Vol. 2, No. 7
Eckert's Cartridges for Safe Phosgenations

Introduction / Applications / Phosgene and Substitutes / Instructions for Use / References

Phosgene and Substitutes
Because phosgene is a poisonous gas, many attempts have been made to substitute it with phosgene equivalents. The most common substitutes are diphosgene (DP; 15,159-9), triphosgene (TP; 33,075-2), carbonyl diimidazole (CDI; 11,553-3), disuccinimidyl carbonate (DSC; 22,582-7), shown in (Scheme 8). Of these substitutes, only DP and TP behave like phosgene in all four basic transformations (introduction of carbonyls, chloro substituents, chlorocarbonyls, and dehydration products). CDI is also very well-known, particularly in carbonylation reactions. A comparison of physical data of phosgene and its substitutes is given in (Table 1).
Table 1. Physical Data of Phosgene and Phosgene Substitutes
  Phosgene DP TP CDI DSC
BP (°C) 8 128 208 - -
MP (°C) -132 - 80 120-124 190
Phosgene is the only volatile reagent in Table 1. The other reagents are not volatile at all, and are therefore difficult to remove by simple evaporation. A comparison of the reactivities of phosgene and its substitutes has also recently been investigated and reported (Table 2).9
Table 2. Relative Reactivities in Pseudo First Order Reactions with Methanol
  Phosgene DP TP
Relative reactivity 170 19 1
Many additional reactions and other useful information will be available soon in the phosgenation handbook of Cotarca and Eckert.1 The handbook provides numerous safe phosgenation procedures. Visit http://dr-eckert-gmbh.com for more information.

Phosgene is 170 times more reactive than TP, the main phosgene substitute. Therefore, reactions with phosgene can be carried out under much milder conditions than with TP. Compounds will react faster and at lower temperatures (often at -78°C), preserving sensitive moieties against attack- a weighty argument when considering high-priced compounds.

When using phosgene substitutes, the removal of excess reagent is often problematic during the workup of a reaction. Since the substitutes are non-volatile, purification requires an extra distillation or recrystallization step. Only phosgene can easily and quantitatively be separated from the product by evaporation or stripping with nitrogen, as it is the lone volatile reagent of the group. Therefore, products resulting from reactions with phosgene are mostly of high purity and can be directly reacted further without investing additional time in cost-intensive purification.

Another method used to remove phosgene substitutes from the desired products is to destroy them with appropriate nucleophiles such as water or alcohols. This method can be applied only when the product is not sensitive to those nucleophiles, as is the case for carbamates, carbonates, ureas, cyanides, isocyanides, and alkyl chlorides. But chloroformates, carbamoyl chlorides, isocyanates, acyl chlorides, N-carboxylic anhydrides, and carbodiimides cannot be purified by this method. These groups are advantageously synthesized by use of phosgene to give these functional groups quickly and easily.

For example, regarding the synthesis of methyl 2-isocyanato-3-phenyl-2-butenoate by dehydration of the corresponding saturated compound with either phosgene or diphosgene, product yields are 68% and 54% respectively.10 The products are of quite different purities as demonstrated by their boiling points: the product prepared with DP has a boiling range of 90-110°C/0.001 mmHg, whereas the product prepared with phosgene has a sharp boiling point of 90°C/0.07 mmHg. Effenberger writes: "In the reaction phosgene is distinctly superior to diphosgene."

In optimizations by Eckert1 of the production of benzyl chloroformate (Z-Cl) from benzyl alcohol using triphosgene, they demonstrate that product yields do not exceed 15%. However, when phosgene is used as the chloroformylation reagent, the reaction affords 97% Z-Cl after distillation of the crude product!