Cliff Kubiak

Clifford P. Kubiak

Preperation of Isocyanides

1. Preparation of Methyl Isocyanide; CNMe

CH3NHCHO + p-C6H4Me.SO2Cl + 2C9H7N → CH3NC + 2C9H8N+ + p-C6H4Me.SO3 + Cl-

Caution! Isocyanides are very toxic materials having an extremely obnoxious odor. Methyl isocyanide has a very high vapor pressure and will also polymerize at room temperature over a period of time. It should be stored in glass (reacts with septa) in a freezer.


To a 500 mL three neck round bottom flask(a) equipped with a stir bar and heating mantle is added 118 mL (129 g) of quinoline.(b) The temperature of the flask and quinoline is raised to 75 ± 10 °C (this can be monitored by a thermometer positioned between the heating mantle and the flask). During this time, 72.5 g of toluene-p-sulphonyl chloride(c) is added and dissolved in the warm quinoline. N-methyl formamide 14.8 mL (15.0 g) is placed in the addition funnel (Figure 2-1), the system is sealed and placed under a N2 atmosphere by three evacuation/flush cycles. Place system under vacuum [60 mm using a controlled bleed and a manometer, however without use of a manometer, simply pull a full vacuum on the system and shut the vacuum line stopcock off to prevent CNCH3 from collecting in vacuum line trap (do this regularly to keep up vacuum)]. Cool stages 2, 3, and 4 (Figure 2-1) in liquid nitrogen traps.(d) If temperature is now regulated, slowly add the N-methyl formamide dropwise over a 20 min period to the stirred solution. Methyl isocyanide will distill rapidly and be collected in the receiving flask (stage 2). Don't worry about fluctuations in the temperature, self refluxing may drive the temperature to ~90 °C, this means that more quinoline is being driven into the receiving flask. A second bulb to bulb distillation is required anyway. A simple procedure to follow is to simply close off stage 2 and let the CNMe condense into stage 3. Expect yields of 80-90% and select an appropriate receiving flask.(e)


Formula weight 41.05 g/mol; Density 0.69 g/mL; IR(neat) à(CN) 2170 cm-1 (previously reported 2166 cm-1); 1H NMR (neat) δ 2.85 (t).


(a) Scaling up the reaction does not decrease yield. However, a large dead volume in the reaction flask should be maintained to allow vigorous refluxing of the reaction solution. Therefore, increase the size of the three neck flask accordingly; 2 liter round bottom for a scale of 4x ... etc.

(b) Quinoline need not be freshly distilled. However, at least 1/2 the volume used should be from a freshly opened bottle.

(c) Toluene-p-sulphonyl chloride need not be recrystallized, reagent grade is sufficient.

(d) Improvements in yield come from additional vacuum trap stages by preventing loss of already prepared CNCH3. Stage 4 is recommended but not required for high yields; it is simply a precaution. Stages 3 and 4 allow the greatest condensation in stage 2, by regulating vacuum.

(e) Isocyanides can be decomposed by two methods, both of which should be used in clean up. Clean up should be done immediately after isolation of CNCH3 while quinoline is still warm. If allowed to polymerize, glassware is forfeited. Add an equal volume of warm H2O and carefully add H2SO4 to the quinoline solution. This mixture can now be disposed of down a hood drain with a copious amount of water. Rinse glassware with a 50/50 mixture of H2O/bleach then clean glassware in the base bath. Hands should be rinsed quickly with fresh bleach mixture and washed with soap and water.


1. Casanova, J.; Schuster, R. E.; Werner, N. D. J. Chem. Soc. 1963, 4280.


2. Preparation of Methyl 13C-Isocyanide; 13CNMe

K13CN + AgNO3 → Ag13CN + KNO3

Ag13CN + MeI → "Ag(13CNMe)I"

"Ag(13CNMe)I" + 2KCN → 13CNMe + (K2Ag(CN)2)


Silver 13C-cyanide (99% enriched, prepared from K13CN and AgNO3(a), 1.937 g, 0.0144 mol) was placed in a 50 mL Pyrex high-pressure reactor.(b) After addition of 0.90 mL of MeI (99%, 0.0145 mol) by syringe, the reactor was heated with shaking at 70-75°C for two hours. The mixture became a dark brown liquid.(c) Upon cooling to room temperature, a solution of 2.4 g of KCN (0.037 mol) in approximately 6 mL water was added by syringe, and the contents were vigorously shaken until all solids dissolved. The reactor was attached to an empty bubbler trap which is attached to a 100 mL Schlenk flask which served as a trap for 13CNMe. The bubbler trap is used due to the likeliness of the reaction mixture to bump this trap keeps any bumped material from contaminating the final product. The volatiles from the reaction mixture were distilled into the trap (cooled in liquid N2) under vacuum until only a thick paste remained in the reactor. To facilitate distillation, the reactor was warmed by using a water bath at 40-45°C.(d) The trap was warmed to room temperature affording an aqueous solution of 13CNMe.(e) In reactions where large amounts of water are a problem, the 13CNMe can be extracted into CH2Cl2 using 3X 6 ml of CH2Cl2.


(a) Silver cyanide is prepared by reaction of a stoichiometric amount of KCN and AgNO3 in water. The resulting precipitate is air dried and protected from light prior to use. (Extreme care should be observed when handling KCN and MeNC in view of their high toxicity.)

(b) The reactor was constructed from a thick-walled glass tube to which a "T-tube" teflon stopcock was attached (Figure 2-2).

(c) The mixture was best shaken by continually rolling the tube in the oil bath as often as possible. During this period, the solid mixture gradually turns into a brown syrup but sometimes solidifies upon reaction completion.

(d) Extreme care must be taken to prevent contamination of the distillate by the reaction mixture (which contains excess cyanide) through bumping.

(e) Just as N-methyl formamide can be dehydrated to give MeNC, MeNC can be hydrated to give N-methyl formamide. The hydration is acid and base catalyzed. It is best to separate the MeNC from the H2O as soon as possible.

(f) KC15N is also commercially available. Using the same techniques as above Me15NC can be prepared.


1. DeLaet, D. L.; del Rosario, R.; Fanwick, P. E.; Kubiak, C. P. J. Am. Chem. Soc. 1987, 109, 754.

2. Mottern, J. G.; Fletcher, W. H. Spectrochimica Acta 1962, 18, 995.

3. Preparation of Perdeuteriomethyl Isocyanide; CNCD3

KCN + AgNO3 → AgCN + KNO3

AgCN + CD3I → "Ag(CNCD3)I"

"Ag(CNCD3)I" + 2KCN → CNCD3 + K2Ag(CN)2


The preparation is the same as the preparation of 13CNMe except using CD3I instead of CH3I and KCN instead of K13CN.