Topic 14: Nucleophilic addition to carbonyl compounds

14.1What is a carbonyl group?
 
14.2What is a carbonyl compound?
 
14.3What two categories does your author propose to use to distinguish between types of carbonyl compounds based on their reactivity?
 
14.4What is the outcome when a nucleophile and an aldehyde or ketone react? What is the technical name of this reaction?
 
14.5What is the outcome when a nucleophile and a “carboxylic acid derivative” react? What is the technical name of this reaction?
 
14.6What is the outcome when a nucleophile such as hydroxide and a carboxylic acid react? What is the technical name of this reaction?
 
14.7So, aren‘t there three fundamental types of carbonyl compound in terms of how they react with a nucleophile?
 

Topic 15: Reduction of carbonyl compounds

15.1Both NaBH4 and LiAlH4 reduce aldehydes and ketones to hydroxy compounds. Why would a chemist in the lab prefer one over the other? What is the underlying principle here?
 
15.2If NaBH4 and LiAlH4 were assigned personalities, which would be the “gentle, but effective, one,” and which would be the “Get out of my way, I‘m coming through NOW!” one? See, for example, https://tinyurl.com/y77ntyjy. Any idea why this might be?
 
15.3The exact mechanism of reduction with NaBH4 and LiAlH4 is not known (despite what your book might say). The real mechanistic question is this: Is this reaction reversible or not? What do you think? Is it OK to just think of this as “H−”, the same way as we speak of “Br+” or “H+”? Why or why not? What reagent does in fact act exactly and only like H− in terms of only being a very strong base?
 
15.4What is the design idea behind the invention of diisobutylaluminum hydride (DIBAL-H) or lithium tri-tert-butoxyaluminum hydride? Where have you seen this before? (Give at least three examples, probably out of Chapters 11 or 12.)
 
15.5What is the difference in result when one uses one of these reagents instead of LiAlH4 on a carboxylic acid derivative such as an acid chloride or ester?
 

Topic 16: Oxidation of carbonyl compounds

16.1Why is only the oxidation of aldehydes discussed in this chapter in relation to the oxidation of carbonyl compounds?
 
16.2Can you think of any reaction you have learned that can oxidize a ketone to a carboxylic acid?
 
16.3What‘s special about Ag2O/NH4OH?
 
16.4What is “NH4OH”, by the way?
 

Topic 17: Organometallic reagents

17.1What is the definition of an organometallic compound?
 
17.2What three metals are particularly highlighted in this chapter?
 
17.3What change in oxidation state of the metal occurs when Li reacts with an alkyl halide? How about Mg?
 
17.4Does the same sort of thing happen in the reaction of copper(I) iodide with methyllithium?
 
17.5Given that information about oxidation state change of the metal, is the formation of an alkyllithium or Grignard reagent from an alkyl halide technically an organic oxidation or an organic reduction? If it is an oxidation, where did the electrons go? If it is a reduction, where did they come from? How many electrons are we talking about?
 
17.6Acetylides are a special fourth case (along with alkyllithiums, Grignard [pronounced GRIN-yard] reagents, and organocuprates). What makes them so special?
 
17.7[OK, here‘s the answer to Question 6: They are the only ones that can be formed by deprotonation by a strong base.] Approximately what is the pKa of 1-butyne? Given that pKa, which of the following bases could be used to remove that terminal proton — Na2CO3, NaOH, NaNH2, NaH, CH3Li?
 

Topic 18: Nucleophilic reactions of organometallic reagents

18.1Why is acetylide ion a better nucleophile than methyllithium? (two reasons)
 
18.2Methyllithium is such a strong base, it is generally only useful for one thing. What is that? (See Section 17.9A)
 
18.3sec-butylllithium and tert-butylllithium are never used as nucleophiles. Why is that?
 
18.4Section 17.9D overgeneralizes. What two (of the four) organometallic reagent types are the only ones that are genererally used for nucleophilic addition to ketones and aldehydes?
 
18.5All of these reagents are extremely reactive with water and O2. Thus, they must be used only by experienced professionals. In https://tinyurl.com/y88xnfq7>this video, what is the purpose of toluene, isopropanol, and dry ice? How do they work in this case?
 
18.6What are all the precautions taken by this graduate student that minimize the risk of explosion, fire, and exposure to harmful chemicals? (Two are surprisingly not mentioned but might be guessed.)
 
18.7Given that information, how is it that the mechanisms in your book involve H2O? [Hint: What is the difference in an organic synthesis laboratory between the reaction and the work up?]
 
18.8How can the reaction of these reagents with water be an advantage synthetically? [Hint: Two good answers, one involving isotopes.]
 

Topic 19: Protecting groups for alcohols

19.1What do the following abbreviations stand for in organic chemistry? TMS, TES, TBS, TBDMS, TBDPS, TIPS? Why all the varieties?
 
19.2When are silyl ether protecting groups needed?
 
19.3Why not just use a methyl ether? It would be a lot cheaper and greener.
 
19.4How many times in the synthesis of taxol by Robert Holton (Florida State Univ, 1994, Wikipedia) were silyl ether protecting groups used?
 
19.5In the figures of that Wikipedia article, how many reagents do you recognize?
 

Topic 20: Organometallic reagents: general reactions

20.1What three types are the only ones used to open epoxides?
 
20.2What is the limitation associated with the reaction of alkyllithium and alkylmagnesium halide reagents with esters and acid chlorides?
 
20.3What solution was developed to solve at least part of this problem?
 
20.4What problem remains to be solved?
 
20.5How could the reaction of organometallic reagents with CO2 be useful, particularly in aromatic chemistry? What is an example of a problem this solves?
 
20.6How could the reaction of organometallic reagents with H2O be useful, particularly in aromatic chemistry? What is an example of a problem this solves?
 

Topic 21: Organometallic reagents: 1,2- vs. 1,4- addition to α, β-unsaturated aldehydes and ketones

21.1The most important use of organocopper reagents is in relation to the addition to α, β-unsaturated aldehydes and ketones. What‘s the issue there, and how did the discovery of organocopper reagents provide a major new method for organic synthesis?
 
21.2The mechanism for 1,4-addition of an organocopper reagent to a ketone is not as simple as it might first appear. If you are interested, google ja00086a023, a paper in the Journal of the American Chemical Society (“JACS”) published in 1994 by Robin Smith, at the University of Otago, in New Zealand.
 
21.3In Mechanism 20.10 Part [2] your author proposes a sequence of protonation, with possible tautomerization following a mechanism presented in Section 11.9. What is tautomerization?
 
21.4Why is the mechanism of tautomerization presented in Section 11.9 almost certainly not the mechanism of tautomerization in this case? Can you suggest a more reasonable alternative mechanism?
 

Topic 22: Organometallic reagents: the formation of carbon-carbon bonds

22.1A major focus of this course will be on the formation of carbon-carbon bonds. Take a look at Appendix D to see where we are headed. How many carbon-carbon bond forming reactions does it show there from last semester? (There‘s one missing, by the way — see Table 7.4 in Section 7.8D.) And this semester?
 
22.2Why do you think carbon-carbon bond formation is so important — the stuff of half a dozen Nobel Prizes?
 
22.3How does focusing on carbon-carbon bond formation help in designing a synthesis such as those presented in the sample problems of this chapter or end of chapter problems 20.58-20.71?
 
22.4Smith 24.1A introduces an additional reaction of organocuprate reagents. What is that reaction? How could it be incredibly useful — almost too useful to the organic chemistry student — in organic synthesis?
 
22.5What are the practical limitations of this reaction? (think of two)
 
22.6How does this reaction solve the problem of both overalkylation and cationic rearrangement in Friedel-Crafts alkylation?
 

Topic 23: Aldehydes and ketones: nomenclature, spectroscopy, and synthesis

23.1When does one need to use the suffix “carbaldehyde” and not “aldehyde” when naming aldehydes?
 
23.2IUPAC has two systems (actually, even more than that). The one we have been learning is called the substitutive nomenclature. In that system, we have the sequence: stereo-prefix-root-infix-suffix for all names, where suffix in the case of ketones is “one.” The other system is called additive nomenclature. This system simply lists the substituents in alphabetical order, usually as separate words, followed by the name of the functional group. For example: ethyl bromide, methyl alcohol, diethyl ether. It‘s a simple system designed for simple compounds, that is, ones that don‘t require the use of numbers. Your book uses the term “common names” for IUPAC additive nomenclature. What are examples of this system used in the case of ketones?
 
23.3How could you distinguish between a ketone and an aldehyde using 1H-NMR spectroscopy? How about IR?
 
23.4In 1H-NMR, a normal CH3 group (as in an alkane) appears around δ1.2. Where does that signal shift to when there is a C=O next to that group?
 
23.5What are three ways we have learned to make aldehydes?
 
23.6What are four ways we have learned to make ketones?
 

Topic 24: Irreversible reactions of aldehydes and ketones

24.1What are two irreversible reactions of aldehydes and ketones that we have already learned in previous chapters? What makes those reactions irreversible?
 
24.2What is the new irreversible reaction of aldehydes and ketones that is introduced in this chapter?
 
24.3Looking at Figure 21.7, what do all the reversible reactions (the ones introduced in sections not included in today‘s reading) have in common?
 
24.4What characterizes the Wittig (pronounced “VITT-igg”) reaction? What is the driving force of this reaction? That is, what makes this reaction irreversible?
 
24.5How do you make a Wittig reagent?
 
24.6What is a zwitterion? (See Section 19.11B)
 
24.7What is an ylide (pronounced ILL-id)?
 
24.8Would you consider the Wittig reaction to be a green reaction, or not?
 
24.9What are the limitations of the Wittig reaction?
 
24.10What conditions do all the reversible reactions discussed in these sections have in common?
 

Topic 25: Reversible addition to C=O: formation of cyanohydrins

25.1What is the dual role of HCl in the reaction of NaCN and a ketone to form a cyanohydrin?
 
25.2Why not just use HCN itself? (two reasons)
 
25.3Why might one tape a pill to the side of a hood one is working in when using HCN? See this report
 

Topic 26: Reversible addition to C=O: formation of imines and enamines

26.1What is an imine? How do you pronounce this name?
 
26.2While the mechanism given by your author is plausible, it is certainly not proven. Propose another valid mechanism for this reaction.
 
26.3Experimental evidence is that imine formation is pH-dependent. Why might that be?
 
26.4What is an enamine? How do you pronounce enamine?
 
26.5Equilibrium reactions generally need to be driven in the desired direction.
 
26.6What is an azeotrope, and how can the formation of an azeotrope assist in driving the enamine formation reaction?
 
26.7What is a Dean-Stark apparatus, and how could it be useful here?
 

Topic 27: Reversible addition to C=O: formation of hydrates and acetals

27.1Please do not get the impression from this section that the formation of hydrates from ketones is an important reaction. We are always careful to not use acetone in the presence of water and acids, but it isn‘t because of this. Do hydrates have any synthetic use?
 
27.2The formation of an acetal can be carried out by heating a ketone or aldehyde and an alcohol in the presence of a catalytic amount of p-toluenesulfonic acid in a solvent such as toluene that forms an azeotrope with water, with the collection of water using a Dean-Stark apparatus. Propose a mechanism for this reaction and explain why the reaction is carried out as described here.
 
27.3Why is the mechanism shown in Sample Problem 21.4 absolutely, definitively, not a viable mechanism for the hydrolysis of an acetal? (Besides the fact that the equations are not balanced.)
 
27.4How would you correct that mechanism, being careful to use balanced chemical equations?
 
27.5What is the driving force of the hydrolysis of an acetal, considering the fact that all the reactions are reversible?
 

Topic 28: Acetals as protecting groups for ketones and aldehydes

28.1Acetals, particularly the acetal made from ethylene glycol (1,2-dihydroxyethane) are famous as protecting groups for ketones. Why might that be? (two reasons)
 
28.2What is a 1,3-dioxolane?
 
28.3How is a 1,3-dioxolane protecting group removed?
 
28.4What are two examples of reactions where an acetal protecting group might be useful?
 

Topic 29: Carboxylic acid structure, nomenclature, spectroscopy, and synthesis

29.1Just so you know, there is no single “IUPAC System.” We will be talking about several in this chapter and later in the book. In any case, what are the two suffixes used for naming carboxylic acids using the IUPAC substitutive nomenclature system? What‘s the difference? When do you use one or the other?
 
29.2What are the IUPAC “preferred” names for the following eight compounds: methanoic acid, ethanoic acid, propanoic acid, butanoic acid, benzenecarboxylic acid, ethanedioic acid, propanedioic acid, and butanedioic acid?
 
29.3What is meant by “principal characteristic group” in the IUPAC substitutive system? (See also Appendix B table B.1.) Why is it important in understanding how to name carboxylic acids?
 
29.4What characteristic signals do we find for carboxylic acids in IR, 1H-NMR, and 13C-NMR?
 
29.5What ways do we already know how to make carboxylic acids? Is there anything new in this regard in this chapter?
 

Topic 30: Relative acidity of carboxylic acids

30.1What is meant by the term amphoteric? [look it up] How does that apply to carboxylic acids?
 
30.2Which oxygen atom of a CO2H group is more basic — the doubly-bonded O, or the OH oxygen? Explain that.
 
30.3What is the difference between a strong acid and a weak acid? [recall general chemistry or look it up]
 
30.4How does this standard definition of “strong acid” conflict with the section heading for Section 19.7?
 
30.5How do we know that all carboxylic acids are weak acids? — That there is no such thing as a “strong carboxylic acid”? (Hint: See Appendix A. What is the strongest carboxylic acid on that list? Why would it be so strong, yet still be called “weak”? Why is it unlikely that any other carboxylic acid would be any stronger than that one?)
 
30.6Why is a carboxylic acid more acidic than phenol? Why is phenol more acidic than cyclohexanol?
 
30.7What is the inductive effect, and what does it have to do with carboxylic acid pKa?
 
30.8How does your author suggest we predict the relative acidity of substituted benzoic acids?
 
30.9Based on the pKa table below, how might we modify the claimed "rule" that "electron donating groups decrease the acidity of benzoic acid"?
grouportho pKameta pKapara pKa
NH26.974.784.92
OH2.974.064.48
OMe3.733.844.37
Me4.273.914.36
H4.194.194.19
Cl2.923.823.98
NO22.163.473.41

 

Topic 31: Properties of carboxylic acid derivatives

31.1Identify the functional groups: carboxylic acid, acid chloride, anhydride, ester, amide, nitrile.
 
31.2What does the prefix “anhydro” always mean in chemistry? How does that relate to the name “anhydride”?
 
31.3What are the three types of amides, and what characterizes them as such?
 
31.4What is a lactone? a lactam?
 
31.5What is the order of reactivity of acid chloride, anhydride, ester, amide toward nucleophiles? What explains this ordering?
 

Topic 32: Nomenclature and spectroscopy of carboxylic acid derivatives

32.1What are the various suffix changes for acid chlorides, anhydrides, esters, and amides?
 
32.2Both esters and amides have the added complication of groups attached to O or N. How does the IUPAC system handle this?
 
32.3The NMR and IR spectra of carboxylic acid derivatives are similar to those of carboxylic acids except for what one missing peak?
 
32.4What makes the IR spectrum of an anhydride unusual?
 

Topic 33: Reactions of acid chlorides and anhydrides

33.1The reactions of acid chlorides and anhydrides are very similar. What is the one difference?
 
33.2Why are two equivalents of an amine required for the formation of an amide from an acid chloride or anhydride?
 
33.3Let‘s say the amine you were using was actually pretty expensive. Maybe it has taken you two months to make it. How could you still make an amide using it, but avoid throwing away half of it? (two ways — for one, Google acid chloride to amide and check images; for the other, think about what you have done in lab this semester for work-ups.]
 

Topic 34: Reactions of carboxylic acids

34.1What does “derivative” mean in this context?
 
34.2Besides the obvious acid/base reaction, what do all the reactions of carboxylic acids have common?
 
34.3Why might it be very important to do the reaction of a carboxylic acid with thionyl chloride in a fume hood?
 
34.4Generally, in mechanisms we are not allowed to use Cl− as a base. Why is that? Why is it allowed here?
 
34.5The acid-catalyzed formation of an ester from a carboxylic acid is a famous reaction. Propose a viable mechanism for this reaction, labeling each of the steps one of: proton transfer, nucleophilic addition, or loss of a leaving group.
 
34.6What is DCC?
 
34.7What problem does DCC solve in the formation of amides from carboxylic acids?
 
34.8Propose a viable mechanism for this reaction, again labeling each step one (and only one) of: proton transfer, nucleophilic addition, or loss of leaving group.
 

Topic 35: Reactions of esters and amides

35.1The mechanism of the acid-catalyzed hydrolysis of an ester is (must be!) exactly the reverse of mechanism you gave in #6, above. Can you write that without looking at the mechanism you wrote in #5? Use your answer there to check.
 
35.2Esters can also be hydrolyzed using aqueous NaOH. This is a much simpler mechanism. Write it, labeling each step one of: proton transfer, nucleophilic addition, or loss of leaving group.
 
35.3What makes this reaction irreversible?
 
35.4Amides are especially stable and require “strenuous” conditions to hydrolyze. What does strenuous mean in this context? Why are these very harsh conditions required?
 
35.5The mechanism your author gives for the hydrolysis of an amide in Section 22.13 is not supported by experimental evidence. This is because Step [2] is not just less likely than the reverse of Step [1], it is 1020 times less likely (due to the enormous difference in pKa between water and ammonia). The mechanism proposed by the experimentalists cleverly involves a water molecule, which first just hydrogen bonds, but then gets involved in a rearrangement that is just a very subtle change in atomic positions. Do you see what is happening in that third step? How does this simple involvement of water avoid the issue presented in that second step of your book‘s mechanism? Cool, huh?
 

Topic 36: Reactions of nitriles

36.1Identify the reagents used to convert nitriles to (a) carboxylic acids, (b) aldehydes, and (c) amines.
 
36.2What makes nitriles especially handy, synthetically speaking?
 
128 questions
472 questions for Organic II

472 Questions for Organic II

Dearest Student. This web page is a set of questions I call Detailed Intended Learning Outcomes For Organic Chemistry (Part II). Some time ago I asked myself, "Bob, what do you think are the key questions that you hope students will be able to answer after taking Chemistry 248 at St. Olaf College?" So here you have them. Some are very simple; some require more thought. All are good questions to be thinking about as you read, discuss, and master the practical aspects of organic chemistry. They are discussion starters and review tips. There are no answers here (though there are some clues). The questions are here to help you focus on what's important (to me, at least!) and organize your learning process. The questions are grouped into topics. Bite-size chunks. Take them a few at a time. Don't feast on them all at one sitting!

(preliminary version 2021.01.15 feeback: Bob Hanson)