Assignment
Instructions:
1. If k1 > k2, is the overall reaction SN1 or SN2?
2. Conversely, if k2 > k1 is the overall reaction SN1 or SN2? Explain why.
The following molecule is chloroethane.
ClCH2CH3
molecule 1
It is unreactive towards hydroxide and most nucleophiles under normal conditions, i.e., the chlorine-carbon bond is not a very good electrophilic center, hence 1 is not a good alkylating agent and does not transfer the CH3CH2 group easily.
On the other hand, there is a class of drugs that contain a chloroethyl group which are good alkylating agents and have been used clinically to treat cancer. An example of this class of drugs is melphalan.
The reason melphalan, is a good alkylating agent, and 1 is not, is due to the formation of the intermediate 3 caused by the close proximity of a basic nitrogen to the carbon-chlorine bond in 2. Reaction of 3 with a nucleophile (Nuc) gives the alkylated nucleophile, 4.
In vivo, in a therapeutic setting, the Nuc is specifically nitrogen or oxygen on a purine in a DNA strand, which once alkylated cleaves from the DNA strand to create errors in reading the DNA code and ultimately death of a cancer cell. The alkylation takes place in two steps defined by the rate constants k1 and k2.
3. If the basic pKa of the nitrogen in the -N-(CH2 - CH2 - Cl)2 in molecule 2 is 1.5 and the basic pKa in the -N-(CH2- CH2 - Cl)2 in Molecule 5 is 6.5, which drug, (molecule 2 or molecule 5) is more likely to go by an SN1 reaction with the nucleophile and why? Note that the rate or ease of reaction k1 for 2 → 3 will depend on how basic is the nitrogen in -N-(CH2 - CH2 -Cl)2
(Cl CH2 CH2.)2 N-CH3
molecule 5
The following molecule, atracurium, is a very complex drug. It is a neuromuscular blocking agent and is related to the natural product tubocurarine. Atracurium exhibits a very short half-life (20-min). The products of the fastest inactivation process are shown below.
4. Research and Explain what chemical mechanism is responsible for the formation of the products.
Hint: The acidic pKa of CH3(C=O)CH3 → CH3(C=O)CH2- is 20.=
