In each case below, identify the Lewis acid and the Lewis base: (a) Cl Al Cl Cl + O Al

All of the following acid-base reactions are reactions that we will study in greater detail in the chapters to follow. For each one, draw a mechanism and then clearly label the acid, base, conjugate acid, and conjugate base: (a) OH O H O H O H @ @ + + (b) O H O H H O H H O H ! ! + + (c) O N O N H @ @ + + (d) OH O O H H O H O @ O @ + +

Each of the following mechanisms contains one or more errorsthat is, the curved arrows may or may not be correct. In each case, identify the errors and then describe what modification would be necessary in order to make the curved arrows correct. Explain your suggested modification in each case (the following examples represent common student errors, so it is in your best interests to identify these errors, recognize them, and then avoid these mistakes): (a) Cl N H Cl N H @ ! + Step 1 Identify the acid and the base. Step 2 Draw the first curved arrow. Step 3 Draw the second curved arrow. (b) N HOH OH H H H N H H @ @ + + (c) HO O O Na HO O OH O O H Na O O @ ! + + ! @ 3.3 In an intramolecular proton transfer reaction, the acidic site and the basic site are tethered together in the same structure, and a proton is passed from the acidic region of the structure to the basic region of the structure, as shown below: O O O H O O O H @ @ Draw a mechanism for this process.

In an intramolecular proton transfer reaction, the acidic site and the basic site are tethered together in the same structure, and a proton is passed from the acidic region of the structure to the basic region of the structure, as shown below: O O O H O O O H @ @ Draw a mechanism for this process.

For each pair of compounds below, identify the more acidic compound: (a) H O H H O (b) H O H H O (c) H C C H H H N H (d) Cl H H H O ! H (e) H C C H H H H H H C C H (f) O S O H O

Propranolol is an antihypertensive agent (used to treat high blood pressure). Using Table 3.1, identify the two most acidic protons in the compound and indicate the approximate expected pKa for each proton: Propranolol O OH N H

L-dopa is used in the treatment of Parkinsons disease. Using Table 3.1, identify the four most acidic protons in the compound and then arrange them in order of increasing acidity (two of the protons will be very similar in acidity and difficult to distinguish at this point in time): L-dopa HO OH OH O NH2

Identify the stronger base in each of the following cases: (a) H C C H N H @ @ (b) O O @ @ (c) O H O H (d) OH O @ @ (e) C C H C C H H H H H @ @ (f) Cl OH @ @

The following compound has three nitrogen atoms: N N N H H H H Each of the nitrogen atoms exhibits a lone pair that can function as a base (to abstract a proton from an acid). Rank these three nitrogen atoms in terms of increasing base strength using the following information: pKa = 3.4 N H pKa = 3.8 N H H H pKa = 10.5

Consider the following pKa values and then answer the following questions: pKa = 10.5 H3C N H H H pKa = 2.2 H3C O H H ! ! (a) For the following compound, will the lone pair on the nitrogen atom be more or less basic than the lone pair on the oxygen atom? N O H H H (b) Fill in the blanks: The lone pair on the ____________ atom is ____________ orders of magnitude more basic than the lone pair on the ____________ atom.

Determine the position of equilibrium for each acid-base reaction below: (a) O H H O H OH O @ + @ + (b) O H OH O H2O @ + @ + (c) H H O H Cl Cl H O H H @ ! + + (d) H C C H NH2 H C C NH3

Hydroxide is not a suitable base for deprotonating acetylene: H C C Acetylene H C C H Hydroxide OH H O H @ @ + + Explain why not. Can you propose a base that would be suitable?

Amino acids, such as glycine, are the key building blocks of proteins and will be discussed in greater detail in Chapter 25. At the pH of the stomach, glycine exists predominantly in a protonated form in which there are two acidic protons of interest. The pKa values for these protons are shown. Using this information, draw the form of glycine that will predominate at physiological pH of 7.4. pKa pK = 2.35 a = 9.87 Glycine

In each compound below, two protons are clearly identified. Determine which of the two protons is more acidic: (a) O H H (b) H C N H H H H (c) HS OH (d) O N H

Nitrogen and sulfur are neither in the same row nor in the same column of the periodic table. Nevertheless, you should be able to identify which proton below is more acidic. Explain your choice: N H S H

In each compound below, two protons are clearly identified. Determine which of the two protons is more acidic: (a) H H (b) H N N H (c) H H (d) O H H (e) O H O O H (f) H O H

Ascorbic acid (vitamin C) does not contain a traditional carboxylic acid group, but it is, nevertheless, still fairly acidic (pKa = 4.2). Identify the acidic proton and explain your choice using resonance structures, if necessary: Ascorbic acid (Vitamin C)

In the following compound two protons are clearly identified. Determine which of the two is more acidic. After comparing the conjugate bases, you should get stuck on the following question: Is it more stabilizing for a negative charge to be spread out over one oxygen atom and three carbon atoms or to be spread out over two oxygen atoms? Draw all of the resonance structures of each conjugate base and then take a look at the pKa values listed in Table 3.1. O H O O H

Identify the most acidic proton in each of the following compounds and explain your choice: (a) O O H F3C H (b) HO OH O O Cl Cl

For each pair of compounds below, identify which compound is more acidic and explain your choice: (a) OH Cl O Cl OH O Cl (b) OH O Br OH Br O

Consider the structure of 2,3-dichloropropanoic acid: OH O Cl Cl This compound has many constitutional isomers. (a) Draw a constitutional isomer that is slightly more acidic and explain your choice. (b) Draw a constitutional isomer that is slightly less acidic and explain your choice. (c) Draw a constitutional isomer that is significantly (at least 10 orders of magnitude) less acidic and explain your choice.

Consider the two protons highlighted in the following compound: O O Cl F H H Do you expect these protons to be equivalent or is one proton more acidic than the other? Explain your choice. (Hint: Think carefully about the geometry at the central carbon atom.)

Identify which of the following compounds is more acidic. Explain your choice: H C C H H H H C C H

Identify the most acidic proton in each of the following compounds:

Amines contain C!N single bonds, while imines contain C!N double bonds: Amine R N H H Imine N R R H Most simple amines have a pKa somewhere in the range between 35 and 45. Based on this information, predict which statement is most likely to be true and explain the reasoning behind your selection: (a) Most imines will have a pKa below 35. (b) Most imines will have a pKa above 45. (c) Most imines will have a pKa in the range between 35 and 45.

In each compound below, two protons are clearly identified. Determine which of the two protons is more acidic: (a) OH H (b) O O H H (c) NH2 HO O N (d) N H H (e) N N H H (f) HO SH O S (g) N H H (h) O OH HO (i) N S O O O H

For each pair of compounds below, predict which will be more acidic: (a) HCI HBr (b) H2O H2S (c) NH3 CH4 (d) H H H2C CH2 (e) OH Cl3C CCl3 OH

The following compound is one of the strongest known acids: F3C F3C CF3 CF3 N N S N CF3 O S N O S O O S O S O O H (a) Explain why it is such a strong acid. (b) Suggest a modification to the structure that would render the compound even more acidic.

Amphotericin B is a powerful antifungal agent used for intravenous treatment of severe fungal infections. Identify the most acidic proton in this compound: Amphotericin B O O O O OH O OH OH HO NH2 OH OH OH OH HO OH OH

Predict the position of equilibrium for each of the following reactions: (a) + + OH O @ @ (b) + + NH2 O O NH OH O @ @ (c) + OH + H2O

As we will learn in Chapter 21, treating a lactone (a cyclic ester) with sodium hydroxide will initially produce an anion: NaOH Initially formed O O O O H O @ This anion rapidly undergoes an intramolecular proton transfer (see Problem 3.3), in which the negatively charged oxygen atom abstracts the nearby acidic proton. Draw the product of this intramolecular acid-base process and then identify which side of the equilibrium is favored. Explain your answer.

In each of the following cases, identify whether the reagent shown is suitable to accomplish the task described. Explain why or why not: (a) To protonate using H2O N @ (b) To protonate using N H @ (c) To deprotonate using NH2 H C C H H H @ (d) To protonate using H2O O O @ (e) To protonate @ using H2O (f) To deprotonate H C C H using NH2

We will learn the following reactions in upcoming chapters. For each of these reactions, notice that the product is an anion (ignore the positively charged ion in each case). In order to obtain a neutral product, this anion must be treated with a proton source in a process called working up the reaction. For each of the following reactions, identify whether water will be a suitable proton source for working up the reaction: (a) NaOH O O O O @ Na! Chapter 21 (b) NaOH Heat Cl O Na @ ! Chapter 19

Predict which of the following compounds is more acidic: After making your prediction, use the pKa values from Table 3.1 to determine whether your prediction was correct. OH Ethanol H O H Water

In each case below, identify the Lewis acid and the Lewis base: (a) Cl Al Cl Cl + O Al Cl Cl Cl O @ ! (b) O H O H + + O H H O H H ! ! (c) Br Al Br Br + Br Br AlBr Br Br Br Br @ ! (d) H O H O O R + + H O H H O O H R ! ! (e) F B F F + O B F F F O

Identify the compounds below that can function as Lewis bases: O N N !

Draw the conjugate base for each of the following acids: (a) OH (b) O (c) NH3 (d) H3O+ (e) OH O (f) N H (g) NH4 +

Draw the conjugate acid for each of the following bases: (a) @ (b) O @ (c) NaNH2 (d) H2O (e) OH (f) NH2 (g) O (h) NaOH

Compound A has a pKa of 7 and compound B has a pKa of 10. Compound A is how many times more acidic than compound B? (a) 3 (b) 3000 (c) 1000

In each reaction, identify the Lewis acid and the Lewis base: (a) OH + O H ! ! (b) OH F B F F + F B F O F H @ ! (c) Cl Al Cl Cl Cl + Cl Al C

What reaction will take place if H2O is added to a mixture of NaNH2/NH3?

Would ethanol (CH3CH2OH) be a suitable solvent in which to perform the following proton transfer? Explain your answer: + + NH3 H NH2 @ @

Would water be a suitable proton source to protonate the following compound? ONa

Write an equation for the proton transfer reaction that occurs when each of the following acids reacts with water. In each case, draw curved arrows that show the mechanism of the proton transfer: (a) HBr (b) H O S O O O H (c) O! H

Write an equation for the proton transfer reaction that occurs when each of the following bases reacts with water. In each case, draw curved arrows that show the mechanism of the proton transfer: (a) @ (b) O @ (c) @ (d) N

In each case, identify the more stable anion. Explain why it is more stable: (a) @ vs. @ (b) vs. N @ @ (c) @ vs. @

In each group of compounds below, select the most acidic compound: (a) N H N H (b) O O O O Cl

For each pair of compounds below, identify the more acidic compound: (a) OH SH (b) OH OH (c) OH Cl Cl Cl Cl Cl OH (d) NH2 (e) O O O O H O H (f) O O (g) O (h) NH2 O OH

HA has a pKa of 15, while HB has a pKa of 5. Draw the equilibrium that would result upon mixing HB with NaA. Does the equilibrium favor formation of HA or of HB?

For each reaction below, draw the mechanism (curved arrows) and then predict which side of the reaction is favored under equilibrium conditions: (a) H O H OH + + O HO @ @ (b) SH OH + + O S @ @ (c) H2S SH S + HS + S S @ @ (d) O N H O N

Rank the following anions in terms of increasing basicity: HO O O O O @ @ @ @

For each compound below, identify the most acidic proton in the compound: (a) NH2 H (b) H2N OH SH (c) (d) O (e) HO O OH NH2 (f) H O (g) HO O Cl Cl OH O O OH (h) HS OH

In each case below, identify the acid and the base. Then draw the curved arrows showing a proton transfer reaction. Draw the products of that proton transfer and then predict the position of equilibrium: (a) O O H + LiOH (b) H O Li + H @ ! (c) O O + NaOH

Draw all constitutional isomers with molecular formula C2H6S and rank them in terms of increasing acidity

Draw all constitutional isomers with molecular formula C3H8O and rank them in terms of increasing acidity

Consider the structure of cyclopentadiene and then answer the following questions: Cyclopentadiene (a) How many sp3 -hybridized carbon atoms are present in the structure of cyclopentadiene? (b) Identify the most acidic proton in cyclopentadiene. Justify your choice. (c) Draw all resonance structures of the conjugate base of cyclopentadiene. (d) How many sp3 -hybridized carbon atoms are present in the conjugate base? (e) What is the geometry of the conjugate base? (f) How many hydrogen atoms are present in the conjugate base? (g) How many lone pairs are present in the conjugate base?

In Section 3.4, we learned four factors (ARIO) for comparing the relative acidity of compounds. When two of these factors are in competition, the order of priority is the order in which these factors were covered (atom being the most important factor and orbital being the least important). However, we also mentioned that there are exceptions to this order of priority. One such exception was covered at the end of Section 3.4. Compare the two compounds below and determine if they constitute another exception. Justify your choice: pKa = 4.75 pKa = 10.6 OH SH

Consider the pKa values of the following constitutional isomers: OH O OH pKa = 3.0 Salicylic acid O OH HO pKa = 4.6 para-Hydroxybenzoic acid Using the rules that we developed in this chapter (ARIO), we might have expected these two compounds to have the same pKa. Nevertheless, they are different. Salicylic acid is apparently more acidic than its constitutional isomer. Can you offer an explanation for this observation?

Consider the following compound with molecular formula C4H8O2: O OH C4H8O2 (a) Draw a constitutional isomer that you expect will be approximately one trillion (1012) times more acidic than the compound above. (b) Draw a constitutional isomer that you expect will be less acidic than the compound above. (c) Draw a constitutional isomer that you expect will have approximately the same pKa as the compound above.

There are only four constitutional isomers with molecular formula C4H9NO2 that contain a nitro group (!NO2). Three of these isomers have similar pKa values, while the fourth isomer has a much higher pKa value. Draw all four isomers and identify which one has the higher pKa. Explain your choice.

Predict which of the following compounds is more acidic and explain your choice: N NH2 N NH2

Below is the structure of rilpivirine, a promising new anti-HIV drug that combats resistant strains of HIV. Its ability to side-step resistance will be discussed in the upcoming chapter. N N N H N N N H Rilpivirine (a) Identify the two most acidic protons in rilpivirine. (b) Identify which of these two protons is more acidic. Explain your choice.

Most common amines (RNH2) exhibit pKa values between 35 and 45. R represents the rest of the compound (generally carbon and hydrogen atoms). However, when R is a cyano group, the pKa is found to be drastically lower: R N H H H pKa = 3545 N C N H pKa = 17 (a) Explain why the presence of the cyano group so drastically impacts the pKa. (b) Can you suggest a different replacement for R that would lead to an even stronger acid (pKa lower than 17)?

In one step of a recent total synthesis of (-)-seimatopolide A, a potential antidiabetic drug, the following two structures reacted with each other in an acid-base reaction (Tetrahedron Lett. 2012, 53, 5749 5752): O O O 7 O Si O H N ! (a) Identify the acid and the base, draw the products of the reaction, and show a mechanism for their formation. (b) Using the pKa values provided in Problem 3.9 as a rough guideline, predict the position of equilibrium for this acid-base reaction.

Deuterium (D) is an isotope of hydrogen, in which the nucleus has one proton and one neutron. This nucleus, called a deuteron, behaves very much like a proton, although there are observed differences in the rates of reactions involving either protons or deuterons (an effect called the kinetic isotope effect). Deuterium can be introduced into a compound via the process below: (a) The C!Mg bond in compound 3 can be drawn as ionic. Redraw 3 as an ionic species, with BrMg+ as a counterion, and then draw the mechanism for the conversion of 3 to 4. (b) The IR spectrum of compound 4 exhibits a group of signals between 1250 and 1500 cm-1 , a signal at 2180 cm-1 , and another group of signals between 2800 and 3000 cm-1 . Identify the location of the C-D signal in the spectrum and explain your reasoning (J. Chem. Ed. 1981, 58, 7980). Mg D2O 1 2 4 1) Br2 H , h D Br Br2 h MgBr 3 Et Chapter 2O 11 Chapter 13

The bengamides are a series of natural products that have shown inhibitory effects on the enzyme methionine aminopeptidase, which plays a key role in the growth of new blood vessels, a necessary process for the progression of diseases such as solid tumor cancers and rheumatoid arthritis. During the synthesis of bengamides, it is often required to convert OH groups into other, less reactive groups, called protecting groups, which can be converted back into OH groups when desired. For example, compound 1 is protected upon treatment with compound 2 in the presence of compound 4 (Tetrahedron Lett. 2007, 48, 87878789). First, 1 reacts with 2 to give intermediate 3, which is then deprotonated by 4 to give 5: (a) Draw the structure of 5 and show a mechanism for its formation from 3. (b) Use a quantitative argument (pKa values) to verify that 4 is an appropriate base for this transformation. (c) Explain how you would use IR spectroscopy to verify the conversion of 1 to 5. OMe OMe OSiMe3 OSiMe3 O O O O O Me3Si H Me N Me = OH O Ph O Ph Ph Ph Ph Ph

Asteltoxin, isolated from the cultures of Aspergillus stellatus, exhibits a potent inhibitory effect on the activity of E. coli BF1-ATPase. During S. L. Schreibers synthesis of asteltoxin, compound 1 was treated with a strong base to form anion 2 (J. Am. Chem. Soc. 1984, 106, 41864188): O O O O O O O O HO HO H Strong base 2 1 Asteltoxin (3) (a) Identify the most acidic proton in 1 and justify your choice using any necessary drawings. (b) Determine whether each of the following bases would be suitable for deprotonating compound 1 and explain your decision in each case: (i) NaOH, (ii) NaNH2, or (iii) CH3CO2Na.

In a key step during a recent synthesis of 7-desmethoxyfusarentin, a compound that is known to display cytotoxicity against breast cancer cells (MCF-7), an acid-base reaction was employed, in which the following two structures reacted with each other (Tetrahedron Lett. 2012, 53, 40514053). Predict the products of this reaction, and propose a mechanism for their formation: O OR O H Si N NH

During a synthesis of (+)-coronafacic acid, a key component in the plant toxin coronatine, the following reaction was performed, in which a ketone was converted into an acetal (the acetal functional group will be covered in Chapter 20). In this case, p-toluenesulfonic acid (p-TsOH) functions as an acid catalyst (J. Org. Chem. 2009, 74, 24332437): O O O OH OH p-TsOH O O O O ( H2O) p-TsOH = S O O OH 89% (a) The mechanism for this process begins with a proton transfer step in which the ketone is protonated. Draw this mechanistic step using curved arrows. (b) For this protonation step, predict whether the equilibrium favors the protonated ketone. Justify your prediction with estimated pKa values.

Phakellin (3), a natural product isolated from marine organisms, has been studied for its potential use as an antibiotic agent. During studies aimed at developing a strategy for the synthesis of phakellin and its derivatives, compound 1 was investigated as a potential precursor (Org. Lett. 2002, 4, 26452648): N N O O H H 1 N Li (LDA) 2 N N O N N H H2N 3 @ ! 1 (a) Identify the most acidic proton in compound 1, draw the corresponding conjugate base, 2, and justify your choice. (b) Using a quantitative argument based on pKa values as well as a qualitative argument based on structural comparisons, justify why lithium diisopropyl amide (LDA) is a suitable base to deprotonate 1. (c) Draw a mechanism for the conversion of 1 to 2.

The Nazarov cyclization is a versatile method for making fivemembered rings, a common feature in many natural products. This process has been used successfully in the preparation of many complex structures with a wide variety of biological activities, including antibiotic and anticancer properties (Org. Lett. 2003, 5, 49314934). The key step of the Nazarov cyclization involves a Lewis acid, such as AlCl3. In the first step of the mechanism, compound 1 interacts with AlCl3 to form a Lewis acid-Lewis base complex. Determine the site within compound 1 that interacts most strongly with the Lewis acid and justify your choice by exploring the resonance structures of the resulting complex: O O AlCl3 O O 1 2

Crude extracts from the ginkgo tree, Ginkgo biloba, have been used for centuries to alleviate symptoms associated with asthma. There are four principal components of Ginkgo extracts, called ginkgolide A, B, D, and M. During E. J. Coreys classic synthesis of ginkgolide B, compound 1 was converted into compound 5 (J. Am. Chem. Soc. 1988, 110, 649651): O O 3a O H3CO H3CO TfO Tf Tf N Tf N = S O O CF3 N Tf Li Li 1 2 4 6 5 3b + @ ! @ ! (a) Draw the resonance-stabilized anion (3) that is expected when compound 1 is treated with LDA (compound 2), which was introduced in Problem 3.69. (b) Draw a mechanism for the conversion of 1 to 3 and explain why this step is irreversible. (c) Upon treatment with 4, anion 3 is converted into compound 5, and byproduct 6 is formed. Describe the factors that render 6 a particularly stable anion.

The pKa of the most acidic CH2 group in each of the following compounds was measured in DMSO as solvent (J. Org. Chem. 1981, 46, 43274331). Acid CH3COCH2CO2CH2CH3, 1 14.1 PhCH2CN, 2 21.9 PhCH2CO2CH2CH3, 3 22.7 PhCH2CON(CH3)2, 4 26.6 pKa Ph = Given the data above, determine which of the following two compounds (5 or 6) is more acidic by comparing the stability of the corresponding conjugate bases. Include all necessary resonance contributors in your discussion. Consider the given pKa values in determining which resonance contributors are more effective in stabilizing the conjugate bases. O 5 6

The following compound has been designed to allow for labeling of a specific site of a protein (J. Am. Chem. Soc. 2009, 131, 8720 8721): H2N CO2H N H O O Consider each of the possible positions on this molecule that can be deprotonated. Predict the likely product of an acid/base reaction of one mole of this molecule with each of the following: (a) One mole of EtNa (b) Two moles of EtNa (c) Three moles of EtNa (d) Four moles of EtNa (e) One mole of EtONa (f) Two moles of EtONa (g) Three moles of EtONa (h) Four moles of EtONa