EMPHASIS TOPICS FOR THE SECOND EXAM IN CH 610B:Bauld

CHAPTER 13: NMR

• You should know what chemical shift is and how electron density around the nucleus affects the shift. Be able to explain this effect and illustrate it.
• You should be able to explain why hydridic hydrogens absorb at higher fields, and protonic hydrogens at lower field.
• Be able to explain why alkene and arene type hydrogens absorb at unusually low field, arene hydrogens lower than alkenes.You should be familiar with the terms anisotropy and ring current.
• You should know the approximate chemical shifts of various types of protons, including CH3,allyl, benzyl,-OCH3,alkene, arene, carboxylic acid protons, and aldehyde protons.
• You should be able to predict the splitting pattern of protons via the n+1 rule for equivalent protons and the 2 to the nth rule for nonequivalent protons.
• You should be able to simulate a proton NMR spectrum for a specific structure provided. You should be able to place the equivalent proton groups at approximately the right chemical shift and be able to explain what effects cause these particular protons to absorb in this chemical shift region. You should also be able to simulate and explain the multiplicity of the peaks.
• You should know that tetramethylsilane is the standard for the chemical shift and be able to explain why it is a convenient standard.
• You should know that in the mass spectrometer, cation radicals are formed which have the same charge to mass ratio as the parent substance. Thus, the mass spec gives the molecular weight of the molecule in question.
• You should also know that the ionized molecule may also break down (fragment), especially if a stable cation or radical or molecule can be formed.Thus, alcohols often have an m/e ratio which corresponds to the molecular weight of the corresponding alkene, as a result of dehydration of the molecular ion.

CHAPTER 19:Carbonyl Alpha Substitution Reactions: Enols and Enolates

In this section, we learn that carbonyl compounds which have alpha hydrogens (remember not all carbonyl compounds do have such hydrogens! What are some examples of aldehydes or ketones which lack alpha hydrogens?) can undergo alpha substitution reactions via either the enol (acidic solutions) or the enolate (basic solutions).

The enol form of such a carbonyl compound is in equilibrium with the carbonyl form in either acidic or basic solution. The enol form is clearly less stable than the keto form, because the C=C is of the enol is less stable than the C=O of the carbonyl form. However, this does not prevent reactions from occuring via the reactive enol form.

Base Catalyzed Enolization

• You should be able to write the mechanism for the base catalyzed enolization of a carbonyl compound.
• You should know that this involves the formation of the enolate intermediate in the first step, and you should also be able to write the two canonical structures for this enolate.
• You should be able to explain why carbonyl compounds having alpha hydrogens typically have pKa's of about 19, whereas alkane C-H bonds have much higher pKa's (resonance stabilization of the enolate, which has both alkoxide and carbanion character.
• You should also know that the enolate can protonate on either oxygen or the alpha carbon. The latter returns the carbonyl form in the reverse of the first step, while the protonation on oxygen gives the enol form.
• You should know that the enolate is the conjugate base of both the enol and the keto forms.

Acid Catalyzed Enolization

• You should be able to write the detailed mechanism of this reaction, which involves the conjugate acid of the keto form.
• You should be able to write the two canonical structures for this conjugate acid.
• You should know that this is the common conjugate acid of both the keto and enol forms.
• Removal of a proton from oxygen gives back the keto form, but removal of a proton from carbon gives the enol form.

Structure and Reactivity of Enols

• You should be able to write the two canonical structures for the enol form. You should know which is the more stable of the two structures and why (charge separation increases energy).
• You should realize that the enol is a highly electron rich alkene, because the OH group is a strong EDG.
• You should be able to write the dotted line/partial charge structure for the enol.
• You should know that bromine and other halogens react rapidly with the enol form but not at all with the keto form. Therefore ketones without alpha hydrogens do not react with Br2.
• You should be able to write the mechanism for this reaction with Br2, using acid catalysis to generate the enol form (remember, HBr is formed in the reaction and serves as the acid catalyst).
• You must know that the formation of the enol form is rate determining.The subsequent reaction of the very nucleophilic enol with an electrophile is extremely fast. Therefore the reaction with any of the halogens and with other electrophiles occurs at exactly the same rate (the electrophile is not involved in the rds).
• You should know that beta, gamma , or other hydrogens of carbonyl compounds are not reactive under these conditions, but only alpha hydrogens. You should realize that some ketones have non-equivalent alpha hydrogens(there are two sides , i.e., two alpha carbons in a ketone).

:Enolate Formation and Reactions

• Since the pKa for an alpha hydrogen is about 19 and the pKa for water is about 16, you should know that enolates can not be formed quantitatively from hydroxide ion(or alkoxide) ion and the ketone. In fact, K=1/1000. You should, of course, know how to calculate the K for this simple acid base reaction given the pKa's of water and the carbonyl compound.
• You should know how to prepare enolates in a quantitative way, using LDA.
• You should know the structure of LDA and how it is prepared.
• You should know why NH2- is not used, but rather LDA.
• You should know that enolates are strong nucleophiles, even more so than enols.

The Aldol Condensation.

• You should know and be able to write the detailed mechanisms of the base catalyzed aldol reaction..
• You should understand that the two aldehyde (or ketone) molecules which add together have mechanistically distinct roles. One molecule supplies the enolate (or the enol in the acid catalyzed reaction; this is the nucleophile) and the other supplies the carbonyl component (the electrophilic component). By using a nucleophile which reacts at carbon and a electrophile which reacts at carbon, a carbon-carbon bond is formed.
• You should know that the aldehyde (or ketone) must have at least one alpha type hydrogen, in order to be able to form the enol or enolate.
• You should be able to predict the product of the aldol reaction for a given aldehyde or ketone.
• You should know that mixed or "crossed" aldol reactions (i.e. reactions involving two different aldehydes or ketones) are not usually feasible and why (four different compounds can be formed).You should also know a strategy for successful mixed aldols in certain cases (i.e., where one of the aldehydes lacks an alpha hydrogen.).You should also know several examples of aldehydes which can participate in the mixed or crossed aldol (like formaldehyde,benzaldehyde, and 2,2-dimethylpropanal).
• You should know that the products of aldol type reactions are beta-hydroxyaldehydes or ketones, and that these are readily dehydrated in the presence of acid or base (sometimes a little heat is required). You should be able to write the mechanism for the base catalyzed dehydration of an aldol.
• You should know that the aldol reaction taken together with the subsequent dehydrationi of the aldol product is called the aldol condensation reaction. The product of aldol condensation is called (generically) an alpha,beta-unsaturated aldehyde or ketone.
• Know that the aldol reaction with aldehydes usually goes to completion to the aldol adduct, but that with ketones the equilibrium usually lies to the left (starting materials). This is because the ketone carbonyl is, as we have already seen, thermodynamically more stable than the aldehyde carbonyl.
• You should know, however, that in the aldol condensation reaction (giving the alpha,beta-unsaturated carbonyl compound) the reaction goes to completion even for ketones . This is because the last step, the dehydration, supplies the thermodynamic driving force for the overall reaction to go to completion. To be able to implement the aldol condensation reaction, the starting aldehyde or ketone must have two alpa type hydrogens, because one is used to form the enolate and one in the dehydration reaction.
• You should be familiar with the intramolecular aldol condensation reaction for generating 5 and 6 membered rings, using a diketone such as 2,7-octanedione. In this reaction, both the enolate component and the carbonyl component are present in the same molecule.
• You should also be familiar with the directed aldol reaction, in which the desired enolate is first formed quantitatively by treatment with the strong base lithium diisopropylamide (LDA). You should know that this is an excellent strategy for doing crossed aldol reactions and why it works.

THE CLAISEN CONDENSATION

• The Claisen ester condensation is analogous to the aldol reaction in that an enolate component and a carbonyl component is required. In the Claisen reaction, however, these are not supplied by an aldehyde or ketone, but by an ester. As a result of using an ester as the carbonyl component, the adduct is unstable toward loss of the alcohol component of the ester, thus giving a condensation.
• You should be able to write the detailed mechanism for the Claisen ester condensation using ethoxide anion as the catalyst. You should know that the overall reaction only goes to completion because of the final, acid/base neutralization step, which is highly exergonic (negative free energy).
• You should know that the last step is so exergonic because the conjugate acid of the beta ketoester is especially acidic, the conjugate base being substantially resonance stabilized (three good resonance structures, which you should be able to write).
• You should also know that unless the ester has two alpha type hydrogens, the reaction cannot go to completion, because the adduct will not have an alpha hydrogen for the neutralization step.
• You should know that the product is a beta keto ester, which is highly acidic (for an alpha type hydrogen), having a pKa of aoubt 10, because it is resonance stabilized. You should be able to write the three resonance structures for it.
• You should know that the intramolecular version of the Claisen ester condensation is called the Dieckmann condensation. It is useful for forming five and six membered rings from diesters, in the same way that the intramolecular aldol condensation was used.
• You should know that the beta keto esters provided by the Claisen or Dieckann condensations can by easily hydrolyzed to the corresponding beta keto acids, which readily undergo de-carboylation by a cyclic, concerted expulsion of carbon dioxide. You should be able to draw the TS of this reaction, and also to know that the enol is formed first. After ketonization, this reaction provides a nice synthesis of ketones, either cyclic or acylic, depending upon whether the Dieckmann or Claisen condensation is used.
• You should know that crossed Claisen ester condensations are feasible when one of the esters has no alpha hydrogens, and thus cannot supply the enolate component. Examples are ethyl formate, diethyl carbonate, and ethyl benzoate.
• Be able to predict the product of regular or crossed Claisen ester condensations for any given ester or pair of esters.

CLAISEN CONDENSATIONS IN THE BIOCHEMICAL WORLD

You should know that acetyl coenzyme A is a thiolester which can undergo the Claisen ester condensation to give acetoacetyl coenzyme A, which is an important intermediate in the biosynthesis of fatty acids, which we will look at later. You should be able to sketch a mechanism for the condensation of acetyl CoA to give acetoacetyl CoA and then complete the mechanistic sketch up to and including the formation of butyrl CoA.

The Malonic Ester Synthesis of Substituted Acetic Acids and the Acetoacetic Ester Synthesis of Substituted Acetones

• You should be familiar with the structure of diethyl malonate (malonic ester) and its use as an indirect strategy for effecting alpha alkylation to an ester function. The acetoacetic ester synthesis of substituted acetones fills a similar role for substitution alpha to a ketone function, and you should also be familiar with this.
• You should know that both approaches use a synthetic strategy known as an "activating group" strategy.
• You should understand that the enolate of diethyl malonate or ethyl acetoacetate can be formed quantitatively using either hydroxide ion or an alkoxide ion, because the pKa of these beta dicarbonyl compounds is about 13.
• You should know why these compounds have enhanced acidity. For example, the enolate of malonic ester has three resonance structures, with two of them having negative charge on oxygen and one on carbon. The electrons are thus delocalized over five atoms in all (O-CCC-O).In contrast, the electrons in a simple enolate are delocalized over only three atoms, and the charge is delocalized onto only two (oxygen and the alpha carbon). Thus a simple enolate has only two resonance structures.
• You should know that the enolate of malonic ester or acetoacetic ester can by alkylated cleanly. The resulting alkylated product can then be hydrolyzed to the carboxylic acid and de-carboxylated by heating in the same acidic solutions. The result is the formation of a substituted acetic acid or acetone.
• You should know the mechanism of the de-carboxylation reaction (a concerted, cyclic mechanism, with six electrons in the cyclic transition state--therefore an aromatic TS like the DA transtion state).
• You should know that decarboxylation does not occur for simple carboxylic acids, but only for malonic acids or in general a carboxylic acid with a beta carbonyl function (ester or ketone, etc.).
• You should know that the initial product of the de-carboxylation is the enol form of the acetic acid derivative (malonic ester synthesis) or of the ketone (acetoacetic ester synthesis).
• You should be able to write synthetic sketches using both of these syntheses (malonic ester and acetoacetic ester ) to make mono- or di-alkylated acids or ketones.
• You should also be able to use them to sketch the syntheses of cyclic acids or ketones, using the intramolecular version of these reactions (with dihalides).

CHAPTER 19: AROMATICS I

• You should recall that resonance stabilization is especially strong when two or more equivalent canonical structures are available for a single molecule. Resonance stabilization rises to its most powerful whenthe conjugated system is cyclic and (very important) contains 4n+2 electrons in the cyclic conjugated system, where n=0,1,2,3,---; that is for 2,6,10,14 and so on electrons. But, systems having 4n electrons (4,8,12, etc.) are not aromatic and are even considered antiaromatic (see further on).
• In the case of benzene, you should be able to write the two resonance structures (called Kekule structures in the case of benzene) and to show by an orbital picture that this is a cyclic array of orbitals. You should be able to count the electrons by examining any one of the canonical structures (2 electrons per pi bond; three pi bonds; equals six electrons). So benzene has two equivalent resonance structures in a cyclic conjugated system of six electrons.
• The 4n+2 rule is called the Huckel Rule.
• You should be able to draw an energy level diagram for the pi electrons of benzene which shows how the six electrons are accomodated in three BMO's and that the other three MO's are antibonding.. You should know that the 4n+2 rule arises because in such cyclic systems the lowest energy BMO occurs singly, but the higher MO's above it occur in pairs. Thus,. to fill all of the BMO's and only the BMO's we must put in 2 electrons to fill the lowest energy BMO and 4 electrons to fill each other pair of BMO's. Thus 4n+2 relates to the 4 electrons in each pair of degenerate MO's (meaning equal energy MO's) and 2 electrons always in the lowest energy BMO.
• You should know that the resonance stabilization of benzene is at least 36 kcal/mol.
• You should know that as a result of this resonance stabilization, all of the C-C bonds in benzene are equivalent and are intermediate between double and single. However, they are closer to double (1 2/3). Further, benzenes reactions are such as to preserve the pi system, so that it does not undergo addition reactions readily.
• You should know that the term "aromaticity" means the especially large resonance stabilization and delocalization of the electrons in a cyclic conjugated system of 4n+2 electrons, analogous to benzene.

AROMATICITY IN ANIONS AND CATIONS

• Know that aromaticity in cyclic systems of pi electrons depends upon the number of electrons in the cyclic conjugated system and not upon the size of the ring or whether it is charged or uncharged.
• You should know that 1,3-cyclopentadiene is about as acidic as water, even though the conjugate base of this diene is a carbanion, while the conjugate base of water has negative charge on a very electronegative atom (oxygen). You should know that this is because the cyclopentadienide anion is aromatic, having 6 pi electrons in the conjugated system. You should be able to count electrons, knowing the a carbanion site furnishes two electrons. You should also be able to write resonance structures of this anion and know that there are five structures. Finally, you should know that the negative charge is equally distributed over all five carbon atoms of the anion, and that all five C-C bonds are equivalent, as in benzene.Be able to draw an MO energy level diagram of this anion.
• Similarly, you should know that the carbocation formed from 1,3,5-cycloheptatriene is aromatic and is stable enough to store on a shelf and is available commercially. It also has six electrons (remember that a carbocation site contributes zero electrons to the pi system).
• Also, the carbocation from cyclopropene is aromatic, having two electrons.
• You should be able to count electrons in any cyclic anion, cation or neutral and use the Huckel Rule to indicate whether it is aromatic.

AROMATIC HETEROCYCLES

• Know that heterocyclic are cylic molecules containing an atom other than carbon as a part of the ring framework. Many such molecules occur in nature, which have nitrogen, oxygen, or sulfur in the ring.
• Know the structures of furan and pyrrole and that there pi systems are similar to the cyclopentadienide anion, having a five membered ring and 6 electrons.
• You should know the structure of pyridine, which is essentially like benzene, except that a N atom replaces one CH of benzene.In this case, the N has no hydrogen attached, and its unshared pair is in an sp2 orbital perpendicular to the pi system ( it is in the trigonal plane), so it does not enter into the pi system and is not counted. In such a case, nitrogen behaves just like carbon in bringing one pi electron with it. In pyrrole, on the other hand, the N has a H attached to it via the sp2 orbital and its unshared pair is a participant in the cyclic, conjugated system of six electrons.

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• BENZENOID AROMATICS
• Know that benzenoid aromatics are a series of aromatic compounds with structures based upon benzene, but having two, three, four, or more benzene rings fused together by a common C-C bond. You should know the structure of napththalene.

ANTIAROMATICS

• Be familiar with cyclobutadiene as an example of a 4n pi electron system which is not only not highly resonance stabilized but is actually highly unstable. This diene has 4 pi electrons (from two double bonds).
• You should also know that the cyclopropenyl anion, which also has 4 electrons, and the cyclopentadienyl cation, with four electrons are also antiaromatic.

ARENES (SUBSTITUTED BENZENES)

THE CIRCLE MNEMONIC

• You should be familiar with the "circle mnemonic" for the prediction of the pattern of MO's in cyclic pi electron systems and be able to use this to predict or rationalize the aromaticity or antiaromaticity of various pi systems.

• You should know that one or more (even up to all six) of the hydrogens attached to the ring in benzene can be replaced by a variety of substituents.
• You should be able to name these substituted versions of benzene, which are called arenes.This includes monosubstituted benzene derivatives, but also di-, tri-, etc. substituted benzene derivatives.
• For disubstituted benzenes, you should be able to use the ortho (o), meta (m), and para (p) nomenclature as well as the numerical nomenclature (para=1,4; ortho=1,2, etc.).
• You should be especially familiar with: toluene (methylbenzene), benzoic acid, phenol, aniline, and bromobenzene.

PHENOLS

• You should know that phenols have pKz's of about 10 and are much more acidic than normal alcohols.
• You should be able to write four resonance structures for the phenoxide anion which explain in terms of anion stability why phenol is so much more acidic than ordinary alcohols. Remember that alkoxide anions are not resonance stabilized.
• You should know that the negative charge on the phenoxide ion exists not only on oxygen, but on the ortho and para positions of the ring, but not on the meta position.
• You should know that sodium hydroxide is basic enough to convert phenol completely to its sodium phenoxide salt, which is water soluble.
• You should know that phenols and carboxylic acids both are extracted into the aqueous phase by aquueous alkali, but that phenols are not neutralized by sodium bicarbonate, while carboxylic acids are. You should know the reasons for this (carbonic acid is a weaker acid than carboxylic acids, but is a stronger acid than a phenol. You should therefore be able to diagram the separation of a phenol from a mixture containing carboxylic acids and netural organic compounds like ketones, ethers, etc.
• You should be able to sketch the synthesis of aspirin starting from phenol.
• You should be able to write the mechanism for the reaction of phenoxide anion with carbon dioxide to give salicylic acid.
• You should know that phenol is an "enol" from and has a corresponding keto form, which is involved in the aspirin synthesis. You should know that the enol form of phenol is much more stable than the keto form and why.
• Know tha structure of acetic anhydride and that it is used to make the acetate ester from the phenolic hydroxyl group in the aspirin synthesis.

BENZYLIC RADICALS, CARBOCATIONS, AND CARBANIONS

Yous should know the following things about benzyl radicals, carcocations, and carbanions and their involvement in radical bromination and chlorination reactions and in nucleophilic substitution reactions.

• The bond dissociation energy of toluene is about 87 kcal/mol. This is much lower than typical primary C-H bonds because the resulting benzyl radical is strongly resonance stabilized. You should be able to write the four resonance structures of the benayl radical and the dotted line/partial radical character structure for it.
• The benzyl radical has radical character on the benzylic carbon, but also on the o and p positions of the ring. However, there is no radical character on the m position. Why is the radical character greater on the benzylic carbon?
• Benzyl type hydrogens are readily replaced by Cl or Br in radical chain chlorination or bromination, because the benzylic C-H bond is so weak. Benzylic bonds are even more reactive in bromination than tertiary C-H bonds, but about as reactive as allylic C-H bonds.
• You should know that toluene can be selectively chlorinated at the benzylic position even though chlorine atoms are ordinarily unselective with respect to types of C-H bonds. That is because the only other type of C-H bond present in toluene are the ring C-H bonds which, being sp2 hybridized, are much stronger than sp3 bonds, and are not readily abstracted even by chlorine atoms.
• Benzylic C-H bonds are selectively brominated even in the presence of primary, secondary, or even tertiary C-H bonds.
• Benzylic carbocations and carbanions are similarly resonance stabilized. Be able to write the same four kinds of resonance structures as you have for the benzyl radical.
• You should know that, because of this resonance stabilization, benzylic carbocation or benzylic carbanion character is especially favored. Therefore, SN1 reactions of benzylic systems are quite fast. Incidentally, you should also know that the SN2 reactions of benzylic chloride itself are also fast, because it is a primary (unhindered) system.