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Synthesise the CBZ derivative of glycine from glycine and benzyl chloroformate
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Oleksandr Zginnyk
Synthesise the CBZ derivative of glycine from glycine and benzyl chloroformate
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.
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.
dropping funnel, but now I see thats not the case.More
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Under neutral conditions glycine exists as a zwitterion as shown below.
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.
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.
Under neutral conditions glycine exists as a zwitterion as shown below.
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.
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.
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.
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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Under neutral conditions glycine exists as a zwitterion as shown below.
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.
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.
Under neutral conditions glycine exists as a zwitterion as shown below.
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.
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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