Solutions a) IUPAC name = pentanedioic acid Common name = glutaric acid. b) IUPAC name = butanoic acid Common name = butyric acid

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Daniella Norman
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1 CAPTER Preparation of itriles Reactions of itriles R Br R C R C R R 2 R C R C R R R C R 2 Solutions IUPAC name = pentanedioic acid Common name = glutaric acid IUPAC name = butanoic acid Common name = butyric acid c) IUPAC name = benzene carboxylic acid Common name = benzoic acid d) IUPAC name = butanedioic acid Common name = succinic acid e) IUPAC name = ethanoic acid Common name = acetic acid f) IUPAC name = methanoic acid Common name = formic acid c)

2 518 CAPTER ,3,4,4-tetramethylhexanoic acid 2-propylpentanoic acid c) (S)-2-amino-3-phenylpropanoic acid The compound below is more acidic because its conjugate base is resonance stabilized. The conjugate base of the other compound is not resonance stabilized. 3 C The conjugate base is resonance stabilized, with the negative charge spread over two oxygen atoms, just like with carboxylic acids: meta-ydroxyacetophenone should be less acidic than para-hydroxyacetophenone, because in the conjugate base of the former, the negative charge is spread over only one oxygen atoms (and three carbon atoms). In contrast, the conjugate base of parahydroxyacetophenone has the negative charge spread over two oxygen atoms (more stable) K K formic acid potassium formate The conjugate base predominates under these conditions: [conjugate base] (p - pk = 10 a ) = 10 ( ) = 10 1 = 10 [acid] ,3-dichlorobutyric acid is the most acidic and 3,4-dimethylbutyric acid is the least acidic. 2,2-dibromopropionic acid is the most acidic and 3-bromopropionic acid is the least acidic.

3 CAPTER a 2 Cr 2 7, 2 S 4, 2 a 2 Cr 2 7, 2 S 4, 2 c) C 3, Al 3 followed by a 2 Cr 2 7, 2 S 4, 2 d) ac, followed by 3 +, heat or Mg, followed by C 2, followed by 3 + e) a 2 Cr 2 7, 2 S 4, 2 f) Mg, followed by C 2, followed by Br 1) Mg 2) C 2 3) 3 + 4) LA 5) 2 1) a 2 Cr 2 7, 2 S 4, 2 2) LA 3) 2 1) BS, heat 2) a propionic anhydride,-diphenyl-propionamide c) dimethylsuccinate d) -ethyl--methylcyclobutanecarboxamide e) butyronitrile f) propyl butyrate g) succinic anhydride h) methyl benzoate i) phenyl acetate c) d)

4 520 CAPTER Me Me - Me Me Me c) - d) 3-3 2

5 CAPTER e) f) Me Me + Me + Me g) Me Me Me Me Me Me Me Me Me Me

6 522 CAPTER Me Me Me Me Me Me 2 Me Me 2 Me Me

7 CAPTER ) xs LA 2) 2 1) xs PhMgBr 2) 2 Ph Ph c) 1) LiAl(R) 3 2) 2 3) EtMgBr 4) 2 d) 1) Et 2 CuLi 2) LA 3) 2 e) f) ) a 2 Cr 2 7, 2 S 4, 2 2) S 2

8 524 CAPTER C C C C c) + d) +

9 CAPTER ) a 2) C 3 [ + ], Et, - 2 Et 1) S 2 2) Et ) a 2) C 3 a 2 Cr 2 7 [ + ], Et, - 2 Et 2 S 4, 2 1) S 2 2) Et 1) a 2) C 3 a 2 Cr 2 7 [ + ], Et, - 2 Et 2 S 4, 2 1) S 2 2) Et Me 1) xs LA 2) 2 + Me Me 1) xs EtMgBr 2) 2 + Me c) 1) xs LA 2) 2

10 526 CAPTER 21 d) Et Et e) 1) a 2) Et 1) xs EtMgBr f) 2) ) excess LA 2 2) 2 2 excess c) heat + 4

11 CAPTER ) excess 3 2) LA 3)

12 528 CAPTER C 1) xs LA 2) 2 2 Br 1) ac 2) MeMgBr 3) 3 + c) C 1) EtMgBr 2) 2 1) LA 2) 2 C 3 + d) ) excess 3 2) S 2 C 1) ac 2) 3 + Br 1) Mg 2) C 2 3) 3 +

13 CAPTER C C ) 3 + Me 2) S 2 1) S 2 2) excess 3 3) LA 4) 2 2 1) 2 c) 2) S 2

14 530 CAPTER 21 d) Et 1) 3 + 2) S 2 3) excess 3 4) LA 5) 2 2 1) S 2 2) excess 3 C e) 3) S 2 2 f) g) 1) 2 2) [ + ], Et Et 1) ) S 2 h) 3) LiAl(R) 3 4) 2 i) C 1) 3 + 2) excess LA 3) 2 1) a 2 Cr 2 7, 2 S 4, 2 2) S 2 C 3) excess 3 j) 4) S Four steps: 1) oxidize to a carboxylic acid, 2) convert into an acid halide, 3) convert into an amide, and 4) reduce to give an amine.

15 CAPTER ) B 3 TF 2) 2 2, a 3) a 2 Cr 2 7, 2 S 4, 2 4) S ) S 2 2) Et 2 CuLi 3) LA 4) 2 1) Mg Br 2) 3) 2 4) c) C 1) 3 + 2) S 2 3) excess MeMgBr 4) S 2 C 1) EtMgBr [ + ] 2) 3 + (C 3 ) 2-2

16 532 CAPTER C 3 C 1) S 2 2) LiAl(R) 3 3) ) xs LA PBr 3 2) 2 Br 1) Mg 2) 3) 2 C 3 C 3 + 1) xs LA 2) 2 PBr 3 Br Mg 1) Mg 2) C 2 3) 3 + 1) EtMgBr 1) S 2 2) 2 2) LiAl(R) 3 c) 1) S 2 2) LiAl(R) 3 3) 2 C 3 C 3 + 1) xs LA 2) 2 PBr 3 Br 1) S 2 2) xs EtMgBr 3) 2 Mg 1) Mg 2) 3) 2 1) xs EtMgBr a 2 Cr 2 7 2) 2 2 S 4, 2

17 CAPTER d) C 3 C 3 + 1) xs LA 2) 2 PBr 3 Br Mg 1) Mg 2) C 2 3) 3 + 1) xs EtMgBr S 2 2) The signal at 1740 cm -1 indicates that the carbonyl group is not conjugated with the aromatic ring (it would be at a lower wavenumber if it was conjugated), 1) LA 2) Increasing acidity C C C C C 3 C Br 2 Increasing acidity Br Br Br

18 534 CAPTER The second carboxylic acid moiety is electron withdrawing, and stabilizes the conjugate base that is formed when the first proton is removed. The carboxylate ion is electron rich and it destabilizes the conjugate base that is formed when the second proton is removed. c). d) The number of methylene groups (C 2 ) separating the carboxylic acid moieties is greater in succinic acid than in malonic acid. Therefore, the inductive effects are not as strong cyclopentanecarboxylic acid cyclopentanecarboxamide c) benzoyl chloride d) ethyl acetate e) hexanoic acid f) pentanoyl chloride g) hexanamide acetic anhydride benzoic acid c) formic acid d) oxalic acid chirality centers hexanoic acid 2-methylpentanoic acid 3-methylpentanoic acid 4-methylpentanoic acid 2,2-dimethylbutanoic acid 2,3-dimethylbutanoic acid 3,3-dimethylbutanoic acid 2-ethylbutanoic acid

19 CAPTER butanoyl chloride 2-methylpropanoyl chloride ) excess LA 2) 2 1) excess LA 2) 2 3) Ts, py 4) t-buk c) 1) excess LA 2) 2 3) PBr 3 4) ac 5) ) B 3 TF 2) 2 2, a 3) a 2 Cr 2 7, 2 S 4, 2 Br 1) ac 2) As discussed in Chapter 19, the methoxy group is electron donating via resonance, but electron withdrawing via induction. The resonance effect is stronger, but only occurs when the methoxy group is in an ortho or para position.

20 536 CAPTER c) d) e) f) 2 g) h) c) a d) ) xs LA 2) 2

21 CAPTER ) S 2 2) (C 3 ) 2, pyridine S 2 C c) 2 1) 3 + d) Me 2) C 3 C, pyridine Me DIBA e) f) + g) pyridine 1) xs LA 2) 2 h) 3 + i) heat 3 + j)

22 538 CAPTER c) C 3 C 2 C 2 + (C 3 ) 3 C Et [ + ] Et a 2 Cr S 4, 2 DIBA S 2 1) LiAl(R) 3 2) 2 xs a, followed by a 2 Cr 2 7, 2 S 4, 2 ac followed by 3 + c) a, followed by a 2 Cr 2 7, 2 S 4, 2, followed by S 2 d) ac, followed by 3 +, followed by S 2, followed by xs 3 e) a, followed by a 2 Cr 2 7, 2 S 4, 2, followed by S 2, followed by xs 3 f) ac followed by 3 +, followed by [ + ], Et (with removal of water)

23 CAPTER ) Br 2, AlBr 3 2) Mg 3) 4) 2 1) Br 2, AlBr 3 2) Mg 3) C 2 4) 3 + 5) S 2 6) excess (C 3 ) 2 1) (C 3 ) 2 C, Al 3 2) BS, heat 3) Mg c) 4) C 2 5) 3 + 1) 2, Al 3 2) a 2, 3 3), pyridine d) Br 1) Mg 2) C 2 3) Et

24 540 CAPTER 21 1) a 2 Cr 2 7, 2 S 4, 2 2) S 2 3) Et 2 CuLi Br 1) Mg 2) C 2 3) 3 + 1) LA 2) 2 3) 4) S 2 c) 5) excess C 3 2 d) Br 1) ac 2) EtMgBr 3) A methoxy group is electron donating, thereby decreasing the electrophilicity of the ester moiety. A nitro group is electron withdrawing, thereby increasing the electrophilicity of the ester group

25 CAPTER Br 1) Mg 2) C 2 3) 3 + 4) S 2 5) excess Et ) excess MeMgBr 2)

26 542 CAPTER R R - R R R R - R R R R R R R c) Ph Ph Ph CF 3 S decanoic acid

27 CAPTER ) Br 2, AlBr 3 2) Mg 3) 4) phenylalanine 2 aspartic acid Ph Ph Ph Ph - Ph Ph Ph Ph

28 544 CAPTER 21 c) d) 2 2 -

29 CAPTER e) C C C C The three chlorine atoms withdraw electron density via induction. This effect renders the carbonyl group more electrophilic heat + C S Ampicillin

30 546 CAPTER (glycolic acid) hydroxyacetic acid Polymer

31 CAPTER ) S 2 2) Et 2 CuLi 3) C 2 C 2, [ + ], - 2 1) 3 + 2) S 2 2 3) LiAl(R) 3 4) 2 5) [ + ], C 3 2, - 2 1) MCPBA 2) 3 + c) 3) S 2 4) (C 3 ) 2 d) Me 1) 3 + 2) S 2 3) LiAl(R) 3 S 4) SC 2 C 2 S, [ + ], - 2 S 1) S 2 e) C 2) LiAl(R) 3 3) C 2 C 2, [ + ], - 2 1) a 2 Cr 2 7, 2 S 4, 2 f) 2) MCPBA 3) 3 + 1) excess LA 2) 2 3) g) [ + ], - 2

32 548 CAPTER ) 2, Al 3 1) a 2) 3, 2 S 4 2), Zn

33 CAPTER xs 3 2 Compound A An IR spectrum of butyric acid should have a broad signal between 2500 cm -1 and 3600 cm -1. An IR spectrum of ethyl acetate will not have this signal The 1 MR spectrum of para-chlorobenzaldehyde should have a signal at approximately 10 ppm corresponding to the aldehydic proton. The 1 MR spectrum of benzoyl chloride should not have a signal near 10 ppm Me If the oxygen atom of the group in the starting material is an isotopic label, then we would expect the label to be incorporated into the ring of the product: R S R R R R S S R S R R

34 550 CAPTER The lone pair of the nitrogen atom in this case is participating in resonance and is less available to donate electron density to the carbonyl group. As a result, the carbonyl group is more electrophilic than the carbonyl group of a regular amide (where the lone pair contributes significant electron density to the carbonyl group). Also, when this compound functions as an electrophile in a nucleophilic acyl substitution reaction, the leaving group is particularly stable because it is an aromatic anion. With a good leaving group, this compound more closely resembles the reactivity of an acid halide than an amide DMF, like most amides, exhibits restricted rotation about the bond between the carbonyl group and the nitrogen atom. This restricted rotation causes the methyl groups to be in different electronic environments. They are not chemically equivalent, and will therefore produce two different signals (in addition to the signal from the other proton in the compound). Upon treatment with excess LA followed by water, DMF is reduced to an amine that does not exhibit restricted rotation. As such, the methyl groups are now chemically equivalent and will together produce only one signal. Restricted rotation causes the methyl groups to be in different electronic environments. As a result, the 13 C MR spectrum of DMF should have three signals.

Nucleophilic Addition Reactions of Carboxylic Acid Derivatives

Nucleophilic Addition Reactions of Carboxylic Acid Derivatives Lecture 5: bjectives: Nucleophilic Addition eactions of Carboxylic Acid Derivatives By the end of this lecture you will be able to: draw the mechanism of a nucleophilic addition-elimination reaction with