1,5-Benzodiazepine Educational Synthesis – Conclusion

Good afternoon, everyone!

After nearly eight weeks of literature research and experimenting in the lab, I have finalized my initial procedure for the synthesis of 2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepine using ortho-Phenlenediamine, an excess of acetone, and sulfamic acid catalyst.  I made several alterations to the skeletal procedure by Fletcher given to me by Prof. Lashley, including an increase in reaction time (from 30 minutes to 60 minutes), an increase in catalyst (from 10% molar to 20% molar), the use of reagent-grade acetone (instead of solvent-grade), the use of magnesium sulfate drying agent (instead of sodium sulfate drying agent), the use of a drying column to eliminate atmospheric water from entering the system, and limiting the extraction solvent to 30 mL of DCM (instead of 50 mL).  With these changes, the reaction yields more pure product, in a timely fashion.

The theoretical yield for the original procedure was 0.86 grams of product, with the original procedure by Fletcher predicting 16 – 80% crude product yield, and 5 – 55% purified product yield.  My actual yield was 0.420 grams of crude product (48% yield), and 0.250 grams of purified product (29% yield).  There was almost 20% more crude yield comparing the use of 10% molar catalyst and 20% molar catalyst (0.308 grams / 35% vs. 0.454 grams / 52%).  Factors that may affected the purified product yield were difficulties obtaining all of purified product from the flask after trituration (resulting in 6% purified product yield during one run); this may require increasing the amount of reagent (ortho-Phenlenediamine) put into the system, to account for such when the procedure is run by students.

Some possibilities for the future, to be added onto this educational procedure to make it a unknown reagent / multi-synthesis procedure for more investigation on the part of the students, would be:  the use of different ketones (such as 2-butanone and acetophenone); using different Lewis acid catalysts (such as boric acid); using different synthesis procedures (such as recrystallization); using TLC plating to keep track of the progress of the synthesis as it is running; and looking into microwave technology to speed up the process, though difficulties would lie with the relatively low (50°C – 60°C and 70°C – 80°C) boiling points of acetone and butanone; the boiling point of acetophenone is much more promising (202°C).

I will be passing this procedure onto the next group of research students under Prof. Lashley.  Thank you very much for the opportunity this summer!  I had a lot of fun and made close friends.  See you later, and good luck!


Olivia White