A Chemical Weapon Employed in WWI Paves the Way for Modern, Chemotherapeutic DNA Alkylating Agents

The man depicted is a WWI solider suffering form mustard gas burns.

The man depicted is a WWI solider suffering form mustard gas burns.

The SN2 (Substitution, Nucelophilic, Bimolecular) reaction is an uninteresting reaction introduced in basic organic chemistry in which a nucleophile, rich in electron density, bombards an electron-deficient carbon and displaces the previously attached electronegative group. If one nucleophilic species attacks an electrophilic carbon within the same molecule (intramolecular), then things get a 100 fold more interesting.

Such an intramolecular SN2 was the basis of the reactivity of mustard gas that was employed in World War I.  Autopsies of soldiers killed by mustard in World War I revealed that they had defects in bone marrow development as well as low white blood cell counts, both indicative of mustard’s malicious effects on rapidly mitotic cells. This profound discovery suggested that mustards might be an effective chemotherapeutic agent. Logically, organic chemists journeyed to find a less reactive mustard that might be applicable in a clinical setting.

Before we discuss the mustards organic chemists found, let’s examine the chemical mechanism that underlies mustard gas’s antitumoric properties. (Click on the picture to get a closer view)

sulfur mustard


The mustard gas, depicted above in the far left, is aggressive because its highly nucleophilic sulfur atom easily donates a lone pair to the electrophilic carbon attached to the chlorine via an intramolecular SN2, forming a cyclic sulfonium compound. This intermediate is impressively reactive because of its strained three-membered ring (the bonds deviate from the optimal 109.5 almost maximally) and because of its excellent, positively charged, weakly basic, sulfur leaving group. Any nucleophile nearby, such as a nitrogen atom in nucleoside bases, can attack the carbon attached to the sulfur, thereby making a sigma bond and dumping the broken sigma bond’s electrons into sulfur as a lone pair.


This covalent modification alone can permanently damaged DNA, but a single molecular of sulfur mustard can conjure even more havoc, for it has one more chlorine atom in which the now neutral sulfur can attack and form a cyclic sulfonium intermediate, which can alkylate yet another base of DNA from a separate strand. The overall result is the formation of an inter-strand crosslink. The mustard is analogous to a rope that fastens itself to two separate ladders. Such molecular lesions are highly cytotoxic because they hinder fundamental processes like replication and transcription.


The entire mechanism is shown below, but with one small change. (Click on it to get a clearer view).

mustard mechanism


The sulfur atom is replaced by nitrogen, hence the term nitrogen mustards. Nitrogen mustards are exactly what the organic chemists were looking for. The nitrogen’s electron cloud contains only 1 lone pair and is much smaller as compared to sulfur’s 2 lone pairs and larger cloud. This prevents nitrogen from be as nucleophilic as sulfur, thereby reducing reactivity to clinically desired levels.


Organic chemists can use the nitrogen mustard as an archetype as modify the functional groups surrounding it to alter its desired and precise physiological function. The cancer drugs shown below are all chemotherapeutic alkylating agents that were essentially inspired by the sulfur mustard employed in WWI. Can you spot the analogous, reactive portions of these clinically prescribed molecules?

cyclophospho         carmustine     chlorambucil

Cyclophosphamide                    Carmustine                                                          Chloroambucil


Can you explain why these mustards are less reactive than the archetypal molecule? For my answer, scroll to the bottom of this article!


It’s refreshing to analyze alkylating agents rather than the jaded microtubule interfering drugs most people envision when thinking about chemotherapy. Lastly, I’d like to say that next week I will explore marriage and divorce from a sociological perspective! I’ll take a recess from beloved organic chemistry to analyze marriage and divorce through the three theoretical lenses of symbolic interactionism, conflict theory, and structural functionalism.


Answer: The lone pairs on nitrogen are in resonance with the phosphorus-oxygen double bond in cyclophosphamide’s case, with the aromatic ring in chlorambucil’s case, and with the carbonyl in carmustine’s case. This resonance decreases the lone pairs availability to attack the electrophilic carbon attached to chlorine. The nucleophilicity of the nitrogen, and thereby the compound’s overall reactivity, is reduced.



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