Reagent Friday – Diazomethane (CH2N2)
Last updated: March 4th, 2020 |
Reactions Of Diazomethane (CH2N2) And Their Mechanisms
One of the things about learning organic chemistry from a textbook is that about 98% of you will never really have to consider the practical aspects of working with many of the reagents that you learn about. That’s OK. While it’s good to get your hands dirty in the lab as an undergraduate, most of you can probably live without working with today’s reagent. Because today’s reagent, diazomethane (CH2N2) is the kind of reagent that you should only handle if you really, really really have to. Nothing gets a chemists’ adrenaline going like a reagent that is 1) acutely toxic 2) volatile 3) extremely carcinogenic, and 4) highly explosive. So many ways to die! But I’m getting ahead of myself here. Let’s talk about the textbook stuff!
Diazomethane is actually a really simple molecule. It’s merely a methylene carbon (CH2) attached to dinitrogen (N2). Now as you might well be aware, every nitrogen atoms’ goal in life is to regain the freedom it had as a molecule of dinitrogen (N2), in the earth’s atmosphere – and in diazomethane, this can be attained merely through breaking of a single carbon-nitrogen bond. This makes diazomethane a rather frisky little molecule and highly reactive in a number of reactions.
Conversion Of Carboxylic Acids To Methyl Esters By Diazomethane (CH2N2)
So what’s it used for? Three things.
First of all, carboxylic acids treated with diazomethane will make methyl esters. This is a really simple reaction. See that no heat or acid is required? It just works!
Diazomethane And The Wolff Rearrangement
Diazomethane will also add to acid chlorides. When the diazo species is then heated, or treated with a metal like silver, a remarkable transformation occurs: nitrogen is lost, and a rearrangement occurs. After addition of water, the net result is that a carboxylic acid has been extended by one carbon. This is called the Wolff rearrangement.
Cyclopropanation Of Alkenes With Diazomethane
Finally, if you take an alkene and treat it with diazomethane, cyclopropanation reactions can occur. Here’s the scheme:
Conversion Of Carboxylic Acids To Methyl Esters With CH2N2 – The Mechanism
How it works: here’s how the reaction of carboxylic acids proceeds with diazomethane. First, protonation of diazomethane by the carboxylic acid gives CH3-N2. This is now a superb alkylating agent, since N2 is one of the best leaving groups there is. Attack on the carbon by the carboxylate ion (that’s deprotonated carboxylic acid) gives the methyl ester.
Cyclopropanation Of Alkenes With CH2N2 – The Mechanism
Cyclopropanation is worth talking about. See, when diazomethane is heated or treated with light, something very interesting happens: nitrogen takes the pair of electrons in the N–C bond and escapes to freedom as N2, while the carbon is left with an empty orbital in addition to its pair of electrons. This species – a neutral, divalent carbon with a lone pair and an empty orbital – is called a carbene. Carbenes are fascinating and there isn’t enough space here to give them justice. This carbene in particular (“methylene carbene”) is one of the most reactive chemical species known. Here, it adds to the alkene to form the cyclopropane, although in practice methylene carbene can do all kinds of other funky jazz. The actual use of diazomethane for cyclopropanation reactions is usually a little more complicated, reagent-wise, than is depicted here.
Don’t Work With CH2N2 In The Lab Unless You Know What You’re Doing
Real life tips: Oh man, there are so many. Here’s one: don’t ever, ever work with diazomethane unless you have been trained by someone who has worked with it themselves. Although generally never used neat (it boils at –23 deg C) and typically handled as a dilute solution in ether, diazomethane has a nasty tendency to explode when in the presence of high-surface-area materials (such as ground-glass joints, or, God forbid, metal syringes). If dispensing with a pipet, it’s crucial to flame-polish the edges for safety. Furthermore, diazomethane is acutely toxic: people have died from inhaling it. And if it doesn’t kill you in the short term, there’s always the long term. See, diazomethane, being an alkylating agent, has a tendency to react with (i.e. alkylate) your DNA, leading to base-pair mismatches, mutations, and – eventually – cancer.
So why use it at all? Because it’s the best. I confess that the formation of methyl esters from the reaction of carboxylic acids with diazomethane is one of my favorite reactions. You make a solution of your carboxylic acid in ether, dispense the bright yellow diazomethane solution by pipet – slowly – until the yellow color persists, wait about 5 minutes to be sure that all the N2 has bubbled off, kill the excess diazomethane with a few drops of acetic acid, and concentrate. Easiest reaction ever.
For some riveting, mouth-agape horror stories of diazomethane in the lab, check out this thread from In the Pipeline : Diazomethane: How Not To Do It.
P.S. You can read about the chemistry of CH2N2 and more than 80 other reagents in undergraduate organic chemistry in the “Organic Chemistry Reagent Guide”, available here as a downloadable PDF. The Reagents App is also available for iPhone, click on the icon below!
(Advanced) References and Further Reading
Diazomethane is a reagent commonly used in organic chemistry for a variety of transformations. It is too reactive to be sold as a pure compound; it is generated from precursors in solution and used immediately.
- Ueber Diazomethan
Chem. Ber. 1894, 27 (2), 1888-1891
- Ueber Diazomethan
Chem. Ber. 1895, 28 (1), 855-861
The first two papers by Hans von Pechmann on the synthesis and discovery of diazomethane.
J. de Boer and H. J. Backer
Org. Synth. 1956, 36, 16
This procedure, the base-catalyzed decomposition of p-tolylsulfonylmethylnitrosamide, is the most common method for preparing diazomethane today. The diazomethane is generated as an ethereal solution and should be used quickly. Aldrich sells kits for the preparation of diazomethane based on this, and the precursor is commercially available and is commonly called ‘DIAZALD®’.
G. Gassman and W. J. Greenlee
Org. Synth. 1973, 53, 38
Note 1 in this procedure has detailed notes on safety regarding the use of diazomethane. Teflon stirbars should be used, metal should be avoided, the solution kept away from light, and glassware with ground-glass joints should not be used.
- Iron-Catalyzed Cyclopropanation in 6 M KOH with in Situ Generation of Diazomethane
Bill Morandi and Erick M. Carreira
Science 23 Mar 2012: Vol. 335, Issue 6075, pp. 1471-1474
This paper describes a ‘one-pot’ cyclopropanation of styrenes and related compounds without the prior isolation of diazomethane, thereby making this chemistry safer and more practical.
- Trimethylsilyl-substituted diazoalkanes : I. Trimethylsilyldiazomethane
Dietmar Seyferth, Horst Menzel, Alan W. Dow, Thomas C. Flood
Journal of Organometallic Chemistry 1972, 44 (2), 279-290
Trimethylsilyldiazomethane (aka ‘TMS-diazomethane’) is a much easier to handle alternative to diazomethane. It is commercially available and can be used for much of the same reactions that diazomethane undergoes.
- Rapid and convenient isolation and methyl esterification of water-soluble acids using diazomethane
J. Eisenbraun, R. N. Morris, and G. Adolphen
Journal of Chemical Education 1970, 47 (10), 710
This is a short note that describes a modification to the usual esterification procedure with diazomethane to facilitate the esterification of water-soluble carboxylic acids.
- Mechanism of Methyl Esterification of Carboxylic Acids by Trimethylsilyldiazomethane
Erik Kühnel, David D. P. Laffan, Guy C. Lloyd‐Jones, Teresa Martínez del Campo, Ian R. Shepperson, Jennifer L. Slaughter
Angew. Chem. Int. Ed. 2007, 46 (37), 7075-7078
The esterification of carboxylic acids is a common reaction of diazoalkanes, especially diazomethane. TMS-diazomethane can also be used for this reaction as a safer alternative to diazomethane