ch21 - laney college4/25/2012 4 • lialh4 (lah) is a strong reducing agent that can convert an acid...

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• Carboxylic acids are abundant in nature and in pharmaceuticals.

21.1 Introduction Carboxylic Acids

Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e21-1

• The US produces over 2.5 million tons of acetic acid per year, which is primarily used to produce vinyl acetate.

21.1 Introduction Carboxylic Acids

– Vinyl acetate is used in paints and adhesives.

• Carboxylic acid derivatives, such as vinyl acetate, are very common, and they play a central role in organic chemistry.


• Monocarboxylic acids are named with the suffix “oic acid.”

21.2 Nomenclature of Carboxylic Acids

• The carbon of the carboxylic acid moiety is assigned the locant position 1.


• When the carboxylic acid group is attached to a ring, it is named as an alkane carboxylic acid.

• There are also many common names for carboxylic id


acids.


• Dicarboxylic acids are named with the suffix “dioic acid.”

• There are also many common names for dicarboxylic acids:


• Practice with CONCEPTUAL CHECKPOINTs 12.1 through 12.3.


• The carbon atom of the carboxylic acid has a trigonal planar geometry. WHY?

• The acid moiety is capable of strong hydrogen (H‐) bonding including H‐bonding between acid pairs.

21.3 Structure and Properties of Carboxylic Acids

• As a result, carboxylic acids generally have high boiling points.– Consider the BPs of acetic acid (118 °C) and

isopropanol (82 °C).Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e21-6

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• Carboxylate ions end in the suffix “oate.”


• 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.


• In water, the equilibrium generally favors the acid .

K l tl b t 4 d 5 Wh t i K ?


• pKa values mostly range between 4 and 5. What is pKa?


• How does the pKa value for a carboxylic acid compare to a strong acid like HCl, or a very weak acid like ethanol?

H–Cl


pKa = -7

• How can induction and resonance be used to explain the acidity of a carboxylic acid?



• Let’s examine the equilibrium between the carboxylic acid and the carboxylate at physiological pH (7.3).

• The acid and the conjugate base make a buffer. HOW?

• Recall that the Henderson‐Hasselbalch equation can be


used to calculate the pH of a buffer:

• Assuming the pKa is 4.3, calculate the ratio of carboxylate/acid.


• 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.


• Electron withdrawing substituents have a great effect on acidity.


• WHY?


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• Electron withdrawing substituents affect benzoic acid as well.




• In earlier chapters, we already learned some methods to synthesize carboxylic acids.

21.4 Preparation of Carboxylic Acids


• In earlier chapters, we already learned some methods to synthesize carboxylic acids.



• Let’s examine two more ways to make carboxylic acids:1. The hydrolysis of a nitrile can produce a carboxylic acid.

– The mechanism will be discussed later.


The mechanism will be discussed later.

– Carboxylic acids can be made from alkyl halides using a two‐step process.


• Let’s examine two more ways to make carboxylic acids:2. Carboxylation of a Grignard reaction can be achieved using

CO2.


– The Grignard reagent and the H3O+ cannot be added together. WHY?


• This gives us a second method to convert an alkyl halide into a carboxylic acid:




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• LiAlH4 (LAH) is a strong reducing agent that can convert an acid to a primary alcohol:– The LAH acts as a base first.

21.5 Reactions of Carboxylic Acids

– Then, an aldehyde is produced.


• LiAlH4 (LAH) is a strong reducing agent that can convert an acid to a primary alcohol:– The aldehyde is further reduced to the alcohol.


– Can the reduction be stopped at the aldehyde?Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e21-20

• The milder borane reagent can also be used to promote the reduction.

• Reduction with borane is selective compared to LAH


reduction.



• The reduction of acids with LAH or borane result in a decrease in the oxidation number for carbon. HOW?

• There are also many reactions where carboxylic acids don’t change their oxidation state

21.6 Introduction to Carboxylic Acid Derivatives

don’t change their oxidation state.

• What criteria must Z fulfill so that there is no change in the oxidation state?


• When Z is a heteroatom, the compound is called a carboxylic acid derivative.


• Because it has the same oxidation state, a nitrile is also an acid derivative despite not having a carbonyl group.


• Acid halides and anhydrides are relatively unstable, so they are not common in nature; we will discuss their instability in detail later in this chapter.

• Some naturally occurring esters are known to have l d


pleasant odors:


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• Amides are VERY common in nature.

• What type of molecule in nature includes amide li k ?


linkages?

• Many other compounds feature amides, including some natural sedatives like melatonin.


• To name an acid halide, replace “ic acid” with “yl halide.”



• Alternatively, the suffix, “carboxylic acid” can be replaced with “carbonyl halide.”



• Acid anhydrides are named by replacing “acid” with “anhydride.”



• Asymmetric acid anhydrides are named by listing the acids alphabetically and adding the word anhydride.



• Esters are named by naming the alkyl group attached to the oxygen followed by the carboxylic acid’s name with the suffix “ate.”



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• Amides are named by replacing the suffix “ic acid” or “oic acid” with “amide.”



• If the nitrogen atom of the amide group bears alkyl substituents, their names are placed at the beginning of the name with N as their locant.



• Nitriles are named by replacing the suffix “ic acid” or “oic acid” with “onitrile.”


• Practice with CONCEPTUAL CHECKPOINTs 21.12 and 21.13.


• In general, carboxylic acid derivatives are good electrophiles.

• WHY?

21.7 Reactivity of Carboxylic Acid Derivatives


• Reactivity can be affected by – Induction

– Resonance

S i


– Sterics

– Quality of leaving group


• Let’s examine the acid chloride:– The electronegative chlorine enhances the electrophilic

character of the carbonyl. HOW?

– There are 3 resonance contributors to the acid chloride:


– The chlorine does not significantly donate electron density to the carbonyl. HOW does that affect its quality as an electrophile.


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• Let’s examine the acid chloride:– Describe how the presence of the chloride affects the sterics

of the nucleophilic attack on the carbonyl.

– The chloride is a good leaving group, which also enhances its reactivity


reactivity.

• Considering all of the factors involved, the acid chloride is quite reactive.


• Amides are the least reactive acid derivative.

• Examine the factors below to explain amide reactivity:– Induction

– Resonance


– Sterics

– Quality of leaving group


• Aldehydes and ketones are also electrophilic, but they do not undergo substitution.


• WHY? Consider induction, resonance, sterics, and quality of leaving group.


• Nucleophilic acyl substitution is a two‐step process.


– Because C=O double bonds are quite stable, the “loss of leaving group” step should occur if a leaving group is present.

– – H and –R do not qualify as leaving groups. WHY?


• Let’s analyze a specific example:


– The highest quality leaving group leaves the tetrahedral intermediate.


• Do NOT draw the acyl substitution with an SN2 mechanism.


• Sometimes a proton transfer will be necessary in the mechanism:– Under acidic conditions, (–) charges rarely form. WHY?

– Under basic conditions, (+) charges rarely form. WHY?


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• Under acidic conditions, (–) charges rarely form.


– The first step will NOT be nucleophilic attack.

– The electrophile and nucleophile are both low in energy.


• H3O+ is unstable and drives the equilibrium forward by starting the reaction mechanism.

N h h


• Now that the electrophile carries a (+) charge, it is much less stable (higher in energy). Complete the rest of the mechanism.


• Under basic conditions, (+) charges rarely form.

• The OH– is the most bl i i h


unstable species in the reaction and drives the equilibrium forward.

• Continue the rest of the mechanism.


• Neutral nucleophiles are generally less reactive, but they can still react if given enough time.

• An intermediate with both (+) and (‐) charges forms.


• Intermediates with two (+) or two (–) charges are very unlikely to form. WHY?


• Depending on reaction conditions, UP TO THREE proton transfers may be necessary in the mechanism:

f


• Draw a complete mechanism for the reaction below.

– Will the reaction be reversible?

– What conditions could be employed to favor products?

• Practice with SKILLBUILDER 21.1.Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e21-47

• Give necessary reaction conditions and a complete mechanism for the reaction below.


• Describe how conditions could be modified to favor the products as much as possible.


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• Acid chlorides have great synthetic utility. WHY?

• An acid chloride may form when an acid is treated with SOCl2.

21.8 Preparation and Reaction of Acid Chlorides



• The mechanism is more favored in the presence of a non‐nucleophilic base like pyridine. WHY?


• To avoid an acid chloride being converted into an acid, it must be protected from moisture.

21.8 Preparation and Reaction of Acid Chlorides: HYDROLYSIS


• Often acid chlorides are used to synthesize esters.

21.8 Preparation and Reaction of Acid Chlorides: ALCOHOLYSIS

• Give a complete mechanism showing the role of pyridine in the mechanism.


• Often acid chlorides are used to synthesize amides.

• Give a complete h i h i

21.8 Preparation and Reaction of Acid Chlorides: AMINOLYSIS

mechanism showing why TWO equivalents are used.


• Acid chlorides can also be reduced using LAH:



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• Acid chlorides can also be reduced using LAH:– The acid must be added after the LAH has given adequate

time to react completely.



• To stop the aldehyde from being reduced to the alcohol, a bulky reducing agent can be used.


• HOW does lithium tri(t‐butoxy) aluminum hydride allow the reduction to be stopped at the aldehyde?


• Acid chlorides can also be attacked by Grignard nucleophiles:



• Two equivalents of the Grignard yield a 3° alcohol.



• The Gilman reagent is another nucleophilic organometallic reagent that reacts readily with acid chlorides.

• The C–Cu bond is less i i h h C M


ionic than the C–Mg bond. WHY?

• How does the ionic character of the bond affect the reactivity of the organometallic reagent?


• Figure 21.9 illustrates the reactions of acid chlorides that we discussed


discussed.



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• Fill in necessary reagents for the reactions below.



• Acetic anhydride can be synthesized by heating 2 moles of acetic acid.

21.9 Preparation and Reactions of Acid Anhydrides

• Why is so much heat needed to drive the equilibrium forward?

• This process doesn’t work for most other acids because their structures cannot withstand such high temperatures.


• 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.


• Given that they both contain good quality leaving groups, how do you think the reactions of anhydrides compare to the reactions we already saw for chlorides?


• Which has a better leaving group? WHY?


• Figure 21.10 shows how anhydrides can undergo many


g yreactions analogous to those of acid chlorides.


• A non‐nucleophilic weak base such as pyridine is not necessary when acid anhydrides react with a nucleophile. WHY?

• When a nucleophile reacts with an anhydride, there will b b li id b d WHY?


be a carboxylic acid byproduct. WHY?

• Why is it often a disadvantage to have such a byproduct in a reaction?


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• Acetic anhydride is often used to acetylate an amine or an alcohol.






• Fischer esterification combines a carboxylic acid and an alcohol using an acid catalyst.

21.10 Preparation of Esters


• Each step of the Fischer esterification mechanism is equilibrium.

• Under acidic conditions, (–) charges are avoided.



• The overall Fischer esterification reaction is an equilibrium process.


• How might you use Le Châtelier’s principle to favor products?– How might you use Le Châtelier's principle to favor reactants?

• Is there an entropy difference that might be exploited?


• Esters can also be prepared by treating an acid chloride with an alcohol—see Section 21.8.


• What is the role of pyridine?

• Why doesn’t pyridine act as a nucleophile?



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• Esters can undergo hydrolysis in the presence of aqueous hydroxide (SAPONIFICATION).

21.11 Reactions of Esters

• Predict the last steps in the mechanism.

• To produce a carboxylic acid, H3O+ must be added at the end. WHY?


• SAPONIFICATION is an equilibrium process.– Analyze the reversibility of each step in the mechanism.

– How might you use Le Châtelier’s principle to favor products?

– How might you use Le Châtelier’s principle to favor reactants?

h diff h i h b l i d?


– Is there an entropy difference that might be exploited?

• Soap is made through the saponification of triglycerides. EXPLAIN HOW.


• Ester hydrolysis can be catalyzed under acidic conditions.

• The carbonyl of the ester is protonated, and then a water acts as a nucleophile attacking the carbonyl

b


carbon.

• Draw out the complete mechanism.

• Show how regeneration of H3O+ makes it catalytic.


• Esters can also undergo aminolysis.


• The overall equilibrium favors the amide formation.– Because of enthalpy or entropy?

• The synthetic utility is limited because the process is slow and because there are more efficient ways to synthesize amides.


• Esters can be reduced using reagents such as LAH:


– Two equivalents of reducing agent are required.

– Two alcohols are produced.

• Draw a reasonable mechanism.


• LAH is a strong reducing agent, so a full reduction beyond the aldehyde to the alcohol cannot be avoided.

• When performed at low temperature, reduction with DIBAH yields an aldehyde. HOW?



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• Esters can also react with Grignard reagents.

• Two moles can be used to make a tertiary alcohol.



• Esters can also react with Grignard reagents.

• Two moles can be used to make a tertiary alcohol.




• Give necessary reagents for the conversions below.


OO

O

O

HOHO


OH

HO

OHOH

HO

OH

• Nylon is a polyamide.

21.12 Preparation and Reactions of Amides

• Polyester is made similarly. HOW?Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e21-82

• Amides can be hydrolyzed with H3O+, but the process is slow and requires high temperature.


• The mechanism is very similar to that for the hydrolysis of an ester.

• Show a complete mechanism.

• WHY is the process generally slow?Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e21-83

• Amides can be hydrolyzed with H3O+, but the process is slow and requires high temperature.


• Should the equilibrium favor reactants or products? WHY?

• Where does the NH4+ come from?

• Amide hydrolysis can also be promoted with NaOH, although the process is very slow.


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• LAH can reduce an amide to an amine.

• The mechanism is quite


qdifferent from the others we have seen in this chapter.

• When the H‐ attacks, which is the best leaving group?


• The iminium is reduced with a second equivalent of hydride.


• Practice with CONCEPTUAL CHECKPOINTs21.26 through 21.28.


• When a 1° or 2° alkyl halide is treated with a cyanide ion, the CN– acts as a nucleophile in an SN2 reaction.

21.13 Preparation and Reactions of Nitriles

• Nitriles can also be made by dehydrating an amide using a variety of reagents including SOCl2.


• What base might you use?



• An aqueous strong acid solution can be used to hydrolyze a nitrile.


• In the mechanism, the nitrogen is protonated multiple times and water acts as a nucleophile.

• Draw a complete mechanism.


• Basic hydrolysis of a nitrile can also be achieved.


• Which group in the reaction acts as a nucleophile?

• Which group acts to protonate the nitrogen?

• Draw a complete mechanism.


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• 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. SHOW a mechanism.


• Similar to how carboxylic acids can be converted to alcohols using LAH (Section 21.5), nitriles can be converted to amines.




• 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?

21.14 Synthetic Strategies

• We have learned many new FUNCTIONAL GROUP TRANSFORMATIONs in this chapter.

• Practice with SKILLBUILDER 21.2.




• Give necessary reagents for the conversion below. Multiple steps will be necessary.



• There are 2 categories of bond‐forming reactions:



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• 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.


• Practice with SKILLBUILDER 21.3.


• Recall that C=O stretching is a prominent peak in IR spectra.

21.15 Spectroscopy of Carboxylic Acids and Their Derivatives

• Recall that conjugated carbonyl signals appear at lower wavenumbers (about 40 cm‐1 less).


• The O–H stretch of an acid gives a very broad peak (2500‐3300 cm‐1).

• The C≡N 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.



• 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.



ch21 - laney college4/25/2012 4 • lialh4 (lah) is a strong reducing agent that can convert an acid...

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