phosgenations - a handbook (cotarca: phosgenations o-bk) || materials and resources for phosgenation...

7

Materials and Resources for Phosgenation

Reagents

Most of the phosgene equivalents and substitutes are commercially available, albeit

at widely varying costs, whereas phosgene itself is subject to restrictions. For those

phosgene substitutes that are not available, procedures or references for their

preparation are given herein. In some phosgenation reactions, the role of phos-

gene is played by rather simple, ordinary chemicals, which can be found in any

catalogue of fine chemicals and hence need not be mentioned further in this

chapter.

7.1

Sources of Phosgene

Phosgene is nowadays produced in two ways, in stationary plants or special facili-

ties that operate continuously producing 100s of kilograms up to 1,000s of tons a

day, and in rather small amounts on a scale of grams to kilograms a day in bottles,

lecture bottles, or dissolved in toluene. Recently, a process whereby phosgene is

evolved from a safe precursor has been developed [1], which has also been applied

in the form of cartridges for safe phosgenations [2].

7.1.1

Industrial Plants

Most of the annual worldwide consumption of 5–6 million tons of phosgene is

produced from carbon monoxide and chlorine in the presence of a catalyst based

on activated carbon (charcoal) in special plants. The process, the tetrachloro-

methane problem associated with it, and the approaches to solve it, are described

in Section 2.1.

To provide phosgene on the demand of consumer by producing it on location,

Modular Phosgene Generators are offered by Davy Process Technology (DPT), Swit-zerland [3], in seven output sizes ranging from 3 kg/h up to 10,000 kg/h (Table

7.1). These Modular Generators produce phosgene from carbon monoxide and

chlorine and consist of two sections, the intrinsic phosgene generator (see Scheme

2.3, Section 2.1) and a safety absorption module.

Phosgenations – A Handbook. L. Cotarca, H. EckertCopyright 8 2003 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-29823-1

612

7.1.2

Safety Phosgenation

If the advantages of phosgene (such as high reactivity, high yields, and pure prod-

ucts; see the evaluation in Chapter 6) could be combined with the convenience of

safe phosgene equivalents without any loss of potential reactivity, this would con-

stitute a valuable method in preparative chemistry. This has been achieved through

the method known as ‘‘safety phosgenation’’.

7.1.2.1 The Process

Triphosgene, as a safe precursor, is ‘‘depolymerized’’ into three equivalents of

phosgene by a special catalyst in a controlled reaction [1, 4]. The process is patented

worldwide by Dr. Eckert GmbH [1] (see also Chapter 2).

Triphosgene as a solid (mp 80 �C) is rather stable under most conditions. As a

liquid, it decomposes according to route a (as does diphosgene) under several con-

ditions, such as in the presence of metal salts, to give one equivalent each of

phosgene, carbon dioxide, and tetrachloromethane. In the presence of catalysts

based on special amines or imines, the decomposition takes an entirely different

route, route b, forming three equivalents of phosgene. Route a is exothermic,

whereas route b is endothermic and thus the rate of this decomposition can be

controlled by heating from 80 to 110 �C. This temperature increment increases the

rate of the phosgene generation threefold [2]. During the whole decomposition

reaction, from start to finish, an absolutely constant phosgene stream is evolved at

a pre-selected heating temperature. The reaction can be stopped immediately by

cooling to below 80 �C, whereupon triphosgene crystallizes. Other catalytic systems

work in a similar manner [5] (see Chapter 3).

O O

Cl

Cl

Cl ClCl

Cl

O

Cl Cl

O

Cl Cl

O dec. cat.

+ CO2 + CCl4 3a b

triphosgene phosgene

dec. = decomposition catalyzed by metal salts, silica gel,

etc., "dirt", heat (>150°C)cat. = catalyst: "deactivated"

amine or imine

The main advantage of the process lies in its safety. The generated phosgene is

immediately consumed in the phosgenation reaction, and hence the actual amount

Tab. 7.1. Modular phosgene generators from Davy Process Technology (DPT) [3].

Type G/A 30 G/A 100 G/A 200 G/A 600 G/A 1200 G/A 2000 G/A 10000

Output [kg/h] 2–30 10–100 20–200 60–600 120–1,200 200–2,000 1,000–10,000

7.1 Sources of Phosgene 613

of phosgene present in the whole facility at any given time is a diminutive fraction

of the entire reagent; in fact, the maximum amount corresponds to the dead

volume of the equipment. In this respect, the method is superior to all procedures

in which phosgene is stored or is present in large excess. It is also superior to

phosgene dissolved in toluene or other solvents, because in such protocols phos-

gene is present in excess at the beginning of the reaction, and in the case of spill-

age the entire amount of phosgene evaporates immediately.

The process of safety phosgenation is recommended by the Accident Insurance ofthe German Chemical Industry [6].The process of safety phosgenation can be conducted in two ways.

7.1.2.2 External Phosgene Source

As depicted in Scheme 7.1 (safety phosgenation equipment), vessel A, containing

triphosgene and the catalyst [2] without a solvent, is fitted at the top with a reflux

condenser B, which is connected by a tube C to the reaction vessel D containing

the well-stirred reaction mixture. Vessel D is fitted at the top with a dry-ice reflux

condenser E (or a reflux condenser cooled to �20 �C by a cryostat). The outlet of

the reflux condenser E is connected via a tube to a drying tube F, which, in turn, is

connected to scrubber G, containing aqueous sodium hydroxide, which absorbs

hydrogen chloride and traces of phosgene. Phosgene generation is initiated by

heating vessel A with an oil bath at a pre-selected bath temperature between 80 and

110 �C as described above. The generation can be stopped immediately at any time

by removing the oil bath and cooling, such that triphosgene crystallizes.

7.1.2.3 Cartridges for Safety Phosgenations

The method of safety phosgenation/external phosgene source described above (Sec-

tion 7.1.2.2) has been performed with pre-packaged cartridges for the production of

10 mmol (1 g), 20 mmol (2 g), or 50 mmol (5 g) of phosgene from an equivalent

amount of triphosgene [7, 8]. The cartridge consists of a small tube (length 10 cm,

°C

110

80

A

BC

phosgene

generation

phosgenation

reaction

D

E

F

scrubber

G

Scheme 7.1. Safety Phosgenation equipment with an external phosgene source.

7 Materials and Resources for Phosgenation Reagents614

diameter 1.6 cm), containing the aforementioned amounts of triphosgene and a

bead of catalyst, sealed by a cap. This serves as a storage vessel. Before use, the cap

is removed and the cartridge and reaction vessel are connected by a length of tub-

ing with a gas-tight adapter. A dosimeter badge and paper for measuring phosgene

dosage are also supplied. The cartridges are commercially available from Sigma-

Aldrich [8] (Table 7.2). Instructions for their use are given in [2, 8] and can be

retrieved from [2].

7.1.2.4 In situ Phosgene Source

The requisite amount of triphosgene to generate the desired amount of phosgene

is placed in the reaction vessel, together with the catalyst for the ‘‘depolymeriza-

tion’’ [1, 2, 5], the other reactants and reagents, and the solvent. (In contrast to

solid triphosgene, in solution it is decomposed by the catalyst even at temperatures

below its mp). As above, phosgene is released over a defined period. In the pres-

ence of certain nucleophiles, particularly certain amines (as reactants or scav-

engers), the phosgene might be released all at once. If this were the case, the

method would operate as a usual phosgenation reaction, but the safety aspect of

safety phosgenation would be somewhat reduced. Nevertheless, the method is ad-

vantageous in terms of its simple handling.

7.2

Sources of Phosgenation Reagents

Available phosgenation reagents for laboratory use are listed in Table 7.2. Some are

commercially available, while preparative procedures for others are either given in

the relevant section of Chapter 4 in this book, or in the literature. For the struc-

tures of all these phosgenation reagents, see Scheme 2.1, Chapter 2.

Phosgene can be obtained on a large scale from Van De Mark (now part of

SNPE), located in Lockport, N.Y., who sell the gas on the merchant market.

Diphosgene can be obtained on a large scale from Degussa, UK, Dona FineChemicals, Poland, Fabricolor Vus, US, Fine Organics, UK, Ubichem, UK and Hun-

gary, VUOS, Czech Republic, or Vujin Organic Chemical Plant, PR China.

Triphosgene can be obtained on a large scale from Dr. Eckert GmbH [2], Ger-

many, Ubichem, UK and Hungary, or Synergetica, PR China/US.

7.3

Safety Precautions

The high toxicity of phosgene and several of its substitutes, as well as of some

products (!) from phosgenation reactions such as alkyl isocyanates (see Table 3.4,

Section 3.4), necessitates restrictive regulations about exposure to them. In this

section, instructions are given with a view to obtaining maximum benefit from

these synthetically highly valuable reagents with a minimum of hazard. A general

7.3 Safety Precautions 615

Tab. 7.2. Available phosgenation reagents for laboratory use from commercial sources [2, 8–

10], or prepared as described in sections of Chapter 4 of this book [Sec.], or in the literature

[11–13]. For the structures of all these phosgenation reagents, see Scheme 2.1, Chapter 2.

Phosgenation Reagents Phosgene, Equivalents

and Substitutes

CAS Reg. No. Source Order No.

Phosgene, cartridges for safe phosgenation,

0.01 mol

32315-10-9

75-44-5

2 CDC0.01


0.02 mol

32315-10-9

75-44-5

8, 9

2

51,975-8

CDC0.02


0.05 mol

32315-10-9

75-44-5

8, 9

2

51,976-6

CDC0.05


starter kita32315-10-9

75-44-5

8, 9 51,978-2

Phosgene, cylinder 75-44-5 10 79372

Phosgene, in toluene 75-44-5 10 79372

Diphosgene (trichloromethyl chloroformate) 503-38-8 10 23261

Triphosgene (bis(trichloromethyl) carbonate,

BTC)

32315-10-9 9

11, 12

33,075-2

Oxalyl chloride 79-37-8 9 22,101-5

Boron tribromide 10294-33-4 9 20,220-7

Boron trichloride, in dichloromethane 10294-34-5 9 17,893-4

Phosphoryl chloride 10025-87-3 9 26,209-9

Phosphorus oxybromide 7789-59-5 9 37,694-9

Thionyl chloride 7719-09-7 9 23,046-4

Thionyl bromide 507-16-4 9 25,125-9

Phosphorus pentoxide 1314-56-3 9 25,605-6

Triphenylphosphine dibromide

(dibromotriphenylphosphorane)

1034-39-5 9 27,094-6

Cyanuric chloride (CyCl), (2,4,6-trichloro-1,3,5-

triazine)

108-77-0 9 C9,550-1

Trichloroacetyl chloride 76-02-8 9 15,159-9

Methanesulfonyl chloride (MsCl) 124-63-0 9 47,125-9

p-Toluenesulfonyl chloride, (tosyl chloride, TsCl) 98-59-9 9 24,087-7

Benzyl chloroformate 501-53-1 9 11,993-8

4-Nitrobenzyl chloroformate (NZxCl) 4457-32-3 9 22,280-1

Methyl chloroformate 79-22-1 9 M3,530-4

Ethyl chloroformate 541-41-3 9 18,589-2

1-Chloroethyl chloroformate 50893-53-3 9 30,148-5

Phenyl chloroformate 1885-14-9 9 16,752-5

Phenyl chlorothionoformate 1005-56-7 9 23,452-4

Bis(4-nitrophenyl) carbonate 5070-13-3 9

Sec. 4.3.3.2

16,169-1

Di-t-butyl dicarbonate (Boc2O) 24424-99-5 9 20,524-9

Ethylene carbonate (EC) 96-49-1 9 53,555-9

Chloroethylene carbonate 3967-54-2 9 16,763-0

Nitrophenylene carbonate (NPC) 25859-54-5 Sec. 4.3.3.2

Dimethyl carbonate (DMC) 616-38-6 9

Sec. 4.3.3.7

Sec. 4.3.3.8

Sec. 4.3.3.9

51,712-7


Tab. 7.2 (continued)


and Substitutes


Diethyl carbonate 105-58-8 9 51,713-5

Diphenyl carbonate (DPhC) 102-09-0 9

Sec. 4.3.3.2

Sec. 4.3.3.7

Sec. 4.3.3.8

D20,653-9

Di-2-pyridyl carbonate (DPC) 1659-31-0 Sec. 4.3.3.2

Sec. 4.3.3.4

Disuccinimidyl carbonate (DSC) 74124-79-1 9

Sec. 4.3.3.4

22,582-7

1,1-Carbonyldiimidazole (CDI) 530-62-1 9 11,553-3

1,1-Carbonyl-bis(2-methylimidazole) 13551-83-2 9 32,307-1

1,1-Carbonyl-bis(benzotriazole) 68985-05-7 9 51,297-4

Ethyl acetoacetate 141-97-9 9 24,070-2

Acetic anhydride 108-24-7 9 53,999-6

Isatoic anhydride 118-48-9 9 I-1,280-8

Trifluoroacetic acid anhydride (TFAA) 407-25-0 9 10,623-2

Trifluoromethanesulfonic anhydride (triflic

anhydride, Tf2O)

358-23-6 9 17,617-6

1,1-Dichlorodimethyl ether 4885-02-3 9 D6,565-8

Dimethoxymethane (formaldehyde

dimethylacetal, methylal)

7149-92-0 9 D13,465-1

Diethoxymethane 462-95-3 9 53,828-0

Phosgene iminium chloride

(dichloromethylene)dimethylammonium

chloride (Viehe’s salt)

33842-02-3 9 16,287-6

(Chloromethylene)dimethylammonium chloride

(Vilsmeier reagent)

3724-43-4 9 28,090-9

Pyridine–phosgene adduct 1-[2-(chloroformyl)-

2-azacyclohexa-3,5-dienyl]pyridinium chloride

(2-DHPP)

117371-69-4 13

Benzotriazol-1-yloxytripyrrolidino phosphonium

hexafluorophosphate (PyBOP)

128625-52-5 9 37,784-8

Benzotriazol-1-yloxy tris(dimethylamino)

phosphonium hexafluorophosphate (BOP)

(Castros reagent)

56602-33-6 9 22,608-4

Carbon monoxide, CO 630-08-0 9 29,511-6

Carbon dioxide, CO2 124-38-9 9 29,510-8

Trimethylsilyl isocyanate 1118-02-1 9 25,264-6

Chlorosulfonyl isocyanate 1189-71-5 9 14,266-2

(Methoxycarbonylsulfamoyl) triethylammonium

betaine (Burgess reagent)

29684-56-8 9 36,548-3

1,3-Dicyclohexylcarbodiimide (DCC) 538-75-0 9

Sec. 4.5.3.1

D8,000-2

1,3-Diisopropylcarbodiimide 693-13-0 9 D12,540-7

1,3-Bis(2,2-dimethyl-1,3-dioxolan-4-

ylmethyl)carbodiimide [bis-4-(2,2-dimethyl-

1,3-dioxolyl)methyl carbodiimide (BDDC)]

159390-26-8 9

Sec. 4.5.3.2

48,212-9

7.3 Safety Precautions 617

overview on handling hazardous chemicals and disposal of chemical waste has

been reported [15].

7.3.1

Material Safety Data Sheets

To ensure safe working, material safety data sheets (MSDS) have to be consulted,

particularly for the phosgenation reagents listed in Table 3.2, where the relevant

risk and safety (RþS) phrases are presented. Further information can be found in

the appropriate section of the relevant MSDS.

A special report on phosgene toxicology and treatment is given in [14].

7.3.2

Some Practical Hints

The following practical hints should facilitate the planning and realization of syn-

theses involving phosgenation reactions, and are particularly aimed at the chemist

not trained or experienced in the procedures.

1) Phosgenation reactions must be performed in an efficient hood.

2) Consult the MSDS and take the necessary precautions (protective clothing,

gloves, eye protection, etc.).

3) Minimize the risk by choosing the appropriate method and the appropriate

phosgenation reagent according to Chapter 6. Use progressive methods and

tools!

4) Use dosimeters (if available) to measure the degree of exposure to high risk

compounds (these could also be products such as alkyl isocyanates).

5) Regarding high risk compounds, make sure that excesses (and unreacted frac-

tions) are decomposed in an appropriate manner.

Tab. 7.2 (continued)


and Substitutes


2-Chloro-1,3-dimethylimidazolium chloride

(CDC)

125376-11-6 9 52,924-9

2-Chloro-1,3-dimethylimidazolium

hexafluorophosphate

101385-69-7 9 42,033-6

2-Chloro-1,3-dimethylimidazolium

tetrafluoroborate

153433-26-2 9 43,927-4

Diethyl azodicarboxylate (DEAD) 1972-28-7 9 56,311-0

Diphenylphosphoryl azide 26386-88-9 9 17,875-6

Dibutyltin oxide 818-08-6 9 18,308-3

aContains one cartridge for Safe Phosgene Generation, 0.02 mol, one

gas-tight adapter with tubing, one dosimeter badge þ paper, and

instructions.


6) Regarding high risk compounds, clean all of the reaction equipment that may

have become contaminated while it is still in the hood; in no case remove the

apparatus from the hood before decontamination of the high risk compounds.

7) Ethanol can often be used for a quick deactivation of all phosgene equivalents,

including chloroformates, carbamoyl chlorides, isocyanates, and acyl chlorides.

7.4

References

1 H. Eckert, B. Gruber, N. Dirsch, to

Dr. Eckert GmbH, German Patent DE19740577, 1999; Chem. Abstr. 1999,130, 211406; WO 9914159, 1999;

European Patent EP 1017623, 2002.

2 http://Dr-Eckert-GmbH.com3 http://www.davyprotech.com4 L. Cotarca, Org. Proc. Res. Dev. 1999,5, 377.

5 L. Pasquato, G. Modena, L. Cotarca,

S. Mantovani, P. Delogu, J. Org.Chem. 2000, 65, 8224–8228.

6 Sichere Chemiearbeit (Accident Insur-ance of the German Chemical Indus-

try), 2001, 53(May), 56 (in German).

7 S. C. Stinson, Chem. Eng. News 2001,79(44), 23–26.

8 Aldrich, ChemFiles 2002, 2(7).

9 Aldrich, Catalogue of Fine Chemicals,2003/2004.

10 Fluka, Catalogue of Fine Chemicals,2001/2002.

11 H. Eckert, B. Forster, Angew. Chem.Int. Ed. Engl. 1987, 26, 894–895.

12 L. Cotarca, P. Delogu, A. Nardelli,

V. Sunjic, Synthesis 1995, 553–576.13 J. A. King, Jr., P. E. Donahue, J. E.

Smith, J. Org. Chem. 1988, 53, 6145–6147.

14 T. C. Marrs, R. L. Maynard, F. R.

Sidell, Chemical Warfare Agents.Toxicology and Treatment, J. Wiley &

Sons, Baffins Lane, Chichester, 1996,

p. 185.

15 Org. Synth., 2002, 79, XIII–XVII(prefix).

7.4 References 619

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