mass spectrometry.

General Description

Off-white crystals.

Air & Water Reactions

Water soluble.

Reactivity Profile

In aqueous solution, Methoxyammonium chloride behaves as an acid. Materials in this group are generally soluble in water. The resulting solutions contain moderate concentrations of hydrogen ions and have pH's of less than 7.0. They react as acids to neutralize bases. These neutralizations generate heat, but less or far less than is generated by neutralization of inorganic acids, inorganic oxoacids, and carboxylic acid. They usually do not react as either oxidizing agents or reducing agents but such behavior is not impossible. Many of these compounds catalyze organic reactions.

Fire Hazard

Flash point data for Methoxyammonium chloride are not available. Methoxyammonium chloride is probably combustible.

Purification Methods

Crystallise the hydrochloride from absolute EtOH or EtOH by addition of diethyl ether. [Kovach et al. J Am Chem Soc 107 7360 1985, Beilstein 1 IV 1252.]

InChI:InChI=1/CH5NO.ClH/c1-3-2;/h2H2,1H3;1H

Synthetic route

N-methoxyphthalimide (1914-20-1) → N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
Stage #1: N-methoxyphthalimide With methylhydrazine In dichloromethane at 0 - 20℃; for 2h; Stage #2: With hydrogenchloride In 1,4-dioxane at 0℃;	90%
With hydrogenchloride for 0.5h; Hydrolysis; Heating;
With methylhydrazine In dichloromethane
Stage #1: N-methoxyphthalimide With hydrogenchloride; acetic acid In water for 1.5h; Reflux; Inert atmosphere; Stage #2: With hydrogenchloride at 0 - 20℃; for 1h; Inert atmosphere;

N-methoxyacetamide (5806-90-6) → N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
With hydrogenchloride In ethanol; water at 65℃;	69.3%
With hydrogenchloride In ethanol; water at 65℃;	69.3%

benzyl bromide (100-39-0) + 6-chloropurine (87-42-3) → N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide at 25℃; for 10h;	48%

N-Methoxy-acetimidic acid ethyl ester → N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
With hydrogenchloride for 0.25h; Heating;

N-methoxybenzamide (2446-51-7) → N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
With hydrogenchloride In ethanol for 0.25h; Hydrolysis; Heating;

hydrogenchloride (7647-01-0) + (MeON=C(Me)-CMe=NOMe) (29144-51-2) → N-methoxylamine hydrochloride (593-56-6) + dimethylglyoxal (431-03-8)

ethylbenzhydroximic acid methyl ester → N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
With hydrogenchloride

methyl ether of benzaldoxime → N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
With hydrogenchloride

N-methoxysuccinimide (5904-50-7) → N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
With hydrogenchloride

O-Methylhydroxylamin (67-62-9) → N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
With hydrogenchloride In water
With hydrogenchloride In ethanol
With hydrogenchloride	30.2 g
With hydrogenchloride
With hydrogenchloride In water at 0 - 20℃; for 1h;

hydrogenchloride (7647-01-0) + (CH3O)H2N*BH3 (91572-26-8) + water (7732-18-5) → N-methoxylamine hydrochloride (593-56-6) + boric acid (11113-50-1)

Conditions	Yield
In hydrogenchloride acidic hydrolysis;;

N-phenylacetyl-O-methylhydroxylamine (112403-78-8) → phenylacetic acid (103-82-2) + N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
With Escherichia coli penicillin acylase; potassium chloride; water at 24.84℃; Equilibrium constant; Enzymatic reaction;

dimethyl sulfate (77-78-1) → N-methoxylamine hydrochloride (593-56-6)

Conditions	Yield
With hydrogenchloride; sodium meta bi sulfate; sulfur dioxide; sodium nitrite In water at 100℃; for 3h; pH=4; Alkaline conditions;

(butan-2-ylidene)(methoxy)amine (27685-12-7) → N-methoxylamine hydrochloride (593-56-6) + butanone (78-93-3)

Conditions	Yield
With hydrogenchloride at 120℃; for 2.33333h; Temperature; Overall yield = 91 percent;

6-phenyl-hex-5-en-2-one (69371-59-1) + N-methoxylamine hydrochloride (593-56-6) → N-Methoxy-1-phenyl-1-hexen-5-one oxime (134025-31-3)

Conditions	Yield
With sodium acetate In water Heating;	100%

N-methoxylamine hydrochloride (593-56-6) + 4-methoxy-benzaldehyde (123-11-5) → 4-methoxybenzaldehyde O-methyl oxime (70286-37-2, 87861-04-9, 33499-40-0)

Conditions	Yield
With sodium hydroxide In methanol; water at 0 - 20℃; for 1h;	100%
With sodium acetate In ethanol	92%

N-methoxylamine hydrochloride (593-56-6) + 4-methyl-benzoyl chloride (874-60-2) → N-methoxy-4-methylbenzamide (25563-06-8)

Conditions	Yield
With potassium carbonate In water; ethyl acetate at 0 - 20℃; for 2h; Inert atmosphere;	100%
With potassium carbonate In water; ethyl acetate at 0 - 20℃;	99%
With potassium carbonate In water; ethyl acetate at 0 - 20℃;	93%

N-methoxylamine hydrochloride (593-56-6) + 4-methoxy-benzoyl chloride (100-07-2) → N-methoxy-4-methoxylbenzamide (24056-08-4)

Conditions	Yield
With pyridine In dichloromethane at 20℃; for 2h;	100%
With sodium carbonate In water; benzene at 20℃; for 18h; Cooling;	98%
With potassium carbonate In water; ethyl acetate at 0 - 20℃;	98%

N-methoxylamine hydrochloride (593-56-6) + benzyl chloroformate (501-53-1) → O-benzyl-N-methoxycarbamate (121989-74-0)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 5h;	100%
With sodium carbonate In water; benzene for 5h; Ambient temperature;	98%
With sodium carbonate In water; toluene at 20℃; for 5h;	54%

N-methoxylamine hydrochloride (593-56-6) + 2α-azido-5α-cholestan-3-one (35647-02-0) → 2α-Azido-3-(methoxyimino)cholestane

Conditions	Yield
With pyridine at 0℃; for 3.5h;	100%

2-(4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (1086-43-7) + N-methoxylamine hydrochloride (593-56-6) → 2-(4-methoxyphenyl)-1-indanone oxime methyl ether (145962-42-1)

Conditions	Yield
With sodium acetate In methanol Ambient temperature;	100%

N-methoxylamine hydrochloride (593-56-6) + 2-(N-allylbenzylamino)-4-oxo-4H-pyrido<1,2-a>pyrimidine 3-carboxaldehyde → 2-(Allyl-benzyl-amino)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde O-methyl-oxime (183968-81-2)

Conditions	Yield
With sodium acetate In methanol for 3h; Ambient temperature;	100%

N-methoxylamine hydrochloride (593-56-6) + 2--4-oxo-4H-pyrido<1,2-a>pyrimidine-3-carbaldehyde → 2-[Benzyl-((E)-but-2-enyl)-amino]-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde O-methyl-oxime

Conditions	Yield
With sodium acetate In methanol for 3.5h; Ambient temperature;	100%

N-methoxylamine hydrochloride (593-56-6) + benzaldehyde (100-52-7) → (E)-benzaldehyde O-methyloxime (10229-53-5)

Conditions	Yield
With sodium acetate In tetrahydrofuran; water at 20℃; for 4h;	100%
With hydrogenchloride In ethanol Heating;	71%
With sodium acetate In ethanol; water for 2h; Reflux;	68%

platanic acid (6060-06-6) + N-methoxylamine hydrochloride (593-56-6) → (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bS)-9-Hydroxy-1-{1-[(Z)-methoxyimino]-ethyl}-5a,5b,8,8,11a-pentamethyl-icosahydro-cyclopenta[a]chrysene-3a-carboxylic acid

Conditions	Yield
With sodium acetate In methanol	100%

N-methoxylamine hydrochloride (593-56-6) + C17H24O5 → N-methoxy-4-(4-methoxy-3-methyl-phenyl)-butyramide (626239-69-8)

Conditions	Yield
With triethylamine at 0℃; for 1h;	100%

3-(2,4-dimethoxy-phenyl)-2-methyl-propionic acid + N-methoxylamine hydrochloride (593-56-6) → O-methyl (+/-)-3-(2,4-dimethoxyphenyl)-2-methylpropiohydroxamate

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 9h;	100%

5-formyl-1-methyl-2-tert-butylindolizine (906361-94-2) + N-methoxylamine hydrochloride (593-56-6) → 2-tert-butyl-1-methyl-indolizine-5-carbaldehyde O-methyl-oxime

Conditions	Yield
With pyridine In ethanol at 20℃; for 5h;	100%

N-methoxylamine hydrochloride (593-56-6) + indole-2,3-dione (91-56-5) → 1H-indole-2,3-dione 3-(O-methyloxime) (107976-78-3)

Conditions	Yield
With dipotassium hydrogenphosphate In methanol at 20℃; for 2h;	100%
With sodium hydrogencarbonate In methanol; water at 50℃; for 8h;	92%
With sodium hydrogencarbonate In methanol; water at 20℃; for 1.08333h;	80%

methyl 2-[(4-hydroxyphenyl)methyl]-3-oxopentanoate (361576-47-8) + N-methoxylamine hydrochloride (593-56-6) → 2-(4-hydroxy-benzyl)-3-methoxyimino-pentanoic acid methyl ester (851181-19-6)

Conditions	Yield
With sodium acetate In methanol at 20℃; for 5h;	100%
With sodium acetate In methanol	90%

N-methoxylamine hydrochloride (593-56-6) + 4-methoxy-benzaldehyde (123-11-5) → 4-methoxy-benzaldehyde-(O-methyl-seqtrans-oxime ) (70286-37-2)

Conditions	Yield
	100%

methyl (E)-3-methoxy-2-trans[2-(3-(2-(1-oxoheptyl-1-yl)cyclopropyl)phenoxymethyl)phenyl]-2-propenoate + N-methoxylamine hydrochloride (593-56-6) → methyl 3-methoxy-2-trans-[2-(3-(2-(methoximinohept-1-yl)cyclopropyl)phenoxymethyl)phenyl]-2-propenoate

Conditions	Yield
In methanol at 20℃; for 12h;	100%

C19H15N5O (672318-77-3) + N-methoxylamine hydrochloride (593-56-6) → C20H18N6O (672319-03-8)

Conditions	Yield
With pyridine In tetrahydrofuran; dichloromethane at 25℃; for 72h;	100%

2-(2,3,5-trimethylcyclopentadienyl)benzaldehyde + N-methoxylamine hydrochloride (593-56-6) → O-methyl-2-(2,3,5-trimethylcyclopentadienyl)benzaldehyde oxime

Conditions	Yield
With sodium acetate In tetrahydrofuran; water at 25℃; for 0.5h;	100%

(5-fluoro-4-methyl-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-carbamic acid benzyl ester (864074-10-2) + N-methoxylamine hydrochloride (593-56-6) → (5-fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-carbamic acid benzyl ester

Conditions	Yield
With pyridine at 70℃;	100%

4-Trifluoromethylbenzaldehyde (455-19-6) + N-methoxylamine hydrochloride (593-56-6) → (E)-4-trifluoromethylbenzaldehyde O-methyloxime (1012051-66-9)

Conditions	Yield
	100%
With sodium acetate In ethanol; water at 70℃; for 2h;

3,4 difluorobenzaldehyde (34036-07-2) + N-methoxylamine hydrochloride (593-56-6) → 3,4-difluorobenzaldehyde O-methyloxime (646051-28-7)

Conditions	Yield
	100%

N-(3-oxobutyl)phthalimide (3783-77-5) + N-methoxylamine hydrochloride (593-56-6) → N-[3-(N-methoxyimino)butyl]-phthalimide

Conditions	Yield
With sodium hydroxide In methanol	100%

3-(3-acetyl-4-chloro-6-fluoro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil (193676-14-1) + N-methoxylamine hydrochloride (593-56-6) → 3-[4-chloro-6-fluoro-3-(1-methoxyiminoethyl)-2-methylbenzofuran-7-yl]-1-methyl-6-trifluoromethyluracil

Conditions	Yield
With potassium acetate In methanol; ethyl acetate	100%

C18H20O4 (1029697-36-6) + N-methoxylamine hydrochloride (593-56-6) → C20H26N2O4

Conditions	Yield
With pyridine; acetic acid at 20 - 40℃; for 2h;	100%

1-ethyl-2,3,4,10,10a-pentaaza-cyclopenta[b]fluoren-9-one (941568-39-4) + N-methoxylamine hydrochloride (593-56-6) → 1-ethyl-2,3,4,10,10a-pentaaza-cyclopenta[b]fluoren-9-one O-methyl-oxime (1022084-11-2)

Conditions	Yield
With pyridine at 60℃; for 2 - 3h; Molecular sieve;	100%

C26H35BrN4O2 (1149581-07-6) + N-methoxylamine hydrochloride (593-56-6) → 4-bromo-2-{2-[4-(diethylamino)phenyl]-2-(methoxyimino)ethyl}-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (1149581-81-6)

Conditions	Yield
In ethanol at 80℃; for 1h;	100%

Stanolone (521-18-6) + N-methoxylamine hydrochloride (593-56-6) → stanolone 3-Z,E-methyloxime

Conditions	Yield
With triethylamine; sodium hydroxide In tetrahydrofuran; water at 20 - 60℃; for 5h;	100%

8-fluoro-2,2-dimethyl-7-(piperidin-1-yl)chroman-4-one (1221444-84-3) + N-methoxylamine hydrochloride (593-56-6) → (E)-8-fluoro-2,2-dimethyl-7-(piperidin-1-yl)chroman-4-one O-methyl oxime (1221444-85-4)

Conditions	Yield
With pyridine at 20℃; for 16h;	100%
With pyridine at 20℃; for 16h;	100%

Upstream product

• 2446-51-7 N-methoxybenzamide 
• 7647-01-0 hydrogenchloride 
• 29144-51-2 (MeON=C(Me)-CMe=NOMe) 
• 1914-20-1 N-methoxyphthalimide 
• 91572-26-8 (CH₃O)H₂N*BH₃ 
• 7732-18-5 water 
• 112403-78-8 N-phenylacetyl-O-methylhydroxylamine 
• 546-88-3 acetylhydroxamic acid 
• 77-78-1 dimethyl sulfate 
• 54615-10-0 (E)-4-nitrobenzaldehyde O-methyl oxime 
• 61042-20-4 2-hydroxybenzaldehyde methyl oxime 
• 33581-31-6 4-bromobenzaldoxime O-methyl ether 
• 135436-97-4 2-nitrobenzaldehyde-(O-methyl oxime) 
• 33581-43-0 acetaldehyde O-methyl oxime 

Downstream Products

• 861367-95-5 hydroxy-methoxyamino-malonic acid amide-p-toluidide 
• 106837-95-0 3-amino-2-hydroxy-benzaldehyde-(O-methyl oxime ) 
• 106837-42-7 5-amino-2-hydroxy-benzaldehyde-((E)-O-methyl oxime ) 
• 67-56-1 methanol 
• 1516-60-5 4-nitrophenyl azide 
• 103756-13-4 O-methyl-N,N-bis-(3-oxo-3-phenyl-propyl)-hydroxylamine 
• 15312-05-7 [1,4]Benzoquinone mono-(O-methyl-oxime) 
• 56336-01-7 hept-3-en-2-one O-methyl-oxime 
• 97767-22-1 benzil-bis-(O-methyl-seqtrans-oxime ) 
• 7266-76-4 O-methyl-N,N-bis(trimethylsilyl)hydroxylamine 
• 105449-97-6 diethylhydrogensilyl-cyclic diethylsilylene derivative of thromboxane B₂ methyl ester-methyloxime (anti isomer) 
• 105449-97-6 diethylhydrogensilyl-cyclic diethylsilylene derivative of thromboxane B₂ methyl ester-methyloxime (syn isomer) 
• 121989-26-2 2-(3,4-Dimethoxy-phenyl)-N-methoxy-acetamide 
• 135635-23-3 ethyl 2,3,4-trideoxy-2-methoxyamino-4-methoxyimino-α-D-threo-hexopyranoside 

Relevant articles and documents

Preparation method O - alkyl substituted hydroxylamine salt

The invention relates to a preparation method of N - alkyl substituted hydroxylamine salt, and belongs to fine chemical engineering. Pesticide or bulk pharmaceutical chemicals technical field. The present invention reacts with the N - alkyl of the oxime with an inorganic salt of hydroxylamine to give N - alkyl-substituted hydroxylamine salt and oxime. The invention provides an efficient and environment-friendly method for preparing N - alkyl substituted hydroxylamine salt, and simultaneously, an N - alkyl substituted hydroxylamine salt is prepared, and the oxime can be re-prepared to form N - alkylate of oxime so as to realize the material circulation. No equivalent acid is used in the reaction process. Alkali neutralization, avoided the current method to use a large amount of acid, alkali and produce inorganic salt solid waste shortcoming, environmental protection more. The preparation method is mild in reaction condition, and the defects of high pollution and high energy consumption of the traditional process are overcome. In-flight R1 , R2 What is R is as claimed in the claims and the description.

Preparation method of methoxyamine hydrochloride and preparation method of N-methoxyacetamide

The invention relates to a preparation method of methoxyamine hydrochloride and a preparation method of N-methoxyacetamide, belonging to the technical field of organic synthesis. The preparation method of the methoxyamine hydrochloride comprises the following steps: 1) carrying out a methylation reaction on acetohydroxamic acid and dimethyl sulfate in water to generate N-methoxyacetamide, wherein in the process of the methylation reaction, sodium bicarbonate and sodium hydrogen salt are adopted to control the pH value of a reaction system to be 7-9, and a molar ratio of sodium bicarbonate to sodium hydroxide is (0.03-0.09): 1; and 2) preparing methoxyamine hydrochloride from N-methoxyacetamide. According to the preparation method of methoxyamine hydrochloride, composite alkali of sodium bicarbonate and sodium hydroxide is adopted in the methylation reaction process, so the conversion rate of acetohydroxamic acid can be increased, the pH value in the methylation process can be strictly controlled to be 7-9, generation of polymethylation impurities (O,N-dimethylhydroxylamine hydrochloride) is reduced, and the yield of N-methoxyacetamide is improved.

Preparation method of methoxylamine hydrochloride

The invention provides a preparation method of methoxylamine hydrochloride. The method comprises the following steps of adding diacetylmonoxime (C4H9NO), dimethyl sulfoxide (DMSO, C2H6OS), triethylamine (C6H15N) and a methylation reagent into a reaction vessel, and reacting at 15-75 DEG C to generate O-methyl-2-diacetylmonoxime ether. Compared with the prior art. The method has the advantages thatthe operation is simple, wastes are few, furthermore, reaction raw materials can be completely converted, a generated intermediate by-product can be decomposed into diacetylmonoxime (C4H9NO) and triethylamine (C6H15N), equivalently, no side reaction exists, the yield of synthesized methoxylamine hydrochloride is improved, the use of toxic substances such as sulfur dioxide and sodium nitrite is avoided, the emission of toxic gases such as nitric oxide is reduced, and the sustainable development of enterprises is facilitated.