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Question
The benzyloxycarbonyl group (CBZ) is widely used to protect amines, especially in aminoacid chemistry. A procedure to synthesise the CBZ derivative of glycine from glycine and benzyl chloroformate is given in the description below.

Glycine ($0.1~\mathrm{mol}$) was dissolved in aqueous sodium hydroxide ($50~\mathrm{mL}$ of a $2~\mathrm{M}$ solution) and the solution was cooled in an ice bath. Benzyl chloroformate ($1.2~ \mathrm{eq}$) and aqueous sodium hydroxide ($25~\mathrm{mL}$ of a $4~\mathrm{M}$ solution) were added dropwise simultaneously to the glycine solution at $0°\mathrm{C}$ dropwise over thirty minutes. The mixture was stirred for an extra ten minutes, then warmed to room temperature. The solution was extracted twice with ether. The combined organic layers were acidified to $\mathrm{pH}=1$. The precipitate was filtered, washed with a little cold water and dried to give carbobenzoxyglycine ($18.5~\mathrm{g}$), m.p. $119-120°\mathrm{C}$.

(a) Relative to glycine, how many equivalents of sodium hydroxide are used in this reaction? Explain why this number was used.

(b) Can sodium carbonate ($\ce{Na2CO3}$) be used in place of sodium hydroxide? Explain why it can or cannot be used.

(c) What inorganic by-product will be formed (write its chemical name)?

(d) The procedure given includes a serious mistake, which would result in a yield of $0\%$. What is the mistake, and how might it be corrected?

My answers

(a) I mentioned $1~\mathrm{eq}$ of sodium hydroxide as sodium hydroxide reacts with glycine in a 1:1 ratio.

(b) I mentioned that sodium carbonate cannot be used in place of sodium hydroxide as sodium Carbonate is not basic enough to catalyst the reaction.

(c) Sodium chloride

(d) I mentioned that during the process when the combined organic layers were acidified to $\mathrm{pH}=1$, it could destroy the product by hydrolysing it hence giving a yield of $0\%$.

I'm unsure whether my answers are correct though, could anyone explain? Also, are there any resources on the web that contain practice questions of a similar nature to this?

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I agree with Ron's answer except for d. Using an extra equivalent of NaOH is the right procedure since you need to "mop up" the HCl that is produced when $\ce{CbzCl}$ reacts with the amino group. What is not correct is this: When you wash the reaction mixture with ether you get rid of any impurities and your product should stay in the aqueous phase. So you have to acidify the aqueous layer and not the ether one. pH 1 should be fine for the Cbz unless you leave it there and go away for the weekend.

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  • $\begingroup$ Nice answer K-P, +1. When I read the question I was thinking Cbz and $\ce{NaOH}$ in the same dropping funnel, but now I see that's not the case. $\endgroup$ – ron Nov 12 '14 at 2:05
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Under neutral conditions glycine exists as a zwitterion as shown below.

enter image description here

In this form, there is no "amine" available to react with the carboxybenzyl (or benzyloxycarbonyl, or Cbz, or Z) protecting group.

a) 1 equivalent of sodium hydroxide ("dissolved in aqueous sodium hydroxide (50 mL of a 2 M solution)") was used to convert all of the glycine zwitterion to the glycinate anion. In the anion, we do have a free amine group that can react with Cbz.

b) The $\mathrm{p}K_\mathrm{a}$ of the ammonium group in the glycine zwitterion is around 9.8 (see here for a nice discussion of the acid-base equilibria involved with amino acids), so, as you noted, a strong base is needed to convert the ammonium ion to the amine. Sodium carbonate is not sufficiently basic to accomplish this.

c) After adding sodium hydroxide to the glycine zwitterion, we form sodium glycinate and water. After the Cbz is added it reacts with the free amino group to produce the Cbz protected derivative of glycine plus hydrochloric acid.

enter image description here

The hydrochloric acid and the sodium cation react to produce sodium chloride as the inorganic by-product.

d) the mistake involves the simultaneous addition of Cbz and additional sodium hydroxide ("Benzyl chloroformate (1.2 equiv.) and aqueous sodium hydroxide ($\pu{25 mL}$ of a $\pu{4 M}$ solution) were added dropwise simultaneously"). For one thing, enough sodium hydroxide was added earlier to convert all of the glycine zwitterion to the glycinate anion, there is no need for additional sodium hydroxide. Second, sodium hydroxide and Cbz will react immediately to produce the mono-sodium salt of benzylformate. There won't be enough Cbz left to react completely with the amino acid. Once the free amine has been generated the Cbz should be added separately in a second step to react with the free amine group.

Sorry, not aware of any websites with similar practice questions.

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