Carboxylic Acid and Derivatives Carboxylic acids: Nomenclature, Physical

Carboxylic Acid and Derivatives Carboxylic acids: Nomenclature, Physical

Carboxylic Acid and Derivatives Carboxylic acids: Nomenclature, Physical Properties Synthesis Reactions Carboxylic acid derivatives: Acyl halide, Anhydride, Ester, Amide Nucleophilic Acyl Substitution Reaction of Acyl halide, Anhydride, Ester, Amide Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-1 Klein, Organic Chemistry 2e

Carboxylic Acids Carboxylic acids are abundant in nature and in pharmaceuticals Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-2 Klein, Organic Chemistry 2e Acetic acid and derivatives The US produces over 2.5 million tons/year of acetic acid, primarily used to produce vinyl acetate Vinyl acetate is used in paints and adhesives, such as

crazy glue. Carboxylic acid derivatives such as vinyl acetate are very common and play a central role in organic chemistry Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-3 Klein, Organic Chemistry 2e 1. Nomenclature of Carboxylic Acids Monocarboxylic acids are named with the suffix oic acid The carbon of the carboxylic acid moiety is assigned

locant position 1 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-4 Klein, Organic Chemistry 2e Naming Carboxylic Acids: Ring, etc. carboxylic acid group attached to a ring: cycloXXane carboxylic acid Common names for carboxylic acids Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-5 Klein, Organic Chemistry 2e Dicarboxylic Acids Dicarboxylic acids are named with the suffix dioic acid Common names for dicarboxylic acids: Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-6

Klein, Organic Chemistry 2e 21.3 Structure and Properties of Carboxylic Acids The carbon atom of the carboxylic acid has a trigonal planar geometry. The acid moiety: forming strong hydrogen bonding between acid pairs (DIMERIC) As a result, carboxylic acids generally have high boiling points consider the BPs of acetic acid (118 C) and isopropanol (82 C) Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-7 Klein, Organic Chemistry 2e Conjugate Base of Carboxylic Acids Carboxylate ions end in the suffix oate NaOH Compounds that end in the suffix oate are often found in food ingredient lists as preservatives NaOH is a strong base, so it is capable of reacting 100% with a carboxylic acid Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-8 Klein, Organic Chemistry 2e Acidity of Carboxylic Acids In water, the equilibrium generally favors the acid pKa values mostly range between 4 and 5. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-9 Klein, Organic Chemistry 2e

Carboxylic Acids as Weak Acid Carboxylic acid is stronger acid than alcohol H-Cl pKa = -7 Induction from electron-withdrawing carbonyl group and Resonance between C=O and C-O- be used to explain the acidity of a carboxylic acid. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-10 Klein, Organic Chemistry 2e

The Ionization of Carboxylic Acids depends on pH The equilibrium between the carboxylic acid and the carboxylate depends on pH At physiological pH (7.3), the acid and the conjugate base make a buffer. According to the Henderson-Hasselbalch equation we can calculate the ratio of carboxylate/acid is approximately 400:1. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-11

Klein, Organic Chemistry 2e Carboxylic Acid as Part of Biomolecule Many biomolecules exhibit carboxylic acid moieties Biomolecules such as pyruvic acid exist primarily as the carboxylate under physiological conditions Practice with conceptual checkpoint 21.8 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-12 Klein, Organic Chemistry 2e

Structure Affects the Acidity of Carboxylic Acids Electron withdrawing substituents have a great effect on acidity WHY? Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-13 Klein, Organic Chemistry 2e Electron withdrawing Effect on Acidity of Benzoic Acid Electron withdrawing substituents affect benzoic acid as

well Practice with conceptual checkpoint 21.9 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-14 Klein, Organic Chemistry 2e 21.4 Preparation of Carboxylic Acids In previous chapters Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-15 Klein, Organic Chemistry 2e Nitrile (R-CN) to Carboxylic Acid 1. The hydrolysis of a nitrile can produce a carboxylic acid The byproduct is ammonia/ammonium Starting from alkyl halides to carboxylic acids: two-step process (SN + hydrolysis) Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-16

Klein, Organic Chemistry 2e Carboxylic Acid from Grignard and CO2 2. Carboxylation of a Grignard reaction can be achieved using CO2 -MgBr It is actually two-step: Grignard Rxn, followed by acidification. The Grignard reagent and the H3O+ can not be added together. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-17

Klein, Organic Chemistry 2e Another way for R-X to R-COOH This gives us a second method to convert an alkyl halide into a carboxylic acid Practice with conceptual checkpoint 12.10 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-18 Klein, Organic Chemistry 2e

Reduction of Carboxylic Acids by LAH Reduction by LiAlH4 : RCOOH RCH2OH Mechanism: Deprotonation, Aldehyde intermediate Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-19 Klein, Organic Chemistry 2e Reduction of Carboxylic Acid by Borane The more mild borane reagent (in tetrahydrofuran, THF) can also be used to achieve reduction Reduction with borane is selective compared to LAH

reduction Practice with conceptual checkpoint 21.11 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-20 Klein, Organic Chemistry 2e 21.6 Carboxylic Acid Derivatives RCOZ: When Z is a heteroatom (not carbon), the compound is called a carboxylic acid derivative Nitrile is also an acid derivative despite not having a carbonyl group, due to its association from Amide.

Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-21 Klein, Organic Chemistry 2e Carboxylic Acid Derivatives in Life Esters are known to have pleasant odors Amides are important in structures of protein. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-22 Klein, Organic Chemistry 2e

Naming of Acid Halide or Acyl Halide To name an acid halide, replace ic acid with yl halide Alternatively, the suffix, carboxylic acid can be replaced with carbonyl halide Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-23 Klein, Organic Chemistry 2e

Naming Anhydrides Symmetrical Acid anhydrides (RCO-O-OCR) are named by replacing acid with anhydride Asymmetrical acid anhydrides (RCO-O-OCR) are named by listing the acids alphabetically and adding the word anhydride Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-24

Klein, Organic Chemistry 2e Naming Esters Esters are named by naming the alkyl group attached to the oxygen followed by the carboxylic acids name with the suffix ate Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-25 Klein, Organic Chemistry 2e Naming Amide Amides are named by replacing the suffix ic acid or

oic acid with amide Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-26 Klein, Organic Chemistry 2e Naming Amide with N-alkyl Group If the nitrogen atom of the amide group bears alkyl substituents, their names are placed at the beginning of the name with N (italics!) as their locant Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-27 Klein, Organic Chemistry 2e Naming Nitriles Nitriles are named by replacing the suffix ic acid or oic acid with onitrile Practice with conceptual checkpoints 21.12 and 21.13 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-28 Klein, Organic Chemistry 2e

21.7 Reactivity of Carboxylic Acid Derivatives Carboxylic acid derivatives have electrophilic sites on Carbonyl carbon The nearby heteroatom affects the reactivity on carbonyl carbon: Induction increases electrophilicity of carbonyl carbon Resonance stabilizes positive charge on carbonyl charge, thus reducing electrophilicity of carbon.

Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-29 Klein, Organic Chemistry 2e Factors Affecting Reactivity of Carboxylic Acid Derivatives Reactivity can be affected by

Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-30 Induction Resonance Sterics Quality of leaving group Klein, Organic Chemistry 2e High Reactivity of Acid Halide Induction: The electronegative chlorine

enhances the electrophilic character of the carbonyl. Resonance: The high electronegativity of chlorine prevents donation electron density to the carbonyl. Chloride does not affects the sterics of the nucleophilic attack on the carbonyl The chloride is a good leaving group, which also enhances its reactivity Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-31 Klein, Organic Chemistry 2e

Low Reactivity of Amide Induction: nitrogen has high electronegativity Resonance: The lone pair on N significantly stabilizes positive charge on carbonyl carbon atom Sterics effect from NH2 is minimal. As strong nucleophile, amino group is poor leaving group Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-32 Klein, Organic Chemistry 2e

Nucleophilic Acyl Substitution Mechanism as two-step process Nucleophilic Addition yields tetrahedral intermediate. Elimination (intramolecular): Due to the stability of C=O, the loss of leaving group step should occur if a leaving group is present H and R are poor leaving group, thus no loss. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-33 Klein, Organic Chemistry 2e Example of Acyl substitution

Reaction between benzoyl chloride and NaOMe: The highest quality leaving group leaves the tetrahedral intermediate Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-34 Klein, Organic Chemistry 2e Acyl Substitution vs. SN2 Acyl substitution is not concerted process. Do NOT draw the acyl substitution with an SN2 mechanism

Sometimes a proton transfer will be necessary: Under acidic conditions, () charges rarely form due to protonation Under basic conditions, (+) charges rarely form due to depronation Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-35 Klein, Organic Chemistry 2e Acyl substitution in Acidic Condition Under acidic conditions, (-) charges rarely form The first step will NOT

be nucleophilic attack The electrophile and nucleophile are both low in energy Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-36 Klein, Organic Chemistry 2e Acyl substitution in Acidic Condition Begins with Protonation H3O+ is unstable and

drives the equilibrium forward by starting the reaction mechanism Now that the electrophile carries a (+) charge, it is much less stable (higher in energy. Complete the rest of the mechanism Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-37 Klein, Organic Chemistry 2e

Acyl substitution in Alkaline Condition Under basic conditions, (+) charges rarely form The OH- is the most unstable species in the reaction and drives the equilibrium forward Continue the rest of the mechanism Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-38

Klein, Organic Chemistry 2e Acyl substitution in Neutral Condition Neutral nucleophiles are generally less reactive, but they can still react if given enough time An intermediate with both (+) and (-) charge forms Intermediates with two (+) or two (-) charges are very unlikely to form due to electrostatic repulsion. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-39 Klein, Organic Chemistry 2e

Multiple Proton Transfer is likely Depending on reaction conditions, up to 3 proton transfers may be necessary in the mechanism Draw a complete mechanism for the reaction below Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-40 Klein, Organic Chemistry 2e Practice: Mechanism of Acyl Substitution

Give necessary reaction conditions and a complete mechanism for the reaction below O O O excess O + O OH O

+ O Note: This is a bifurcated process, each yielding one fo the two esters. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-41 Klein, Organic Chemistry 2e 21.8 Preparation and Reaction of Acid Chlorides Acid chlorides is useful in synthesis due to high

reactivity. Mechanism of An acid chloride from reaction between an acid and SOCl2 : Nucleophilic addition, then elimination Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-42 Klein, Organic Chemistry 2e Mechanism: Acyl chloride from Acid and SOCl2.The Cl- Strikes Back! Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-43 Klein, Organic Chemistry 2e Preparation Acid Chlorides: Pyridine and Moisture The mechanism is more favored in the presence of a non-nucleophilic base like pyridine. To avoid an acid chloride being converted into an acid, it must be protected from moisture Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-44 N Klein, Organic Chemistry 2e ALCOHOLYSIS of Acid Chlorides Often acid chlorides are used to synthesize esters Give a complete mechanism showing how pyridine acts as a base in the mechanism Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-45

Klein, Organic Chemistry 2e AMINOLYSIS of Acid Chlorides Often acid chlorides are used to synthesize amides Give a complete mechanism showing WHY two equivalents are used Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-46 Klein, Organic Chemistry 2e Reduction of Acid Chlorides Acid chlorides can also be reduced using LAH, yielding a primary alcohol (RCOCl RCH2OH). Aldehyde is the reaction intermediate. To stop the aldehyde from being reduced to the alcohol, a bulky reducing agent can be used Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-47

Klein, Organic Chemistry 2e RCOCl + 2 RMgBr 3 Alcohol Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-48 Klein, Organic Chemistry 2e Gillman Reagent + Acid Chlorides The Gilman reagent is another nucleophilic organometallic reagent that reacts readily with acid chlorides The C-Cu bond

is less ionic than the C-Mg bond O Gilman reagent R C R The low ionic character of the C-Cu bond reduces the reactivity of the organometallic reagent Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-49 Klein, Organic Chemistry 2e Reaction of Acid Chlorides: Overview Practice with conceptual checkpoints 21.18 through 21.20 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-50 Klein, Organic Chemistry 2e Practice: Acid Chlorides

Fill in necessary reagents for the reactions below O CO2H COCl O N Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-51 Klein, Organic Chemistry 2e

Preparation of Acid Anhydrides at High Temperature Acetic anhydride can be synthesized by heating 2 moles of acetic acid High heat is needed to drive the equilibrium forward: endothermic, entropy increase This process doesnt work for most other acids, because their structures can not withstand such high temperatures Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-52

Klein, Organic Chemistry 2e Preparation of Acid Anhydrides from ROCl A more practical synthesis occurs when an acid chloride is treated with a carboxylate The R groups attached to the anhydride do not have to be equivalent Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-53 Klein, Organic Chemistry 2e

Acid Anhydride vs. Acid Chloride Given that they both contain quality leaving groups, acyl chloride has better leaving group than acid anhydrides, thus higher reactivity. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-54 Klein, Organic Chemistry 2e Reactions of Acid Anhydrides Figure 21.10 shows how anhydrides can

undergo many reactions analogous to those of acid chlorides Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-55 Klein, Organic Chemistry 2e Reactions of Acid Anhydrides A nonucleophilic weak base such as pyridine is not necessary when acid anhydrides react with a nucleophile, as carboxylate is a weak base. When a nucleophile reacts with an anhydride, there will be a carboxylic acid byproduct. It is often a

disadvantage to have such a byproduct in a reaction Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-56 Klein, Organic Chemistry 2e Reactions of Acid Anhydrides Acetic anhydride is often used to acetylate an amine or an alcohol Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-57

Klein, Organic Chemistry 2e Reactions of Acid Anhydrides in Synthesis Practice with conceptual checkpoint 21.21 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-58 Klein, Organic Chemistry 2e Ester from Fischer Esterification Fisher et al (1895): A Nucleophilic Acyl Substitution. Carboxylic

acid and Alcohol (1 or 2) or even Phenol; Acid catalyst O C H+ + HO R' O C +

H OH OH R Entropy O change? R' Slow,R Reversible process (as in winery). Carbonyl in RCOOH as poor electrophile ROH as poor nucleophile Protonation activates Carbonyl & facilitates dehydration Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-59 Fischer Esterification Mechanism Protonation Nucleophilic Attack Deprotonation Protonation Dehydration O + C R O H+ HO

R' + C OH R O R' Protonation activates Carbonyl & facilitates dehydration

Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-60 H OH Fisher Esterification is Reversible Fischer esterification reaction is an reversible/equilibrium O + C R

O H+ HO R' OH + C R O

H OH R' Use Le Chateliers principle to promote product: Increase concentration of reactant Remove product (low b.p. ester? Remove water (desiccant; Dean Stark trap refluxing with nonpolar, low density, high b.p. solvent ) Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-61

Esters from Acyl Chloride & ROH Acyl Chloride (RCOCl) as strong electrophile Aprotic weak base (pyridine or 3 amine) to remove byproduct HCl Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-62 Klein, Organic Chemistry 2e Reactions of Esters: Alkaline Hydrolysis Hydrolysis in alkaline condition (saponification) This is followed by deprotonation, yielding carboxylate

ion To produce a carboxylic acid, H3O+ must be added at the end. WHY? Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-63 Klein, Organic Chemistry 2e Ester in Acidic Hydrolysis Ester hydrolysis can be catalyzed under acidic conditions Activation of Carbonyl: The carbonyl of the ester is protonated, Water acts as a nucleophile attacking the carbonyl carbon

Draw out the complete mechanism Show how regeneration of H3O+ makes it catalytic Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-64 Klein, Organic Chemistry 2e Aminolysis of Esters Amine as nucleophile: The synthetic utility is limited, because the process is slow and because there are more efficient ways to synthesize amides

Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-65 Klein, Organic Chemistry 2e Reduction of Esters Esters can be reduced using reagents such as LiAlH4 Two equivalents of reducing agent are required Two alcohols are produced LiAlH4 is a strong reducing agent, the intermediate aldehyde is difficult to achieve Mechanism:

Hydride as nucleophile Aldehyde as intermediate Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-66 Klein, Organic Chemistry 2e Reduction of Ester to Aldehyde When performed at low temperature, reduction with DIBAH yields an aldehyde. HOW? Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-67

Klein, Organic Chemistry 2e Grignard Reactions of Esters Two moles can be used to make a tertiary alcohol Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-68 Klein, Organic Chemistry 2e Synthesis using Esters Give necessary reagents for the conversions below O

HO O O HO O OH OH OH HO

OH HO Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-69 Klein, Organic Chemistry 2e Preparation of Amides Nylon is a polyamide Polyester is made similarly. HOW? Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-70 Klein, Organic Chemistry 2e Hydrolysis of Amides The process is slow and requires high temperature The mechanism is similar to hydrolysis of an ester Protonation of carbonyl Water as nucleophile The hydrolysis of amide can also be promoted with NaOH Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-71

Klein, Organic Chemistry 2e Reductions of Amides LiAlH4 can reduce an amide to an amine The mechanism is unique Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-72 Klein, Organic Chemistry 2e

Preparation of Nitriles Substitution: 1 or 2 alkyl halide is treated with a cyanide ion, the CN- acts as a nucleophile (SN2). Dehydration: also from an amide using a variety of reagents including SOCl2 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-73 Klein, Organic Chemistry 2e Hydrolysis of Nitriles Acidic hydrolysis:

Mechanism: The nitrogen is protonated multiple times and water acts as a nucleophile Alkaline hydrolysis: Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-74 Klein, Organic Chemistry 2e Grignard Reactions of Nitriles Nitriles can also react with Grignards After the nitrile is consumed, H3O+ is added to form an

imine, which can be hydrolyzed with excess H3O+ (aq) to form a ketone. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-75 Klein, Organic Chemistry 2e Reductions of Nitriles to 1 Amine Similar to how carboxylic acids can be converted to alcohols using LAH (section 21.5), nitriles can be converted to amines Practice with conceptual checkpoints 21.29 through

21.31 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-76 Klein, Organic Chemistry 2e 21.14 Synthetic Strategies When designing a synthesis, there are two general considerations that we make 1. Is there a change in the carbon skeleton? 2. Is there a change in functional groups? We have learned many new functional group

transformations in this chapter see next slide Practice with SkillBuilder 21.2 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-77 Klein, Organic Chemistry 2e Reaction Map Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-78

Klein, Organic Chemistry 2e Practice: Synthetic Strategies Give necessary reagents for the conversion below. Multiple steps will be necessary O CN H Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-79 Klein, Organic Chemistry 2e

Bond-forming Reactions There are 2 categories of bond-forming reactions Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-80 Klein, Organic Chemistry 2e More practice When forming new carbon-carbon bonds, it is critical to install functional groups in the proper location Give necessary reagents for the conversion below. More than one step will be necessary Br

OH O Practice with SkillBuilder 21.3 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-81 Klein, Organic Chemistry 2e 21.15 IR Spectroscopy: >C=O Recall that C=O stretching is a prominent peak in IR spectra

Recall that conjugated carbonyl signals appear at lower wavenumbers (about 40 cm-1 less) Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-82 Klein, Organic Chemistry 2e IR and NMR: O-H, -CN The O-H stretch of an acid gives a very broad peak (2500-3300 cm-1) The CN triple bond stretch appears around 2200 cm-1 Carbonyl 13C peaks appear around 160-185 ppm Nitrile 13C peaks appear around 115-130 ppm

The 1H peak for a carboxylic acid proton appears around 12 ppm Practice with conceptual checkpoint 21.38 Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-83 Klein, Organic Chemistry 2e Practice: NMR Predict the number and chemical shift of all 13C peaks for the molecule below Predict the number, chemical shift, multiplicity, and integration of all 1H peaks for the molecule below

O HO O Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-84 O Klein, Organic Chemistry 2e Ester from Fischer Esterification Fischer-Speier esterification: carboxylic acid and an alcohol (1 or 2) using an acid catalyst

O + C R O H+ HO R' OH

Copyright 2015 John Wiley & Sons, Inc. All rights reserved. + C R 21-85 O R' H OH

Fischer Esterification Mechanism (contd) Each step is an equilibrium Under acidic conditions, (-) charges are avoided Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-86 Klein, Organic Chemistry 2e Additional Practice Problems Give an appropriate name for the compound below

O OH Cl Cl Cl Cl Copyright 2015 John Wiley & Sons, Inc. All rights reserved. HO 21-87

O Klein, Organic Chemistry 2e Additional Practice Problems Rank the following molecules by increasing pKa values. O O OH O OH

SH OH O A B Copyright 2015 John Wiley & Sons, Inc. All rights reserved. C 21-88

D Klein, Organic Chemistry 2e Additional Practice Problems Predict the products for the reactions below. Br Br 1) Mg / ether 2) CO2 3) H3O+ / H2O 1) NaCN

2) H3O+ / H2O Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-89 Klein, Organic Chemistry 2e Additional Practice Problems Give an appropriate name for the amide below O N Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

21-90 Klein, Organic Chemistry 2e Additional Practice Problems Using induction, sterics, and resonance, explain why acid halides are especially electrophilic from a kinetic perspective. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-91 Klein, Organic Chemistry 2e

Additional Practice Problems Using the quality of the leaving group, explain why acid halides are especially reactive from a thermodynamic perspective. Copyright 2015 John Wiley & Sons, Inc. All rights reserved. 21-92 Klein, Organic Chemistry 2e Additional Practice Problems Give reagents necessary for the synthesis below where all carbon atoms in the product come from a molecule of the reactant

O O O Copyright 2015 John Wiley & Sons, Inc. All rights reserved. O 21-93 Klein, Organic Chemistry 2e

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