1 / 9

Lecture 9a

Lecture 9a. Protective group chemistry. The Problem. The need of protective groups arises from the low chemoselectivity of many reagents used in synthetic organic chemistry The main problem is that the use of protective groups usually adds two (or more) steps to the reaction sequence

darrion-carry
Download Presentation

Lecture 9a

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Lecture 9a Protective group chemistry

  2. The Problem • The need of protective groups arises from the low chemoselectivity of many reagentsused in synthetic organic chemistry • The main problem is that the use of protective groups usually adds two (or more) steps to the reaction sequence • This generates additional waste  • It also decreases atom economy (=atoms used that are part of the final product versus atoms used in the reaction sequence)  • Therefore the need for new reagent arises that only target one specific functional group

  3. Grignard Reaction I • When performing Grignard reactions, many functional groups react with the Grignard reagent due to various reasons: • Some functional groups protonate the Grignard reagent because they possess hydrogen atoms that are acidic: -OH (pKa~16-18 (alcohol), pKa~8-12 (phenols)), -NHx (pKa~35), -C≡CH(pKa~25), -SH(pKa~9-12), -COOH (pKa~3-5) • Some functional groups react with the reagent because they contain electrophilic atoms: -CHO, -COR, -CONR2, -COOR,-C≡N, -NO2, -SO2R, epoxides (ring opening) • If more than one of these functional groups is present in the molecule, the groups that are not suppose to react will have to be protected temporarily because some of these reactions are irreversible (i.e., C-C bond formation)

  4. Grignard Reaction II • Example 1: Reaction of a ketone in the presence of a phenol group • Pathway 1 • Step 1: Acid-base reaction • Step 2: Nucleophilic attack • Step 3: Acidic workup • Pathway 2 • Step 1: Protection of OH-group • Step 2: Nucleophilic attack • Step 3: Acidic workup • In both reactions, the same final product is obtained but the first pathway requires two equivalents of the Grignard reagent due to the initial acid-base reaction -PhH

  5. Grignard Reaction III • Example 2: Reaction of a ketone in the presence of an aldehyde function • The problem in this reaction is that aldehydes are generally more reactive than ketones which means that both groups would react with the Grignard reagent, albeit with different rates • The higher reactivity of the aldehyde is exploited in the formation of the cyclic acetal using 1,3-propanediol • The acetal does not react with the Grignard reagent • After the Grignard reaction is performed, the protective group is removed during the acidic workup which restores the aldehyde function

  6. Reduction I • Sodium borohydride (NaBH4) is less reactive and more chemoselective than lithium aluminum hydride (LiAlH4) • NaBH4will only reduce ketones and aldehydes and tolerates the presence of esters, amides, C≡C, nitro, sulfone, R-X, etc. • LiAlH4 will reduce all carbonyl functions and a broad variety of other functional groups as well 

  7. Reduction II • Example 3: Reduction of an ester in the presence of a ketone/aldehyde • The ketone function has to be protected using ethylene glycol to form a cyclic ketal before the reduction of the ester function is performed • The protective group is removed during the acidic workup, which restores the ketone function

  8. Peptide Synthesis I • If the two amino acids, glycine (Gly) and alanine (Ala), were reacted, four dipeptides (aside of polypetides) would be possible: Gly-Gly,Gly-Ala,Ala-Glyand Ala-Ala • In order to obtain one specific dipeptide i.e., Gly-Ala only, several protective groups have to be used during the dipeptide formation • The amino group in glycine is protected using the Boc-group • The carboxylic acid group of alanine is protected by a benzyl group (benzyl ester)

  9. Peptide Synthesis II • The protected forms of the amino acids are then reacted to form one specific dipeptide • DCC is used to activate the carboxylic acid • The treatment of the initial product with • Acid removes the BOC group (CO2, tert.-BuOH) • Pd-C/H2 removes the benzyl group as toluene • The resulting dipeptide is Gly-Ala only!

More Related