Amine Basicity. 1. Rank each of the following sets of nitrogen bases in terms of basicity, and explain your rankings. least basic sp hybridized

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1 Amine Basicity 1. Rank each of the following sets of nitrogen bases in terms of basicity, and explain your rankings. C sp 2 hybridized least basic sp hybridized most basic sp 3 hybridized the other amino group acts as an electronegative (EWG) substituent most basic least basic oxygen is more electronegative than nitrogen and thus is a stronger EWG C 3 least basic chlorine is an EWG C 3 most basic alkyl groups are EDGs Me 2 least basic the other nitrogen in the ring acts as an EWG most basic the dimethylamino group is an EDG by resonance (protonation takes place in the in the ring) C 3 the lone pair electrons are conjugated with the neighboring pi bonds C 3 least basic protonation of the would destroy the aromaticity of the ring system most basic the lone pair electrons cannot be conjugated with the neighboring pi bonds (Bredt's rule)

2 Amine Synthesis: Reagents Each of the following transformations can be carried out in no more than three steps. Fill in the reagents required for each step. If a step is not needed, mark an X for that step. 1. a 3 Br ,Pd/C 3. X LiAl 4 + workup ab 3 C, p 5, Me 2 2. Me 2, ab 3 C, p 5 3. X , 2 S 4 Sn, X ac, C LiAl 4 + workup

3 Amine Mechanisms Practice 1. Provide a complete curved-arrow mechanism for each of the following transformations. a.) 1. Me 2, + cat. Me 2. ac, C C (+/-) + + transfer 2 Me Me Me 2 (+/-) C Me Me sol: Me (+/-) C :C Product b.) Me Me 2 I 2 Me 2 I I I Me Me 2 I Me Me 2 Me Me 2 : 2 I : 2 Me 2 2 Me 2 Product Me Me + transfer Me I I I

4 More Amine Mechanism Practice 1. You learned in lecture that reductive amination may be performed by treating an aldehyde or ketone with an amine in the presence of the weak reducing agent sodium cyanoborohydride (ab 3 C). The transformation below is an alternative means of performing a reductive amination. Provide a complete curved-arrow mechanism for this transformation, keeping in mind that the reagents and conditions shown are the only ones present. (formic acid) Me 2 + C2 Me 2 Me 2 Me 2 + transfer 2 Me 2 Me 2 Me 2 + C2 power of the lone pair push!

5 The Mannich Reaction 1. Provide a complete curved-arrow mechanism for the following transformation. Me 2 Me 2 p 5 Me 2 : 2 *addition of enol occurred to f orm the - C-C bond; remember, is from the enol, and is the "carbonyl carbon" of the iminium! *enol f ormation Me 2 + transf er 2 : Me 2 2 Me 2 Me 2 *iminium formation *C-C bond f ormation 2. Provide reagents and a mechanism that show how a Mannich reaction could be used to complete the following synthetic transformation. p 5 2 : + transf er 2 : 2

6 Beckmann and Curtius Rearrangements Provide complete curved-arrow mechanisms for the following transformations, and fill in the structures of the products in each case , p transf er :sol 2 : 2 2 : :sol 1. a Me : 3 C + transf er (similar to nitrile hydrolysis) Me Me Me Me

7 ofmann Rearrangements Provide a complete curved-arrow mechanism for the following transformation, and fill in the structure of the product (xs) 2. Br 2,a 3 + transf er 2 : 3 Br : Br Br 2 : 3 : : Br C 2 :

8 Putting It Together: Amine Synthesis Using cyclohexanone as your starting material, provide a complete synthesis for each of the following amines. 1. 2, p LiAl workup ab 3 C, p 5 Me 3 ab 4 S 2 a Me pyridine (etc.) Pd/C ab 3 C, p 5 (as above) ac C 1. LiAl workup (R 2,Pd/C) Br 2 Br a cat. Pd/C 2 ab 3 C, p 5 Me 2, p 5 Me 2

9 Putting It ALL Together: Synthesis 1. Provide a synthetic pathway for the following multistep transformations. Starting Material 1. Et 2 CuLi 2. MeI 2, p , p Desired Product Starting Material LDA Li 1. Me Cr workup 2 S workup Cr 3, 2 S 2 Me 2 Me 2 (xs or pyridine) (xs or pyridine) Me Desired Product

10 More Amine Synthesis 1. Bitrex is the most bitter compound known to humans. Although it is unbearably bitter, it poses no long-term health risks, and is therefore added to other dangerous substances in order to deter people from accidentally ingesting them. Provide a multistep synthesis of Bitrex from the indicated starting materials. Me plus any other inorganic reagents, and any organic compounds with eight or fewer carbons Bitrex Me + cat. Me 1. a, 2 TP 2. + workup TP S TP 2 TP Cr 3 pyridine Et 2 ab 3 C p 5 Et 2 Br *ote the quaternary ammonium salt in the product, which you saw in lecture can be f ormed by S 2 displacement of halides by amines.

11 Putting It Together: Amine Mechanisms 1. Provide a complete curved-arrow mechanism for the following transformation. Me 2 Me Me Me ab 3 C p 5 Me Me Me 2 Me : 2 Me 2 Me + transf er 2 Me Me Me Me 2 : Me Me Me Me B C Me Me Me Me

12 Properties and Synthesis of Amino Acids 1. Draw the structures of the following three naturally-occurring amino acids as they would exist at p 7. assify each as neutral, acidic, or basic L-serine L-lysine L-glutamic acid 3 3 neutral basic 3 3 acidic 2. Match these amino acids with their expected isoelectric points. Explain your reasoning glutamic acid serine lysine The isoelectric point of an amino acid is def ined as the p at which the species will be neutral. Glutamic acid will only be neutral if its sidechain is protonated, at low p. Lysine will only be neutral if its sidechain amino group is deprotonated, at high p. Serine can be expected to have an isoelectric point near neutral p. 3. Propose a synthesis of serine (you may ignore stereochemistry) using the Strecker synthesis. 4, ac 2 C C

13 Peptide Synthesis Provide reagents for protection and deprotection of amino acids as shown below. 2 R Me + cat. 2 R Me a 2 2 R 2 Boc 2 t Bu TFA 2 R R R Using a protecting group strategy, provide a synthesis of the peptide below using traditional solution-phase chemistry. You may start with any amino acids you choose, but any protection or deprotection steps must be shown explicitly in your synthesis. Pay attention to stereochemistry! 2 Boc 2 2 Me, + cat. t Bu 2 Me DCC t Bu Me a, 2 TFA 2 glycylalanine

14 Solution-ase Peptide Synthesis Aspartame is an artificial sweetener that is 200 times sweeter than sucrose (table sugar). Provide a multistep synthesis for aspartame using any inorganic reagents, plus the protected amino acid shown below and any organic reagents with 8 or fewer carbons. For the purpose of this question you may ignore the stereochemistry of the product. Starting Material: t Bu 2 Boc , ac t Bu 2 Me Me 2 + cat. t Bu DCC t Bu Me t Bu TFA 2 C 3 aspartame (utrasweet

15 Solid-ase Peptide Synthesis ow provide a solid-phase synthesis of glycylalanine, shown below. You may start with any amino acids you choose, but any protection or deprotection steps must be shown explicitly. 2 Boc 2 t Bu Cs 2 C 3 t Bu Cs (Merrifield resin) 2 Boc 2 t Bu TFA t Bu 2 DCC t Bu F 2 glycylalanine

16 More Peptide Synthesis Provide a solution-phase synthesis of lysylglycine, shown below. You may start with any amino acids you choose, but any protection or deprotection steps must be shown explicitly. You may use any organic or inorganic reagents. The best answer will require seven or fewer steps Boc 2 Me, + cat. t Bu 2 Me t Bu DCC t Bu Me t Bu 1. a, 2 2. TFA 2 2 lysylglycine

17 Putting It Together: Peptide Synthesis Provide a multistep synthesis of the desired product shown below, an unnatural amino acid, from the indicated starting material. You may use any organic or inorganic reagents. The best answer will require eight or fewer steps. Starting Material: Et 1. DIBAL-, 78 C 2. + workup 2 C P 3 C 2 I 2,Zn/Cu , ac Desired Product