1

Allene Chemistry

The simplest cumulated diene is 1,2-propadiene, CH2=C=CH2, also known as allene. Indeed,
cumulated dienes are often called allenes. The central carbon in such compounds is sp-hybridized (it
has only two bonding partners), and the double bond array is linear as a result. Since the π-bonds of
allenes are orthogonal, the planes defined by the end carbon substituents are also orthogonal. As
shown in the following diagram, the overall configuration of allenes resembles that of an elongated
tetrahedron. An interesting consequence of this configuration is that allenes having two different
substituents on each of the terminal carbon atoms are chiral.

The above diagram shows an allene with different substituents (A & B) on each of the terminal
(sp2) carbon atoms. The enantiomeric configurations are displayed relative to a mirror plane placed
to illustrate their mirror-image relationship. To assign a stereochemical prefix, i.e. R or S, to these
configurations we must view them from one end (it doesn't matter which), as shown in the
Newman-like projection on the right. If the sequence order of substituents is A > B, then the two
substituents nearest the viewer are assigned a ranking of 1 (A) and 2 (B), while the remote
substituents are given rankings of 3 (A) and 4 (B). Applying the viewing rule then leads to the
configurational notation shown above. This procedure may be used even when the A & B
substituents on one sp2 carbon are different from those on the other sp2 carbon.

More than two double bonds may have a cumulated structure, as we find in 1,2,3-butatriene
(CH2=C=C=CH2) and 1,2,3,4-pentatetraene (CH2=C=C=C=CH2). The carbon atoms in such
cumulenes all have a linear configuration, but the configuration of the terminal substituents
depends on the number of cumulated double bonds. For an even number of double bonds, an
orthogonal configuration of terminal substituents (as in allene) will be observed. For an odd number
of double bonds, the terminal substituents and all the carbons between them will lie in a plane. If
the terminal substituents at each end are different, the even double bond compounds will have
enantiomeric stereoisomers; whereas, the odd double bond compounds will exist as cis-trans
diastereoisomers.

Some instructive physical properties of a simple cumulated diene, 1,2-butadiene, compared with
its conjugated diene and alkyne isomers are presented in the following table. From the heats of
hydrogenation we see that the methylallene is thermodynamically the least stable of these isomers,
with the conjugated diene being most stable. The ionization potential is intermediate between the
alkyne and the conjugated diene (note than an electron volt is equivalent to 23.05 kcal/mol),
suggesting that the pi-electrons in the allene are less strongly bound than in the alkyne. Finally, the
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gas phase basicity or proton affinity is close to that of the conjugated diene, and slightly greater than
that of the alkyne.

Heat of Ionization Proton

Compound
Hydrogenation Potential Affinity

1,2- 180-186
-69.5 kcal/mol 9.20 e.v.
Butadiene kcal/mol

1,3-
-56.6 9.07 181-187
Butadiene

2-Butyne -65.1 9.58 . 179-185

Addition Reactions of Allenes

Allenes undergo the usual electrophilic addition reactions, and one of the double bonds may even
serve as a dienophile in a Diels-Alder reaction. However, the regioselectivity of electrophilic addition
may seem surprising when examined with reference to the generally accepted order of cation
stability.

Carbocati CH2=C
CH3(+ ≈ RCH=CH RCH2( RCH=CR R2CH( C6H5CH2 R3C(
on ) (+)
< +)
≈ (+)
< +)
≈ H- < (+)
≈ +)
Stability CH2(+)

Meth 1º-
1º-Vinyl 1º 2º-Vinyl 2º 1º-Allyl 3º
yl Benzyl

Thus, addition of HBr to allene gives 2-bromopropene not 3-bromopropene (allyl bromide). From
the relative stability of vinyl and allyl cations the latter product would be expected.

CH2=C=CH2 + H–Br CH3CBr=CH2 not BrCH2CH=CH2

allene 2-bromopropene allyl bromide

To understand why the reaction path proceeding by way of an allyl cation is not favored here we
must recall the orthogonal orientation of the two pi-electron systems. As shown in the following
diagram, protonation of the center, sp-hybridized, carbon atom generates an allyl-like carbocation,
but the empty p-orbital of this cation (red) is initially oriented 90º to the π-orbital (blue) of the
adjacent double bond, so no conjugation can occur. In order to acquire the stabilization and charge
 3

delocalization expected for an allyl cation, a 90º rotation about the bond joining the carbocation to
the double bond must take place. Since this can only occur after the carbocation is fully formed, the
transition state for central carbon protonation has the high activation energy associated with any 1º-
carbocation formation. Indeed, the inductive effect of the adjacent double bond probably raises the
transition state energy even further. Consequently, formation of a 2º-vinyl cation by protonation at
an end carbon (bottom equation) is kinetically favored.

Some other addition reactions to allenes are shown in the following equations. The first
example demonstrates that bromine adds readily to one of the allene double bonds. The inductive
effect of the halogens retards addition of a second equivalent of bromine, but this may take place
under more forcing conditions. The oxymercuration example results in nucleophile (water) bonding
to a terminal carbon, probably because SN2 opening of the cyclic mercurinium intermediate is
favored at that site. The last example is interesting because it shows that independent stabilization
of a terminal carbocation, e.g. by benzyl resonance, changes the initial site of electrophilic attack to
the central (sp-hybridized) carbon. The resulting stabilized cation may then achieve further
stabilization by rotating to conjugate with the remaining double bond. The two isomeric addition
products shown here come from nucleophile bonding at both ends of the resulting allyl cation
intermediate.
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Reduction of Benzene and Derivatives by Sodium in Ammonia

A facile reduction of benzene and substituted benzenes is achieved by treatment with the electron
rich solution of alkali metals, usually lithium or sodium, in liquid ammonia. This reaction, which is
called the Birch Reduction in honor of Australian chemist A.J.Birch, is related to the reduction of
alkynes to trans-alkenes. Reduction is believed to occur by a stepwise addition of two electrons to
the benzene ring, each electron addition being followed by a protonation, as illustrated in the
following diagram. The initial electron addition gives a radical-anion for which many resonance
contributors may be written. Following delivery of a proton by the weak acid ammonia, the resulting
delocalized radical accepts a second electron to give an anion. The anion generated by the second
electron addition is delocalized over three carbon atoms, and is protonated on the central carbon.
The isolated (unconjugated) double bonds in the product do not react under these conditions.

When substituents are present, they may influence the regioselectivity of the Birch reduction. The
product is determined by the site of the first protonation, since the second protonation is nearly
always opposite (para to) the first. Electron-donating substituents such as ethers and alkyl groups
favor protonation at an unoccupied site ortho to the substituent; whereas electron-attracting
substituents such as carboxyl favor para protonation. The influence of a carboxyl group dominates
poly substituted rings, and alkoxy groups have a greater directing influence than alkyl substituents.
An oxy anion group, as in the conjugate base of phenol, prevents reduction from occurring. Two
examples of such Birch reductions are shown below. Although the substrate molecule in the first
reaction may appear very complex, it is essentially a rigid framework with a benzene ring at each
end. The phenolic function on the left hand ring becomes a phenolate anion under the reduction
conditions, and does not react further. The right hand aromatic ring is an ether, and it reduces as
expected. The carboxylic acid in the second example is immediately converted to its conjugate base.
Although this carboxylate anion is negatively charged, it still has an electrophilic carbon atom which
acts to stabilize an adjacent negative charge as shown. After protonation of the para carbanion by
ammonia, the carboxylate dianion remains unchanged until it is doubly protonated by a strong acid,
such as NH4(+) or H3O(+).
 5

Further examples of Birch reductions are presented in the following diagram. The preference
for protonation at unsubstituted sites (unless electron withdrawing groups are present), and for
unconjugated products is again illustrated in the first reaction. Note that the isolated double bonds
are not reduced at the low temperatures of refluxing liquid ammonia (–33 ºC). Reactions #2 & 4
illustrate a particularly useful application of the Birch reduction. Aryl ethers are reduced to 1,4-
dienes, as expected, but one of the double bonds is an enol ether and is readily hydrolyzed to the
corresponding ketone. If mild acid catalysis is used, the other double bond remains unchanged;
more vigorous acid (or base) treatment shifts this double bond to a conjugated location if simple
proton shifts permit. The 3rd reaction again illustrates the regio-directive influence of a carboxyl
group, even in the carboxylate form. The alpha-anion is sufficiently stable that it may induce an
elimination reaction (first stage) and upon regeneration be alkylated by a reactive alkyl halide
(second stage). The last example shows the Birch reduction of pyridine to a bis-enamine, hydrolysis
of which gives a diketone.
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Dissolving Metal Reductions of π-Electron Systems

Reduction of alkynes and benzene rings by solutions of sodium or lithium in liquid ammonia have
been described. Other reactive metals, such as zinc and magnesium have played a role in reductions
of aldehydes and ketones (Clemmensen reduction), alkyl halides and vicinal-dihalides. The ability of
certain metals to donate electrons to (reduce) electrophilic or unsaturated functional groups has
proven useful in several reductive procedures. The facility with which various of these metals donate
electrons is given by their reduction potentials. From these potentials the qualitative order of
reducing power is: Li > K > Na > Mg > Al = Ti > Zn > Fe > Sn.

1. Reduction of Isolated Carbonyl Groups

Lithium, sodium and potassium reduce ketones by a one-electron transfer that generates a radical
anion known as a ketyl. Once such a reactive species is formed, it may react further by several
modes, as described in the following diagram. If a proton source is present, the ketyl undergoes
carbon protonation, and the resulting oxy radical adds another electron to generate an alkoxide salt.
Alternatively, ketyls may dimerize to pinacol salts. Isolation of alcohol or pinacol products requires
further protonation by acids at least as strong as water or ethanol. The H+ notation refers to any of
several possible proton sources, including ammonia, alcohols and the ammonium cation (a strong
acid in the liquid ammonia system). Benzophenone (diphenyl ketone) forms a deep blue ketyl which
is stable in solvents that lack acidic hydrogens, such as hydrocarbons and ethers. It is widely used as
an indicator of oxidizing or acidic impurities during the purification of such solvents.

The solvents used for alkali metal reductions include hydrocarbons, ethers and, most commonly,
liquid ammonia. Alcohols may also be used, but usually as co-solvents, since they react vigorously
with these metals. Examples of metal reductions of ketones to alcohols and pinacols (a dimeric diol)
are shown below. In the first example, reduction of benzophenone in liquid ammonia gives both
alcohol and pinacol products. The ketyl intermediate in this reaction is stabilized by phenyl
substituents, and competitive carbon atom protonation and dimerization generate alkoxide salts
that remain in solution until hydrolyzed prior to product isolation. In the second reaction, two
isolated ketone functions are reduced to alcohols. The ketyl intermediates are not stabilized, and
their rapid protonation is assured by the alcohol cosolvent. Conformational motion is restricted by
the rigid polycyclic carbon framework of the substrate, and an interesting stereoselectivity is
 7

revealed: both alcohols are formed as the equatorial isomer. Aldehydes are not usually reduced in
this manner, because they react with ammonia to form unreactive imine condensation products.

When pinacol products are desired, a less reactive metal having stronger (less ionic) C-O bonds is
chosen for the reduction. Magnesium is often used, and best results have been achieved when the
metal is activated by amalgamation (alloyed with mercury) and Lewis acids are present. Equations
#3 & 4 (above) illustrate pinacol reduction. A di-positive cation may serve to hold two associated
ketyl moieties close to each other so that bonding is facilitated (as shown in equation #3).
Hydrolysis of metal alkoxides releases the product.

Ester functions undergo similar reductions on treatment with sodium. The most useful reaction of
this kind is the acyloin condensation. To avoid protonation at carbon, this reaction is normally
carried out in hydrocarbon solvents. The acyloin condensation creates alpha-hydroxy ketones. Two
examples of this reaction are shown here. The second illustrates the usefulness of this reaction for
constructing medium and large-sized rings. By clicking the "Show Mechanism" button a diagram for
a possible mechanism for the acyloin condensation will be displayed. The reduction of alpha-
diketones to acyloins, as shown on the second line, can be carried out independently.
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2. Reductive Removal of α-Substituents

The partial negative charge on the carbon atom of a ketyl may serve to eliminate an electronegative
substituent at an alpha-location. If further reduction is not desired, aluminum or zinc are often
selected for this reductive elimination. The following examples illustrate three such transformations,
the first being a useful conversion of acyloins to ketones.

3. Reduction of Conjugated π-Electron Systems

Two or more different functional groups are sometimes found together, and interaction of one upon
another may lead to unexpected chemistry. The addition reactions of conjugated dienes are one
example of this phenomenon. A similar situation occurs in conjugated enones, compounds in
which a carbonyl group is bonded to a carbon-carbon double bond.

C=C–C=O (an α,β-unsaturated ketone or enone)

Such functional combinations are often prepared by an aldol condensation, and are particularly
useful as synthetic intermediates. Because the π-electron systems of the two functional groups are
conjugated (the π-orbitals overlap in space), the radical anion formed by electron addition from a
reducing metal is a resonance hybrid of six canonical structures. In addition to the two ketyl
contributors described above, two structures having radical and nucleophilic character at the beta-
carbon are shown in the following diagram, and two others in which the radical anion character is
localized on the double bond are probably least important.
 9

The usual fate of the extended ketyl described here is protonation (or other electrophilic bonding) at
the beta-carbon atom. This creates an enoxy radical which immediately accepts an electron to form
an enolate anion. Protonation or alkylation of this enolate species then gives a saturated ketone,
which may be isolated or further reduced depending on the reaction conditions. Four examples of
such reactions are shown below.

In example #1 the enone substrate is drawn in the yellow box. If the lithium reduction is carried out
in liquid ammonia without any acidic co-solvents, the enolate anion is stable and remains
unchanged until an electrophilic reagent such as methyl iodide is added. This is shown for the
reaction to the right. If an acidic cosolvent such as ethanol is present, the enolate anion is
protonated, and the resulting ketone is then reduced to an alcohol (reaction to the left). Although
the radical anion intermediate usually undergoes protonation at the beta-carbon, this is not a fast
reaction in liquid ammonia. Example #2 presents an interesting case in which intramolecular
alkylation of the beta-nucleophile occurs faster than protonation. Example #3 is a case of cross-
conjugation. The carbonyl group is conjugated with one or the other double bond, but not both
simultaneously. Two different radical anions may be formed by electron addition, and these exist in
equilibrium with each other. Protonation at a beta-carbon effectively traps a radical anion as its
related enolate anion, preventing any further interconversion. This protonation is fastest at the less
substituted site (upper enone), and if the resulting enolate anion is not converted to its keto form by
in situ protonation, it will not react further until quenched by ammonium ion.
Conjugated dienes are also reduced by sodium or lithium solutions in liquid ammonia. 1,3-
Cyclohexadiene is reduced to cyclohexene, but the unconjugated 1,4-diene is not. If a double bond is
conjugated with a benzene ring, as in styrene, it is likewise reduced.
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The Leuckart Reaction

The Leuckart Reaction

A useful procedure for the reductive alkylation of ammonia, 1º-, & 2º-amines, in which formic acid
or a derivative thereof serves as the reducing agent, is known as the Leuckart Reaction. Some
examples of this reaction are shown below.

The manner in which a hydride moiety is transferred from formate to an iminium

intermediate is a matter for speculation, but may be summarized roughly as shown on
the right. Both aldehydes and ketones may be used as the carbonyl reactant. By using
ammonia as a reactant, this procedure may be used to prepare 1º-amines; however,
care must be taken to avoid further alkylation to 2º & 3º-amines. Polyalkylation is
sometimes desired, as in example #3 where dimethylation is accomplished with
formaldehyde. This is sometimes referred to as the Eschweiler-Clarke procedure, and it has
proven to be a useful method for converting 1º-amines to precursors for Hofmann or Cope
elimination reactions

Carbonyl Hydrates & Hemiacetals

Stable Carbonyl Hydrates & Hemiacetals

Although most aldehydes and ketones do not form stable hydrates or hemiacetals, a number of
interesting exceptions are known. Some examples are shown here.
 11

The factors that act to favor hydrate or hemiacetal formation include inductive charge repulsion
(chloral) dipole repulsion (ninhydrin) and angle strain (cyclopropanaone). It is important to note
that cases in which 5 or 6-membered cyclic hemiacetals can form usually favor such constitutions.
The simple sugars offer many examples of this kind. Because these additions are readily reversible,
all compounds of this type exhibit carbonyl-like chemical reactivity.

Derivatives of Aldehydes and Ketones

Aldehyde and Ketone Derivatives

1. Kinetic vs. Equilibrium Control in Semicarbazone Formation

A striking demonstration of kinetic control vs. thermodynamic (equilibrium) control of products is

provided by an experiment in which equimolar amounts of cyclohexanone, furfuraldehyde and
semicarbazide are mixed in a buffered solvent at pH=5.

The semicarbazide reacts with cyclohexanone 60 times faster than it does with the aldehyde, and
within 45 seconds a nearly quantitative amount of the semicarbazone derivative of cyclohexanone
has precipitated and may be isolated by filtration. However, if the initial reaction mixture containing
the cyclohexanone product is refluxed for a few hours an equally good yield of the more stable
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furfuraldehyde semicarbazone is obtained. Note that in both cases the semicarbazone derivative is
favored over the initial reactants, but the equilibrium constant for the aldehyde is about 300 times
greater than that of the ketone. The aldehyde semicarbazone is therefore the thermodynamically
favored product, assuming there is equilibrium at all steps.

2. Dinitrophenylhydrazones

Another commonly used carbonyl derivative is prepared from 2,4-dinitrophenylhydrazine, as shown

below. The reagent and its hydrazone derivatives are distinctively colored solids, which can be
isolated easily. Saturated ketones and aldehydes are usually yellow to light orange in color.
Conjugation of the carbonyl group with a double bond or benzene ring shifts the color to shades of
red.

3. Aldehyde Derivatives

Among aldehydes, formaldehyde, H2C=O, has many unique properties. For

example, with ammonia it reacts in a 3:2 ratio to give a tricyclic product,
shown on the right, and known as hexamethylenetetramine. This interesting
compound may function as an ammonia derivative for the synthesis of 1º-
amines, or as a convenient high-melting source of formaldehyde by way of
acid-catalyzed hydrolysis.

An interesting reagent that distinguishes aldehydes from ketones is the hydrazine derivative, 4-
amino-3-hydrazino-5-mercapto-1,2,4-triazole, best known as Purpald (formula shown below).
Although this reagent reacts with both aldehydes and ketones, only the aldehyde product is further
oxidized to a purple, 10 π-electron aromatic heterocycle on exposure to air. Note that the pair of
electrons on the nitrogen atom common to both rings is part of the π-electron system.
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Enols and Enolate Anions

Enols and Enolate Anions

Specific examples of enol tautomer and enolate anion concentrations for three different compounds
are shown in the following table.

Cyclohexanone is a typical monoketone. Both the enol and enolate anion concentrations are very
small, even at pH=13. Phenol serves as a model for the enol tautomer of cyclohexanone, the
aromaticity of the benzene ring stabilizing the hydroxyl form. The enhanced acidity of phenols was
explained by charge delocalization in the conjugate base, a characteristic that is confirmed by facile
electrophilic substitution of the aromatic ring. Although simple ketones have small equilibrium enol
concentrations, carboxylic acid derivatives such as esters and amides have even less enol, and are
weaker alpha-carbon acids.

The beta-dicarbonyl compound, 2,4-pentanedione, is remarkable in having a much higher enol

concentration than monocarbonyl aldehydes and ketones. Enol concentration is solvent dependent,
being greater than 90% in hexane solution. The acidity of the diketone is also increased
substantially, reflecting charge delocalization over both oxygens.

(–)O–C=C–C=O O=C–C=C–O(–)
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The chemical behavior of beta-dicarbonyl compounds reflects their increased enol concentration
and acidity. Substitution reactions, such as halogenation and isotope exchange, occur more rapidly
at the central methylene group of 2,4-pentanedione than at the terminal methyl groups.
Furthermore, the corresponding enolate anion may be generated in hydroxylic solvents, using
common bases like sodium or potassium hydroxide.
Two other beta-dicarbonyl compounds commonly used in organic synthesis are ethyl acetoacetate, a
beta-ketoester, and diethyl malonate, a diester. The weaker influence of the ester carbonyl on
enolization and acidity is evident from the data in the following table. Even though diethyl malonate
is the weakest acid of the three, it is easily converted to its enolate base by treatment with sodium
ethoxide in ethanol. Useful nucleophilic intermediates of this kind are frequently employed in
synthesis when suitable beta-dicarbonyl reactants are available.

Pyrolytic syn-Elimination

Unimolecular syn-Eliminations

E2 elimination reactions are commonly bimolecular and prefer an anti-coplanar transition state.
This important class of functional transformations is complimented by a small group of thermal,
unimolecular syn-eliminations, described in the following table. The syn or suprafacial character of
these eliminations is enforced by the 5- or 6-membered cyclic transition states (A & B) by which they
take place.
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The temperature variations noted in the table suggest that these eliminations are facilitated by a
negative charge on the O or Z atom and a low C–Y bond energy. Amine oxides have a full negative
charge on the oxygen, and the Cope elimination proceeds well at temperatures near or slightly above
100 ºC. Together with the Hofmann elimination, Cope eliminations have proven useful for removing
a permethylated amino group from a larger molecule. Sulfoxides are eliminated to sulfenic acids at
roughly similar temperatures as the amine oxides. Here, oxygen charge neutralization by p-d
bonding to the positive sulfur atom is balanced by the weaker C–S bond. Selenoxides eliminate
rapidly at low temperature, reflecting a greater charge on oxygen due to poorer p-d bonding
(selenium is much larger than oxygen), and a weak C–Se bond.
Although a six-membered transition state is relatively unstrained, esters and thioesters of alcohols
require higher temperatures for elimination. This is expected because of the stronger C–O bond and
the lower polarity of C=Z. The thioester function of xanthate derivatives of alcohols undergoes
elimination at much lower temperatures than carboxylic esters, probably reflecting a favorable bond
energy change from O–C=S in the xanthate to S–C=O in the eliminated fragment.

Some examples of these syn-thermal eliminations are given in the following diagram. The ester
pyrolysis in equation # 4 demonstrates the importance of a cis-alignment of the eliminating groups,
in this case the acetate ester and the vicinal hydrogen atom. Xanthate ester pyrolysis (equation # 5)
is known as the Chugaev (or Tschugaev) reaction. Finally, the conversion of 1º-alcohols to aryl
selenium ethers prior to selenoxide elimination, as in example # 3, is carried out via a hypervalent
phosphorus species similar to that involved in the Mitsunobu reaction. The preferred aryl group in
the selenocyanate reagent is o-nitrophenyl.
 16

Aldehyde Ketone Reaction Summary

Preparation

Commonly by oxidation of 1º & 2º-alcohols by chromium+6 reagents (e.g. PCC and Jones'
reagent).
Reactions

Aldehydes are oxidized to carboxylic acids by Jones' reagent or Tollens' reagent. Ketones are
not.
Both classes undergo the following chemical transformations:
 17

Acetals and hemiacetals by reversible addition-elimination of alcohols. (acetals require

removal of water)

Imines and enamines by reversible addition-elimination of 1º & 2º-amines respectively.

(removal of water is necessary)

Cyanohydrins by reversible addition-elimination of HCN.

Reduction to1º & 2º-alcohols by NaBH4 and LiAlH4 (irreversible hydride addition).

Reduction to alkanes by Wolff-Kishner or Clemmensen conditions.

Formation of 1º, 2º or 3º-alcohols by addition of organometallic reagents to formaldehyde,

other aldehydes or ketones.

Carboxylic Acid Reaction Summary

Preparation

By oxidation of 1º -alcohols, hydrolysis of nitriles, carboxylation of organometallic reagents

and oxidation of arene side-chains.

Reactions

Carboxylic acids are distinguished from other weak acids by reaction with sodium
bicarbonate solution (gas evolution).

Chemical transformations:

Salts are formed by reaction with a base.

Methyl esters are formed by reaction with diazomethane (CH2N2).

Acyl chlorides (acid chlorides) are formed by reaction with thionyl chloride (SOCl2).

Various esters are formed by reaction with alcohols and an acid catalyst (removal of water)

Reduction to 1º-alcohols by .

Formation of 1º-alcohols by LiAlH4 reduction.

 18

Reaction Summary for Carboxylic Acid Derivatives

Preparation

By reactions of carboxylic acids; or by acyl transfer (see below).

Reactions
1. Acylation:

Acyl Chlorides

Water reacts to give a carboxylic acid and HCl.

Alcohols react to give esters and HCl.

Carboxylate salts react to give anhydrides.

Amines react to give amides and HCl (pyridine neutralizes the HCl).

Anhydrides

Water reacts to give the carboxylic acid.

Alcohols react to give esters and a carboxylic acid. (base removes the acid)

Amines react to give amides and a carboxylic acid. (base removes the acid)

Esters

Water reacts to give the carboxylic acid and the alcohol. (acid or base catalysis)

Alcohols react to give a new ester and an alcohol. (acid or base catalysis)

Amines react to give amides and an alcohol.

Amides and Nitriles

Water reacts to give the carboxylic acid and an amine or ammonia. (acid or base catalysis
is necessary)

2. Reduction:

Acyl Chlorides are reduced to aldehydes by reduction with LiAlH(t-BuO)3, or by H2 and a

poisoned catalyst.

Classes of Intramolecular Ene Reactions

The "ene" (C=C–Z–H) and "enophilic" (X=Y) moieties of an intramolecular ene reaction may
assume different relative orientations that depend on the nature of the linking structure. The most
common relationship is Type I, in which the enophile is joined to the alkene carbon farthest from
the Z–H group. Type II reactions have the enophile joined to the alkene carbon bearing the Z–H
 19

group, and in Type III reactions the enophile is linked directly to the Z atom. These different
arrangements are defined in the following diagram, where the X,Y & Z atoms are colored blue, and
the transferred hydrogen is green.. Most intramolecular ene reactions, including earlier examples,
are Type I.

Equation 1. demonstrates a Type II ene reaction in which the enophile is a carbonyl group
(colored red). The alkene moiety is colored green, and the new sigma-bond is blue.
Equation 2. is a rare example of a Type III ene reaction. There are actually two different ene
reactions that take place, and these may be distinguished by the location of the product double bond
and the origin of the transferred hydrogen atom (colored red and blue in the above illustration).
The last two examples show an interesting variant of the ene reaction in which the enol tautomer of
a carbonyl function serves as the "ene" component, and a carbon-carbon double or triple bond is the
"enophile". Reaction 3 has two equivalent alkyne chains suitably oriented for a Type I reaction, and
 20

both engage sequentially to yield a novel tricyclic "propellane" compound. There are two ene
transformations in equation 4. The first is a Type I retro ene reaction, facilitated by relief of ring
strain. The second is a Type II ene cyclization. An alternative Type III ring closure to 1-methyl-3-
cyclohexenol does not occur.

Orbital Correlation Diagrams

Woodward and Hoffmann's landmark review, "The Conservation of Orbital Symmetry", Academic
Press, 1970, provides one of the best introductions to the use of orbital correlation diagrams, and the
following discussion is derived from this source. In applying orbital correlation analysis, care must
be taken to recognize the pertinent σ and π molecular orbitals and their delocalization as required by
the symmetry of the transition state. This must be done for both the bonding and antibonding
orbitals, and when necessary for n (nonbonded pair) orbitals. The following principles should be
observed:
1. Bonding orbitals undergoing significant change in the reaction, and their antibonding
counterparts, should be identified. Normally, these are orbitals associated with the curved arrow
description of a reaction.

2. If polyene moieties are involved, all the molecular orbitals of that conjugated system must
be used.

3. Ignoring non-participating substituents and heteroatoms, the symmetry elements of the

essential molecular skeleton must be identified. All orbitals not clearly symmetric or antisymmetric
with respect to these molecular symmetry elements need to be mixed or delocalized until they
become so. In this respect, the only important symmetry elements are those that bisect bonds that
are made or broken in the reaction. Mixing is usually required for σ orbital analysis.

4. Each bonding and antibonding orbital included in the correlation is assigned one or more
symmetry designations, S for symmetric, A for antisymmetric, depending on its fit with each
characteristic symmetry element.

5. The molecular orbitals are then arrayed according to their energy (increasing vertically),
and location on the reaction coordinate (horizontally). Correlations of reactant and product orbitals
are drawn so that orbitals of like symmetry are connected. In making these correlations, lines
connecting orbital pairs of opposite symmetry may cross, but lines connecting orbitals of the same
symmetry may not.

To illustrate this method of analyzing pericyclic reactions, we shall use a suprafacial cycloaddition
reaction. The essential elements of the [4+2] Diels-Alder reaction are shown at the top of the
following diagram. As noted in principle 3 above, substituents on the diene and dienophile can be
ignored. Consequently, only the three π-electron functions of the reactants need to be considered.
Corresponding to these, there are three new bonding orbitals in the product, two σ-orbitals and one
π-orbital, and these must also be incorporated in the correlation diagram. The symmetry of all
participating orbitals must be evaluated before the diagram is constructed. Two symmetry
 21

properties of an isolated double bond were described earlier, and may be applied to the dienophile
reactant. For the remaining orbitals a plane perpendicular to the molecular plane is used, as shown
in green in the diagram.

The π- molecular orbitals of 1,3-butadiene were also described in an earlier section. Because of the
geometrical requirements for cycloaddition, the s-trans conformation used in that example must be
changed to the s-cis conformation. To illustrate, the two bonding π-orbitals of the s-cis diene are
shown. The new σ-bonds in the product must be evaluated together (mixed), note principle 3 above.
Two delocalized σ-bonding orbitals of different symmetry are thus produced.

The essential molecular orbitals for this suprafacial cycloaddition reaction may now be arrayed
according to their energy and location on the reaction coordinate. This array will be displayed by
clicking on the above diagram. Bonding orbitals are designated either σ or π, and antibonding
orbitals by an asterisk. Mixing the σ-bonds leads to two energetically different bonding orbitals (σ1 &
σ2). Likewise, there are two different antibonding orbitals (σ3* & σ4*).An approximate atomic orbital
energy level is shown by the horizontal green dashed line, which separates the bonding and
antibonding orbitals. A vertical light blue line separates reactant and product orbitals.
Symmetry designations for each orbital are determined relative to the perpendicular symmetry
planes shown in the first diagram. Once these symmetries are noted, correlations of reactant and
 22

product orbitals may be drawn so that orbitals of like symmetry are connected. By clicking on the
diagram a second time, these symmetry assignments and correlation lines will be added to the
display. The six electrons that occupy the bonding orbitals of the reactant functions are shown as
light blue paired arrows. Since these bonding reactant orbitals correlate with product bonding
orbitals, this is considered to be a symmetry-allowed transformation.

It is constructive to compare the allowed [4s + 2s] cycloaddition with a [6s + 2s] analog. To make this
reaction as favorable as possible the double bonds of the hexatriene reactant are placed in a seven
membered ring, so that the ends of the conjugated π-electron system are located close together. The
appropriate σ and π-orbitals are depicted in the following diagram, and by clicking on the diagram
the mirror plane symmetries and correlation lines will be displayed. Clearly, correlation lines from
the π3 and π4* orbitals of the reactant triene to the π2 and π3* orbitals of the product diene cross the
bonding/antibonding transition (dotted green line). Consequently, this [6+2] suprafacial thermal
cycloaddition is classified as symmetry forbidden.
 23

If the cycloheptatriene is electronically excited by absorption of 260 nm light, one of the electrons in
the π3 bonding orbital is promoted to the π4* antibonding orbital. Once this happens, as shown by
clicking on the diagram a second time, the occupied excited state orbitals correlate with excited state
product orbitals, and the photochemical cycloaddition is symmetry allowed.
This discussion of the [6+2] cycloaddition has assumed a suprafacial configuration, e.g. [6s + 2s].
 24

The possibility of an alternative antarafacial cycloaddition should also be considered. This is

illustrated in the following diagram, and requires a nearly right angle approach of the double bond
reactant to the end carbons of a planar triene conformation. The methylene group that closes the
seven membered ring must be removed to permit this orientation, as shown by the second equation.
A mirror plane no longer provides adequate symmetry characterization of the participating
molecular orbitals, so a C2 rotational axis, two views of which are shown at the bottom of the
diagram, is used instead. The alkene single bonds are colored green in these drawings.

A correlation analysis of the orbitals involved in this [6a + 2s] cycloaddition will be displayed here by
clicking on the diagram. This mode of cycloaddition is seen to be a symmetry allowed thermal
process. However, this is not an easily achieved reaction because the necessary coiled conformation
of the triene is present in very low concentration. Since the [14+2] cycloaddition noted earlier has a
 25

heptaene reactant that is confined in a suitable orientation, the corresponding antarafacial

cycloaddition is facilitated, and in fact takes place.

Orbital correlation diagrams for other kinds of pericyclic reactions may be constructed and used for
evaluation. The Woodward & Hoffmann review provides examples, as does the excellent Imperial
College site. Additional examples will not be supplied here, since the "Frontier Orbital" approach is
more easily applied, in the opinion of the author.

Transition State Aromaticity

In describing pericyclic reactions the reorganization of electrons may be represented by a cycle of

curved arrows - each representing the movement of a pair of electrons. Many common pericyclic
reactions having similar characteristics (e.g. [4+2] suprafacial cycloadditions & [1,5] sigmatropic
shifts, as well as disrotatory electrocyclic reactions of trienes) require three curved arrows, and are
therefore cyclic six-electron transformations. The similarity to the conjugated six π-electron ring of
benzene has led many chemists to designate the cyclic transition states of these reactions as
aromatic. Extending this viewpoint, we note that suprafacial [6+4] and [8+2] ten-electron
cycloaddition reactions, but not [6+2] eight-electron cycloadditions have been observed. Likewise,
six-electron [1,5] sigmatropic shifts are common, but four-electron [1,3] shifts are very rare. A
comparison of these facts with the Hückel Rule for aromaticity is suggestive, leading to the
designation of 4n+2 pericyclic reaction transition states as Hückel transition states.

A short review of Hückel's contribution will be helpful in using this approach. A linear chain of n
conjugated p-atomic orbitals overlap to generate n π-molecular orbitals, as shown for n=6 on the
left of the following diagram. The lowest energy π-orbital has no nodal surface, other than that
defined by the plane of the molecule. The next higher energy orbital has one node, perpendicular to
the molecular plane (colored green), and the other orbitals have increasing numbers of nodes,
paralleling their different energies. The three lowest energy orbitals are bonding, and the three
highest energy orbitals are antibonding.
To examine a model of the p-orbital components of 1,3,5-hexatriene pi-orbitals.

To examine the actual molecular orbitals of 1,3,5-hexatriene

If this linear array of p-orbitals is coiled so that the ends may be joined by a sigma bond, the
resulting cyclic conjugated system (that of the annulene benzene) is markedly changed by the
symmetry of the ring. Hückel showed that the six π-orbitals are now arrayed in four energy levels or
shells. The lowest level has a single molecular orbital, but the next two levels each hold two equal
energy (degenerate) orbitals. The last and highest energy orbital then occupies a fourth shell. As
before, the three lowest energy orbitals (shown here) are bonding, and the others are antibonding.
The number of nodes a given orbital has is determined by the number of phase changes encountered
in one circuit of the ring. The degenerate bonding orbitals π2 and π3 each have two nodes where the
nodal planes (colored green) intersect the ring. The complete set of benzene molecular orbitals was
shown earlier in this text.
 26

Benzene was not the only annulene described by Hückel, and a diagram displaying the π orbital
energies for ring sizes three to seven will be activated by clicking on the above diagram. These
Hückel annulenes (shown at the top of the diagram) are all characterized by a single lowest energy
π-orbital having no nodal surfaces, other than the plane of the molecule. Using the terminology of
atomic structure, this single orbital represents the first shell of the π-electron system. Pairs of
degenerate π orbitals make up the next electronic shells, as shown. The number of nodes associated
with each level increase by two, as the energy increases. Electrons are placed in these orbital shells,
starting with the lowest energy shell and moving to higher energy shells until all the electrons have
been assigned. The aromatic stabilization of benzene comes from its closed shell electronic
configuration, i.e. all the bonding orbitals are occupied by electron pairs. Cyclobutadiene, the four
membered annulene, has four π electrons, but these do not completely fill the second (non-bonding)
shell, and by Hund's rule would produce a diradical. The instability of this 4n electron annulene is
thus explained. Cyclopentadienyl anion and cycloheptatrienyl cation both have closed shell
configurations and are exceptionally stable relative to other organic ions. Hückel concluded that
annulenes having 4n+2 π-electrons would exhibit enhanced (aromatic) stabilization, but those
having 4n electrons (e.g. cyclobutadiene) would be especially unstable.
The bottom section of the diagram describes a novel set of annulenes created by twisting the p-
orbital array before joining the ends. This causes a node or phase change at this junction, and the
resulting π-orbitals have been called Möbius orbitals by H. Zimmerman (Wisconsin), in reference
to the well known topological surface. The calculated energy levels for these orbitals are shown in
the bottom section of the diagram. In contrast to Hückel annulenes, Möbius annulenes have two
degenerate π-orbitals in the first shell. Pairs of degenerate orbitals occupy the remaining shells, so a
closed shell configuration will necessarily have 4n π-electrons. Such 4n configurations are expected
to have aromatic-like stability. No stable Möbius annulenes are known, but a search for such
 27

compounds is ongoing. Because the twist in such annulenes disrupts orbital overlap, only large rings
are likely to accommodate this feature while retaining conjugation.

The unique characteristics of Hückel and Möbius molecular orbital arrays may be used to analyze
pericyclic reactions, thanks to the cyclic movement of electron pairs in their transition states. For
example, a suprafacial configuration in cycloaddition and sigmatropic shift reactions is possible
without introducing a node into the orbital interactions. Consequently, such reactions have Hückel
transition states and will be favored by systems having 4n+2 electron transition states. Similar
reactions involving 4n electron shifts will be favored by a Möbius configuration having a node, as in
an antarafacial configuration.

The two electrocyclic reactions shown below further illustrate this approach. The four-electron
example at the top proceeds best by way of a Möbius transition state, so the conrotatory movement
involving a node at the sigma bonding site is favored. The second example is a six-electron
transformation, and this should occur by way of a Hückel transition state. The absence of a node in
that transition state requires a disrotatory movement during the ring closure or opening.

Frontier - Molecular Orbitals

A useful molecular orbital model for analyzing pericyclic reactions has been proposed by Kenichi
Fukui of Japan. This frontier-orbital approach is based on the assumption that bonds are formed
by a flow of electrons from the highest occupied molecular orbital (HOMO) of one reactant or
participating bond to the lowest unoccupied molecular orbital (LUMO) of another reactant or bond.
To illustrate, consider the [4+2] cycloaddition of 1,3-butadiene and ethylene to give cyclohexene.
 28

The pertinent molecular orbitals involved in this reaction were described elsewhere, and the two
combinations of HOMO and LUMO are shown in the following diagram. Note that regardless of
which combination is examined, the terminal orbital phases match, indicating a bonding
interaction. Since the dienophile often has electron-withdrawing substituents and the diene is
usually electron rich, the electron flow pattern on the left seems to best represent the course of most
Diel-Alder reactions.

This frontier orbital approach to cycloaddition reactions is general, and is simple to apply thanks to
the alternation of terminal orbital phase relationships as a polyene changes from a 4n electron
system to a 4n + 2 electron system. By clicking on the above diagram, these phase relationships will
be displayed for HOMO and LUMO of polyenes in both classes. Only the terminal orbital phases
(colored in the diagram) are important for frontier orbital analysis. The frontier orbital analysis of a
[6s + 2s] cycloaddition reaction will be demonstrated by clicking on the diagram a second time. An
antibonding node is present in both HOMO-LUMO combinations (one is shown), so this reaction is
orbital symmetry forbidden.

An additional feature of this treatment of cycloaddition reactions is its rationalization of the

tendency of Diels-Alder reactions of cyclic dienes to form endo adducts preferentially. This was
noted earlier, and is further illustrated in the following diagram. The first two equations are
straightforward examples of the endo predilection of substituents or rings (colored green) attached
to a bicyclic ring system. The third equation shows a more subtile case of the same orientational
factor, which essentially favors that [4+2] transition state in which unsaturated substituents on the
dienophile are directed toward the diene double bonds. By clicking on this diagram, the secondary
orbital bonding interaction that stabilizes the endo transition state for a typical Diels-Alder reaction
will be displayed.
 29

Not all cycloaddition reactions favor endo products. The predominant product from the [6s + 4s]
reaction shown earlier is the exo adduct. Frontier orbital analysis of this case demonstrates that
secondary orbital interaction destabilizes the endo transition state.

Electrocyclic Reactions

The stereochemistry of electrocyclic reactions is easily predicted by frontier orbital analysis. Two
examples are shown in the following diagram. The upper reaction represents the thermal
interconversion of 1,3-butadiene and cyclobutene; the lower reaction shows the similar
interconversion of 1,3,5-hexatriene and 1,3-cyclohexadiene. The HOMO orbital of the open chain
isomer for each example is displayed on the left. In order to close the ring, the terminal p-orbital
components of this orbital must be rotated so that identical phased lobes can interact to form a new
sigma-bond (green line). It should be evident that the orbitals of the upper example must rotate in
the same direction (conrotatory), either clockwise or counter-clockwise, to permit this bonding to
occur. The terminal orbitals of the lower example must rotate in opposite directions (a disrotatory
motion) to achieve the same bonding interaction. The alternation of terminal orbital phases in the
HOMO of 4n and 4n+2 polyenes, as noted above, is therefore a predictor of the general course of
electrocyclic reactions.
 30

The reverse ring opening electrocyclic process (orange arrows) is conveniently treated by assuming a
flow of electrons from the HOMO of the sigma bond to the LUMO of the π-electron system. Of
course, the same configurational motion is predicted by this analysis, and is in fact required by the
principle of microscopic reversibility.

To examine a model of the p-orbital components of 1,3,5-hexatriene pi-orbitals.

To examine the actual molecular orbitals of 1,3,5-hexatriene

Sigmatropic Reactions

Accounting for the facility of [1,5] hydrogen shifts in contrast to the rarity of documented [1,3] shifts
is a sine qua non of pericyclic reaction theory. One frontier orbital approach to these reactions
establishes the sigma C–H bond as the HOMO site, and the adjacent pi-orbital(s) as the LUMO. In
the following diagram these entities are defined for both the general [1,5] and [1,3] relationships.
Since it is necessary for the origin and terminus of a hydrogen shift to be near each other, a potential
[1,5] system must be coiled in an appropriate manner (top-central formula) for such a
rearrangement to occur. As shown, there is a phase correlation of HOMO and LUMO termini,
rendering these reactions symmetry allowed. Note the stereoelectronic requirement that the
sigma bonds be oriented parallel to the pi-orbital system. The lower row shows a similar analysis of
the suprafacial [1,3] shift, which is found to be symmetry forbidden. A previously described [1,7]
hydrogen shift is antarafacial with respect to the triene moiety, and is therefore symmetry allowed.
If the π-electron system is electronically excited by the absorption of light, the LUMO becomes the
next higher energy orbital, and [1,3] shifts are symmetry enabled. By clicking on the diagram an
interesting example of such a rearrangement will be displayed. Sigmatropic [1,5] hydrogen shifts are
 31

prohibited in this example, because the diene is constrained in a s-trans-configuration so that origin
and terminus of such a shift are kept far apart. The conjugated diene chromophore absorbs UV-
light, and once the [1,3] shift has occurred the unconjugated double bonds no longer absorb 245 nm
light. Two hydrogens at C-6 are candidates for this shift, but only the axial hydrogen (colored
orange) has the necessary parallel orientation (a stereoelectronic discrimination). Other
photochemical products were formed in this reaction, and these may include an isomeric diene
formed by a [1,3] shift of the axial C-12 hydrogen.

When considering the sigmatropic shift of an alkyl group, such as methyl, the possibility of
antarafacial bonding to carbon must be considered. Although such rearrangements are rare, they
have been observed along with the expected inversion of configuration at the migrating group. By
clicking on the above diagram a second time, the general form of these rearrangements will be
shown together with two examples. The [1,3] shift of a methyl group (colored green) is pictured at
the top. The phases of the central p-orbital component are colored light blue and orange, rather than
blue and red, to avoid confusion with the pink and purple phases of the methyl carbon p-orbital in
the transition state. Clearly, symmetry allowed 1,3-bonding takes place with inversion at the methyl
carbon. In the two example shown at the bottom (A & B) the migrating group is marked by an
asterisk.

The most commonly used sigmatropic reactions are those involving a [3,3] shift. Of these, the Cope
rearrangement of 1,5-dienes is a prominent example, and the orbital assignments for this reaction
are shown in the following diagram. One of the terminal double bonds (for our purpose it doesn't
matter which) is defined as the LUMO partner. The central sigma bond (joining C-3 and C-4 of the
diene), together with the remaining double bond, is then the HOMO for this analysis. As shown on
the top of the diagram, the [3,3] shift is found to be symmetry allowed.
An alternative interpretation is shown in the shaded box. Here, the 1,5-diene is dissected into two
allylic radicals. Because an allylic radical has three π-electrons, the HOMO is π2. The central carbon
 32

atom of this fragment is the locus of a node, so the terminal carbons have opposite phases. Bonding
at both ends of the bis-allylic intermediate is therefore allowed.

The spatial orientation of the 1,5-diene may assume either a chair-like or boat-like transition state
configuration. These possibilities will be displayed by clicking on the diagram. In each case the
HOMO and LUMO components are identified, and the orbital lobes in the chair drawing are shaded
to show their relative orientation. Specific cases proceeding by both transition states are known, but
in general, acyclic reactants prefer the chair-like pathway. The boat-like transition state is possibly
destabilized by a non-bonding secondary interaction involving orbitals at C-2 and C-5.
Thermal rearrangement of the diastereomeric 3,4-dimethyl-1,5-hexadienes to isomeric 2,6-
octadienes clearly shows a preference for a chair-like transition state. These reactions will be
displayed above by clicking on the diagram a second time. The top row illustrates reaction paths for
the racemic diastereomer (R = CH3). The conformational equilibrium between the diaxial
conformation shown left of center and the diequatorial conformer to its right will strongly favor the
latter (>99%). Assuming similar activation energies for [3,3] sigmatropic shifts from each, the
formation of (E,E)-2,6-octadiene is expected to predominate. The meso-isomer depicted on the left
of the second row exists as a mixture of equivalent axial-equatorial conformers, each of which
rearranges to (E,Z)-2,6-octadiene. Rearrangement of these diastereomers by way of a boat-like
transition state would generate a different set of products, as shown on the left of the third row for
the meso isomer. The data in the following table clearly show a strong preference for a chair-like
transition state, when that path is available to a rearranging system.
 33

Cope Rearrangement of racemic and meso-3,4-Dimethyl-1,5-Hexadiene to 2,6-

Octadiene
Octadiene Isomer

Hexadiene Isomer E,E E,Z Z,Z

racemic (180 ºC) 90% <1% 9%

meso (220 ºC) 0.3% 99.7% ---

Finally, the example on the right of the second row demonstrates that a [3,3] sigmatropic
rearrangement may serve to transmit chirality from an existing stereogenic center to one that is
newly formed. Once again, chair and boat-like transition states control this transfer in a different
manner.

Ene Reactions

Since ene reactions are often stereospecific, and do not seem to proceed by way of discrete
intermediates, they are sometimes grouped together with other pericyclic reactions. A frontier
orbital analysis of the forward ene reaction is shown in the following diagram., and displays many
features of the [3,3] sigmatropic shift. Thus, hydrogen atom transfer from an allylic site to a double
bond is seen to be symmetry allowed with respect to the HOMO of an allyl radical and the LUMO of
an alkene (right side of diagram). There is also symmetry correlation between the HOMO and
LUMO terminal sites of the ene and enophile reactants, as defined on the left. Ene reactions proceed
best when the enophilic double bond is electron deficient, and the ene reaction is often catalyzed by
Lewis Acids.
 34

End of this supplementary topic

Ene - Like Elimination Reactions

The retro ene reaction fragments a molecule into two pieces, each having a new double bond.
Concerted eliminations of this kind are potentially useful for getting rid of unwanted functions, or
for the introduction of carbon-carbon double bonds. The following diagram shows two such
applications. In the initial display a reference retro ene reaction is written in the shaded box on the
left, and two decarboxylation reactions are shown to the right. The top reaction represents the
decarboxylation of β-ketoacids and malonic acids, that was an important step in syntheses using
acetoacetic ester and malonic ester starting materials. The second reaction demonstrates that this
simple elimination may occur with any β,γ-unsaturated carboxylic acid.

A second set of elimination reactions will be displayed by clicking on the diagram. The first ester
pyrolysis reaction requires strong heating, but the xanthate ester in the second example decomposes
under much milder conditions. The small thiocarbonate fragment undergoes further decomposition
to methane thiol and COS. These eliminations are useful for converting alcohols to alkenes by a syn-
mechanism. Two useful related eliminations, that are not classical retro ene transformations, are the
selenoxide and amine oxide eliminations shown by clicking on the diagram a second time

Dipolar Cycloaddition Reactions

 35

Diazomethane is a useful reagent for preparing methyl

esters from carboxylic acids. However, if a chemist tries
to make methyl acrylate from acrylic acid in this way, he
or she is in for a surprise. An excess of this reagent, as
normally used, not only forms a methyl ester, but also adds to the carbon-carbon double bond. As
shown in the diagram on the right, a substituted pyrazoline is the major product. Here we see a
typical example of a large body of reactions called dipolar cycloadditions. An earlier example
involved the addition of ozone to double bonds, although the initial addition product (a molozonide)
rearranged rapidly to other compounds.

Dipolar cycloaddition reactions take place between unsaturated hetero atom compounds, such as
diazoalkanes, alkyl and aryl azides, nitrile oxides and nitrones, and alkene or alkyne functions.
Although the former reactants are neutral, their Lewis structures have formal charges, and may be
written as 1,3-dipoles. The alkene and alkyne functions to which the dipoles add are called
dipolarophiles. Examples of some common 1,3-dipole reagents are provided at the top of the
following diagram.

The terminology used for these reactions may be confusing unless one pays careful attention to the
electronic structures of the dipolar reactants. Resonance structures for three of these are drawn in
the shaded box. In general, four resonance canonical structures may be written for each compound.
Two have adjacent or 1,2-charge separation, and two have the 1,3-dipolar charge separation noted
above. The 1,2-dipolar structures retain valence shell octets for all heavy atoms, suffer less charge
separation, and have one more covalent bond than do the 1,3-dipolar structures. Therefore, the
most representative Lewis structures for these compounds are 1,2-dipoles, not 1,3-
dipoles.
Another factor in identifying the best structure for a given compound is electronegativity. Negative
charge is best on the most electronegative atom, and positive charge on the least electronegative
atom. In the examples drawn for the nitrile oxides and nitrones, the left hand structure is the best
1,2-dipole that can be written. Similar structures are written following the names in the list at the
top of the diagram. Finally, the general equation written at the bottom demonstrates the danger of
thinking about these reactions as a simple addition of a 1,3-dipole to an unsaturated function.
Movement of electron pairs out of the dipolarophile to one end of the dipole, with a second electron
pair going from the dipole back to the dipolarophile accounts for only four electrons. As shown by
the curved arrows on the right, the cycloaddition actually proceeds by a six pi-electron transition
state, and is suprafacial.
 36

By clicking on the diagram, five examples of dipolar cycloaddition reactions will be displayed.
Examples 1 and 2 show participation of nitrile oxide and diazoalkane reactants. The two phenyl
 37

Reducing Reagents

Reaction
Reagent Preferred Solvents Functions Reduced
Work-up

1) simple
aldehydes to 1º-alcohols
ethanol; aqueous neutraliza
ketones to 2º-alcohols
Sodium Borohydride ethanol tion
1,2-reduction of enones is
NaBH4 15% NaOH; diglyme 2)
favored by CeCl3
avoid strong acids extraction
inert to most other functions
of product

1) careful
aldehydes to 1º-alcohols addition
ether; THF ketones to 2º-alcohols of water
avoid alcohols and carboxylic acids to 1º-alcohols 2)
Lithium Aluminum
amines esters to alcohols dissolve
Hydride (LAH)
avoid halogenated epoxides to alcohols aluminum
LiAlH4
compounds nitriles & amides to amines salts
avoid strong acids halides & tosylates to alkanes 3)
most functions react extraction
of product

1) careful
fast:
addition
acid chlorides to aldehydes
ether; THF of water
(at -78 ºC)
avoid alcohols and 2)
Lithium tri t- 3º-amides to aldehydes (at -78
amines dissolve
Butoxyaluminohydride ºC)
avoid halogenated aluminum
LiAlH(Ot-C4H9)3 nitriles to aldehydes (at -78 ºC)
compounds salts
slower:
avoid strong acids 3)
aldehydes to 1º-alcohols
extraction
ketones to 2º-alcohols
of product

1) careful
fast:
addition
acid chlorides to aldehydes
THF; toluene of water
(at -78 ºC)
avoid alcohols and 2)
Diisobutylaluminum 3º-amides to aldehydes (at -78
amines dissolve
Hydride ºC)
avoid halogenated aluminum
AlH[CH2CH(CH3)2]2 nitriles to aldehydes (at -78 ºC)
compounds salts
slower:
avoid strong acids 3)
aldehydes to 1º-alcohols
extraction
ketones to 2º-alcohols
of product
 38

ether; THF
carboxylic acids to 1º-alcohols 1) dilute
sulfide complex in
aldehydes to 1º-alcohols acid or
CH2Cl2
Diborane ketones to 2º-alcohols H2O2
complexes with
B2H6 = 2 BH3 nitriles to amines 2)
amines
esters & epoxides slowly extraction
avoid alkenes &
reduced of product
alkynes

alkenes & alkynes to alkanes

(fast)
Hydrogen & Catalyst nitro groups to amines (fast)
H2 & Pt, or Pd, or Ru, or imines to amines (fast)
Ni aldehydes & ketones to alcohols
alcohols, ethers, (slow) filter to
hydrocarbons nitriles to amines (slow) remove
or carboxylic acids may remove benzylic groups catalyst
Modified (poisoned)
Catalyst
alkynes to alkenes
acyl chlorides to aldehydes

ketones to 2º-alcohols
liq. ammonia & ether alkynes to alkenes 1) quench
co-solvents conjugated π-systems with
Reactive Metals or alcohols or amines (e.g. aromatic rings, dienes & NH4Cl
Na, or Li, or K enones) 2) extract
cleaves C-X and benzylic groups product

water, alcohols, acetic

Mg or Al or Zn or Fe acid extract
or aqueous mineral cleaves activated substituents product
acid nitro groups to amines from salts
C=O (aldehyde/ketone) to CH2

Many related hydride reagents, having different reductive power and selectivity, incorporate a
variety of organic ligands on the hydride carrier atom. Among these are: lithium triethylborohydride
(super hydride), potassium tri-sec-butylborohydride (K-Selectride), sodium bis(2-
methoxyethoxy)aluminumhydride (Red-Al), sodium cyanoborohydride, sodium
triacetoxyborohydride. various organosilanes and in situ generated aluminum hydride and
dichlorohydride. Organoborane derivatives having modified reactivity relative to borane itself
include: bis(1,2-dimethylpropyl)borane (disiamylborane), 9-borabicyclo[3.3.1]nonane (9-BBN) &
catecholborane (BHcat).
 39

Oxidation Reagents

Reactio
n
Reagent Preferred Solvents Functions Oxidized
Work-
up

1)
destroy
aqueous sulfuric acid & 1º-alcohols to carboxylic acids
excess
Jones Reagent acetone aldehydes to carboxylic acids
reagent
H2CrO4 (avoid acid sensitive 2º-alcohols to ketones
2)
systems) avoid amines and sufides
extract
product

1) filter
inorgani
c salts
2) wash
with
Collins Reagent methylene chloride 1º-alcohols to aldehydes
aqueous
CrO3 • 2 C5H5N (CH2Cl2) 2º-alcohols to ketones
acid
3)
remove
CH2Cl2
solvent

1) filter
inorgani
c salts
2) wash
Pyridinium with
methylene chloride 1º-alcohols to aldehydes
Chlorochromate aqueous
(CH2Cl2) 2º-alcohols to ketones
ClCrO3 • C5H5NH acid
3)
remove
CH2Cl2
solvent

Dimethyl Sulfoxide 1)
(CH3)2S=O & A Mild Procedure neutraliz
DCC or Ac2O or CH2Cl2 or ethers or DMSO 1º-alcohols to aldehydes e
(CF3CO)2O 2º-alcohols to ketones reactant
or SO3 or (COCl)2 s
2)
 40

remove
solvents

aldehydes to carboxylic acids

Potassium 2º-alcohols to ketones
water and alkenes to vicinal-diols (vic.- 1)
Permanganate
aqueous solvent mixtures glycols) destroy
KMnO4
alkynes to carboxylic acids excess
avoid amines and sufides reagent
2)
pyridine extract
Osmium Tetroxide
often used catalytically product
OsO4 alkenes to vicinal-diols (vic.-
glycols)

Periodic Acid 1)
vic.-glycols to carbonyl
HIO4 destroy
water or aqueous mixtures compounds
excess
reagent
2)
Lead Tetraacetate benzene or acetic acid vic.-glycols to carbonyl
extract
Pb(OCOCH3)4 compounds
product

1)
destroy
Peracids alkenes to epoxides excess
CH3CO3H CH2Cl2 or ethers ketones to esters reagent
C6H5CO3H, etc. avoid amines and sufides 2)
extract
product

1)
destroy
excess
cleaves alkenes & alkynes reagent
Ozone CH2Cl2 or CHCl3
avoid benzene derivatives &
O3 (sometimes alcohol)
amines and sufides ozonides
2)
extract
product
 41

Alternatives to Enolate Anions

Reactions of Enolate-Like Species

1. Regioselectivity in Enolate Anion Formation and Reaction

The importance of enolate anions as synthetic intermediates is well established. Nevertheless,

problems remain concerning their selective formation and reaction. For example, aldehyde enolate
bases are likely to undergo the aldol reaction during their formation, and ketones like 2-heptanone
have two different alpha-carbons, each capable of enolization. The ambident nature of enolate
anions also enables electrophilic attack at both oxygen and carbon, but in most synthesis
applications bonding to carbon is desired. Finally, enolate anions may often be formed as E/Z
stereoisomers, and it has been shown that reaction stereoselectivity, when new chiral centers are
created, depends on the enolate configuration.
The following diagram illustrates how the conditions under which enolate anion formation is
accomplished can influence the regioselectivity of the reaction. The two ketone substrates, 2-
heptanone and 2-methylcyclohexanone, each have differently substituted alpha-carbons. In each
case, enolate anion mixtures are generated by reaction with a strong 2º-amide base (LDA is the
usual choice). If the ketone is added to a cold THF solution of excess base, enolate anion formation
is fast and irreversible (procedure a). On the other hand, if a slight excess of ketone is allowed to
remain in solution, an equilibrium involving the ketone and the various enolate species is
established (procedure b). At equilibrium the more stable enolate anion will predominate. The
examples given in the diagram also report results from an equilibrating preparation in which the
lithium metal in LDA is replaced by potassium (procedure c).

Regioselective Formation of Enolate Anions

 42

Several important principles are demonstrated here. First, if the enolate species has substantial
double bond character, the more highly-substituted enolate double bond should predominate at
equilibrium, as predicted from the stabilities of substituted alkenes. Since lithium-oxygen bonds are
more covalent (have less ionic character) than potassium-oxygen bonds, the lithium enolate
approximates an alkene more closely than the potassium enolate. Second, the greater ionic character
of the potassium enolate places an increased negative charge on the alpha-carbon, a condition that
is disfavored by alkyl group substitution. Indeed, the stability order of substituted carbanions is
opposite to that of carbocations thanks to the electron donating character of alkyl groups relative to
hydrogen. Finally, the rate of proton removal from an alpha-carbon site is decreased by alkyl
substitution, probably reflecting a combination of steric hindrance (to bulky bases) and decreased
carbanion stability. In both of the examples shown above, the conditions used in procedure (a) are
typical of kinetically favored enolate formation, whereas those used in procedure (b) favor
thermodynamic enolate formation. The comparative acidities provided by pKa values are
derived from measurements made under equilibrating conditions, and therefore reflect
thermodynamic acidity. Determinations of kinetic acidity require competitive isotope exchange
experiments.

These principles influence the course of enolate alkylation reactions, as shown in the following
diagram. In the first case, 2-methylcyclohexanone is converted to a thermodynamic enolate mixture,
which is then reacted with methyl iodide. The major product is the expected 2,2-
dimethylcyclohexanone (from the more stable enolate anion), but this is accompanied by di- and
trimethylated products together with about 20% unreacted starting material. The complexity of the
product mixture is due to acid-base proton transfer between alkylated products and unreacted
enolate anion. In other words, once a small amount (say 5%) of dimethylcyclohexanone is formed, it
finds itself in solution with a relatively high concentration of a strong base (the remaining enolate
anion) that can remove another alpha-proton, giving a new enolate anion that is further methylated.
If the kinetically favored lithium enolate (see the previous diagram) is used instead of the
equilibrium potassium enolates, 2,6-dimethylcyclohexanone is the chief product.
The second reaction is an intramolecular alkylation that can occur in two different ways. If the
kinetically favored enolate (methyl proton removal) is formed at low temperature, it reacts rapidly
on warming to form a seven-membered ring. Alternatively, the weaker base, potassium tert-
butoxide (in the alcohol as solvent), generates an equilibrium mixture of enolates which eventually
react by intramolecular alkylation. The thermodynamically favored α'-enolate predominates, and
the resulting alkylation generates a five-membered ring.

Examples of Selective Enolate Alkylation

 43

Another aspect of enolate anion alkylation, not yet addressed, is the possibility of electrophilic
bonding at oxygen. One example of such behavior will be displayed by clicking the "Toggle
Reactions" button. Because of the substantial negative charge on the oxygen of ambident anions, it
might be expected that O-alkylation would be the rule rather than the exception. This, in fact, is true
when fully or extensively ionized enolate salts are reacted with strong electrophiles. Ionization of
enolates is facilitated by high dielectric solvents, such as DMSO and DMF (dimethylformamide),
especially for potassium and cesium cation salts. As shown in the lower part of the second diagram,
the negatively charged oxygens of DMSO cluster about a cation, providing substantial solvation
stabilization. No such solvation exists for the enolate anion, leaving it open to reaction with an
electrophile. Lithium enolates have significant covalent character in the metal-oxygen bond, and this
retards electrophile attack at oxygen.

Ether solvents such as THF and DME (dimethoxyethane or glyme) are commonly used for
alkylations because they are inert to strong base and dissolve enolate salts more effectively than
hydrocarbons. The difunctional ether DME (dimethoxyethane) is especially effective at solvating
cations; and this fact has led to the preparation of cyclic polyethers, known as crown ethers, which
are extraordinarily powerful solvating agents. Crown ethers may be added to enolate salt solutions
to enhance their ionization. Indeed, the size of the crown ether can be tailored to fit the cation being
used, providing additional control over the course of enolate reactions.
The nomenclature of crown ethers consists of two numbers. The first (larger) number designates the
overall ring size. The second number indicates the number of ether oxygens. A symmetrical
arrangement of the oxygens in the ring is assumed.

2. Preparation and Reactions of Silyl Enol Ethers

One way of producing selective enolate anion intermediates is to first trap and isolate them as silyl
enol ethers. These relatively stable compounds may then be used to generate isomerically pure
enolate anions, or in some cases as enolic nucleophiles in their own right. In the following diagram,
the first reaction illustrates the formation of a mixture of silyl enol ethers under equilibrating
 44

conditions. If a higher proportion of the minor isomer is desired the kinetically favored lithium
enolate can be prepared and quenched with trimethylsilyl chloride. In either case the silyl ether
mixture may be separated by distillation. Once a pure silyl ether isomer is in hand, it may be used to
generate the corresponding lithium enolate in the manner shown. Alkylation reactions of these
enolates then produces pure regioisomeric products.

By clicking the "Toggle Reactions" button under the previous diagram, two examples of the direct
use of silyl enol ethers will be displayed. Since the silyl ethers are not as reactive as enolate anions,
the electrophiles with which they combine must be made more reactive. When carbonyl
electrophiles are used, this can be accomplished by Lewis acid catalysts, as shown.

3. Enamines as Enolate Anion Surrogates

The formation of enamines by reaction of 2º-amines with aldehydes or ketones has been described.
The double bond of the enamine transmits the nucleophilic character of the nitrogen to the alpha-
carbon, in a vinylagous fashion. Because of the resulting ambident nucleophilicity of the enamines,
reactions with electrophiles may take place at either nitrogen or carbon. Enamines derived from
aldehydes are usually alkylated on nitrogen, an undesirable course for most synthetic applications.
Ketones give significant C-alkylation, the thermodynamically favored course, as first demonstrated
by G. Stork (Columbia). The iminium ion created by C-alkylation cannot react further, and is easily
hydrolyzed to the alkylated ketone. This is particularly useful if dialkylation products are to be
avoided. Thus, in the first example, direct methylation of the enolate anion from this ketone gives
significant amounts of the dimethyl product, due to enolate proton exchange. As shown, the
enamine route gives only mono-methylated product.

The second example demonstrates that enamines may be acylated as well as alkylated. In fact, the
reversible nature of acylation removes the problem of competing N-acylation. This case also
illustrates the general tendency to form the least substituted enamine when two different alpha-sites
 45

are present. Conjugation of the non-bonding electron pair on nitrogen with the pi-electrons of the
double bond forces the alkyl substituents on nitrogen to lie in the same plane as the double bond
(see the resonance equation displayed by the "Toggle Mechanism" button). As a result substitution
of the double bond leads to increased steric hindrance with the nitrogen substituents. The five-
membered cyclic 2º-amine pyrrolidine is widely used for enamine reactions, in part because this
steric hindrance is minimized.

Examples of Enamine Reactions

As noted, N-alkylation of enamines is common for aldehydes and some ketones. Michael addition
reactions avoid this problem thanks to their reversibility. The third example shows such a reaction,
and the "Toggle Mechanism" button displays a possible mechanism. The C-alkylation intermediate
is thermodynamically more stable than the N-alkylation species, so it predominates at equilibrium.
Both the charges in this intermediate are stabilized by delocalization, and hydrolysis rapidly
converts it to the aldehyde-ester product. An interesting alternative is ring closure to a neutral enol
ether compound (shown in the blue shaded box) which would also be hydrolyzed to the same
product.

4. Imine and Hydrazone Anions

Still another way of circumventing some of the undesired aspects of enolate anion chemistry is to
replace the oxygen of an aldehyde or ketone substrate with a 1º-amino group, in other words, to
convert the carbonyl function to an imine. Imine derivatives are relatively easy to prepare, starting
with an aldehyde or ketone and a 1º-amine or hydrazine derivative. The resulting C=N function does
not activate alpha-C-H groups as effectively as a carbonyl function, but very strong bases such as
LDA, alkyl lithiums and Grignard reagents will convert imines to their enamide conjugate bases
quantitatively. This general reaction is shown in the green shaded box below.
 46

Three illustrations of the use of enamide bases in synthesis are displayed above. The first two
examples use aldehyde derivatives, and if we were to attempt these reactions with the aldehyde
enolate anion itself, aldol dimerization would result. The C=N function of imines is a poor acceptor
of nucleophiles, so it does not assume such a role in aldol-like reactions. The third reaction is an
aldol condensation in which a ketone serves as the donor. If cuprous salts are introduced before the
unsaturated aldehyde is added to the enamide solution, conjugate addition takes place in preference
to the 1,2-aldol addition.

Structure & Acidity

Molecular Structure and Acidity

1. Equilibrium Acidity

pKa Acidities of Some Common Hydrides

4 5 6 7

CH3-H NH2-H HO-H F-H

ca. 50 34 15.74 3.2

HS-H Cl-H
6.97 (pK1) -3
 47

HSe-H Br-H
3.8 (pK1) -6
The relative acidities of different acids are
commonly measured and cited as pKa values,
relative to a standard solvent base, often water. HTe-H I-H
These numbers reflect the equilibrium acidities of 2.6 (pK1) -7
the acids. An astounding range of acidities is
displayed by even rather simple compounds. The table on the right lists some elemental hydrides
from groups 4 through 7 of the periodic table. The pKa's determined (or in some cases estimated) for
these compounds are shown beneath the formulas. Approximate values for higher members of
group 4 and 5 hydrides (e.g. silane and phosphine) have not been reported. Note that these
logarithmic numbers encompass nearly sixty powers of ten. This is a greater span than that
encompassed by distance measurements starting from the radius of a hydrogen atom and extending
to the diameter of the known universe.

Why do these relatively simple compounds differ in acid strength so markedly? Two factors may be
discerned:
• First, the compounds in the top row clearly show the importance of electronegativity. All the
heavier elements have greater electronegativities than hydrogen, with carbon being the least
different. The ionic character of these covalent bonds is such that hydrogen carries a partial positive
charge, and the heavier atom a corresponding negative charge. The greatest charge separation is in
H-F, where the electronegativity difference is nearly 2. Removal of a proton is facilitated by this
charge separation. The covalent bond energies do not correlate inversely with acid strength, as one
might have expected, since the two strongest acids have the strongest bonds (H-O 111 kcal/mol & H-
F 135 kcal/mol). Finally, the heavy atoms in the top row have similar sizes, the covalent radii being
0.75 ±0.02 Å. The importance of this fact will become apparent in the following discussion.
• Second, the compounds in the columns representing periodic groups 6 and 7 show an increase in
acidity moving from the top to the bottom. This is opposite to the electronegativity change, and is
best attributed to an increase in heavy atom size. When an acid transfers a proton to a base, the
remaining residue (the conjugate base) must carry a negative charge. Ignoring solvent stabilization
(solvation), the stability of ions is a function of charge density. A small ion has a higher charge
density than a larger ion of the same charge, making the smaller ion less stable. From the covalent
radius of oxygen compared with sulfur, and fluorine compared with chlorine, it can be estimated
that the charge density on the larger atom is half that of the smaller. The resulting stabilization of
the conjugate base more than compensates for the decrease in electronegativity in moving down the
column; so H2S is a stronger acid than H2O, and HCl a stronger acid than HF. Since sulfur and
chlorine are nearly the same size (covalent radii being 1.02 ±0.02 Å), electronegativity explains the
difference in acidity between H2S and HCl.

If the heavy atom of an acid carries a formal

NH4(+) OH3(+) S-H(–) Se-H(–)
charge, its acidity will be changed substantially.
9.24 -1.74 15 (pK2) 11 (pK2)
This is demonstrated by the examples on the
right. Ammonium and hydronium ions carry a
positive charge, and the acidity of the species is increased by over fifteen powers of ten relative to
uncharged ammonia and water. By contrast, hydrogen sulfide and hydrogen selenide are dibasic
acids (they have two acidic protons). Once the first proton has been lost, the acidity of the negatively
charged conjugate base is reduced over a million fold. This is true for most other dibasic acids such
as H2SO4 and H2CO3.
 48

Accurate acidity measurements in the pKa range from 1 to 14 can usually be made in water solution.
However, acids stronger than the hydronium ion (H3O(+)) and bases stronger than hydroxide ion
(OH(–)) react immediately with this solvent, and the resulting "leveling effect" prevents direct
measurement of their pKa's. One way of circumventing this difficulty is to examine the acidity of very
strong ( pKa < 0) and very weak ( pKa > 15) acids in different (non-aqueous) solvents, and to
extrapolate these measurements to water. For example, solvents such as acetic acid, acetonitrile and
nitromethane are often used for studying very strong acids. Very weakly acidic solvents such as
DMSO, acetonitrile, toluene, amines and ammonia are used to study the acidities of very weak acids.
The errors introduced in extreme cases, such as methane, are often large; but the overall range of
acid strengths observed in this manner cannot be questioned.
It must be recognized that pKa values for the same compound measured in different solvents will
generally be different. The two most common solvents in which such measurements have been made
are water and DMSO. The following table presents data for a few representative compounds, with
the pKa difference noted in the right hand column. Since anion solvation by water is superior to that
provided by DMSO, the pKa values from the latter solvent tend to be higher. However, a decrease in
charge density, as with sulfur, or internal delocalization of negative charge, as in the last four
compounds, lessens this difference.

Compound H2O pKa DMSO pKa ∆ pKa

H2O 15.7 31.2 15.5

H2S 7.0 14.7 7.7

C6H5OH 10.0 18.0 8.0

O2NCH3 10.2 17.2 7.0

C6H5COCH3 18 24.7 6.7

(CH3CO)2CH2 8.9 13.3 4.5

2. Hybridization

Hybridization has a strong influence on acidity, as shown by the three carbon acids on the upper left
below. The greater the s-character of the orbital holding the electron pair of the conjugate base, the
greater will be the stability of the base. This corresponds to the lower energy of an s-orbital
compared with p-orbitals in the same valence shell. It also corresponds to the increased
electronegativity or inductive electron withdrawal that is found for different hybridization states of a
given atom, as depicted in the graph on the right. The difference in acidity of 2-butynoic acid and
butanoic acid, shown in the shaded box at lower left, provides a further illustration of this inductive
effect.
Carbocation stability is also influenced by hybridization, but in the opposite direction (sp3 > sp2 >
sp).
 49

Carbon Acids

Hybridizat
sp sp2 sp3
ion
25 44-48 50-55
pKa (H2O)

Inductive Effect

3. Stereoelectronic Control of Enolization

Many carbon acids have enhanced acidity because of a neighboring functional group. The acidity of
alpha hydrogens in aldehydes, ketones and esters is well documented, and is the source of many
important synthetic procedures. The following equation illustrates the general enolate anion
transformation, with the acidic alpha-hydrogen colored red. The resulting ambident anion is
stabilized by charge delocalization, and may react with electrophiles at both carbon and oxygen.
Stereoelectronic factors govern the enolization reaction, as illustrated by clicking on the diagram
below. The bond from the alpha carbon to the acidic alpha-hydrogen must be oriented 90º to the
plane of the carbonyl group, or parallel to the pi-electron system (colored magenta here). The ideal
overlap occurs with a 0º dihedral angle between this bond and the pi-orbital, as shown.

By clicking on the diagram a second time, the importance of this stereoelectronic requirement will
be demonstrated. An increase in the acidity of carbon acids activated by two carbonyl groups is well
known, and is illustrated by the two beta-dicarbonyl compounds on the left side of the diagram. In
such cases the acidic C-H unit may be oriented perpendicular to both carbonyl groups, and the
resulting planar anion is stabilized by additional charge delocalization (over both oxygens and the
 50

central carbon). In the case of the bicyclic diketone on the right, the C-H bond nearly eclipses the
two carbonyl C-O bonds, resulting in a dihedral angle with the pi-electron systems of roughly 90º.
Consequently, the acidity of this hydrogen is similar to that of the hydrogens of an alkane or
cycloalkane. It should also be apparent that if an enolate anion were to be formed to the bridgehead
carbon, the double bond would be prohibited by Bredt's rule.

4. Kinetic Acidity

The most common acid-base terminology, pKa , reflects an equilibrium acidity, extrapolated or
normalized to water. In the following equation a base, B:(–) M(+), abstracts a proton from an acid, H-
A, to form a conjugate acid - base pair (A:(–) M(+) & B-H). The rate of the forward proton abstraction
is k f , and the reverse rate of proton transfer is k r. This kind of equilibrium is usually characterized
by an equilibrium constant, Keq, which is the ratio of the rate constants (k f / k r). If H-A is a weaker
acid than H-B the equilibrium will lie to the left, and Keq will be smaller than 1.

H-A + B:(–) M(+) A:(–) M(+) + B-H

(acid1) (base1) (base2) (acid2)

In cases where H-A is very much weaker than H-B, Keq may be too small to measure, but it may be
possible to determine the rate of the forward proton abstraction under certain circumstances. If an
isotopically labeled conjugate acid of the base is used as a solvent for the reaction (B-D in the
following equations), then any proton abstraction that occurs will be marked by conversion of H-A
to D-A. The green shaded top equation shows the initial loss of the proton, and the second equation
describes the rapid deuteration of the intermediate conjugate base, A:(–). As these reactions proceed,
the H-A reactant will be increasingly labeled as D-A, and the rate of isotope exchange will indicate
the kinetic acidity of H-A. It is assumed that kinetic acidity is roughly proportional to equilibrium
(thermodynamic) acidity, but this is not always true.

solvent = B-D

H-A + B:(–) M(+) A:(–) M(+) + B-H

D-A + B:(–) M(+) A:(–) M(+) + B-D

The following diagram provides an instructive example of these principles. The first equation, in the
yellow shaded box, provides important information about heavy water (deuterium oxide), which will
be used as a solvent for our experiment. Heavy water is similar to water in many respects, but is 10%
more dense and a ten-fold weaker acid. A 1 molar concentration of sodium deuteroxide will serve as
the base, and an equimolar quantity of 3,3-dimethyl-1-butyne will serve as the weak acid. The most
 51

acidic hydrogen in this hydrocarbon (colored red) is at C-1. In practice, we would need to use a co-
solvent to completely dissolve the hydrocarbon in the heavy water, but this has been omitted in
order to simplify the discussion.
The second equation describes the essential changes expected on combining these reactants in the
heavy water solvent. Since the terminal alkyne is a much weaker acid than heavy water, acid-base
equilibria do not favor its conjugate base. Nevertheless, if the acetylide anion is formed, even in low
concentration, it should react quickly by abstracting a deuterium from a neighboring deuterium
oxide molecule. The result would be an observable exchange of deuterium for hydrogen, testifying
that an acid-base reaction has occurred.

The green shaded box contains equations that help us to interpret the experimental results. In order
to evaluate the equilibrium acidity of the substrate, we would need to measure the equilibrium
constant Keq for the initial acid-base equilibrium, shown at the top of the shaded box. Since we know
the Ka 's of 3,3-dimethyl-1-butyne and heavy water, we can estimate Keq by dividing the former (10 -
25) by the latter (10 -17). This calculation reveals a K
eq that would be difficult to measure directly
because of its small magnitude (10 ). Indeed, the equilibrium concentration of acetylide anion is
-8

estimated to be only 2*!0 -10 M.

If we examine this experiment from the viewpoint of kinetics, easily observable evidence of terminal
alkyne acidity is obtained. The last three rows of equations in the green shaded box make this clear.
Since Keq is the ratio of forward and reverse rate constants, it is possible to draw conclusions about
the rate of terminal proton abstraction from the alkyne. This leads to the conclusion that reasonably
rapid hydrogen-deuterium exchange will occur, even though the acetylide anion is never present in
concentrations exceeding 10 -9 M.
 52

This example also demonstrates the limits of the isotope exchange approach. The 3,3-dimethyl-1-
butyne substrate also has nine other hydrogen atoms (colored orange) that do not exchange with
deuterium under these conditions. We know that these hydrogens are much less acidic (Ka ca. 10 -48),
and it is interesting to consider their potential participation in acid-base reactions by the previous
analysis. The estimated Keq for such carbanion formation is ca.10 -30, taking into account the nine-
fold increase in concentration. This implies a concentration of one carbanion in every 109 liters of
solution. The kinetic analysis is equally discouraging. The forward rate constant is estimated to be
10 -20M s-1. The time required to exchange half these hydrogens for deuterium would therefore be
about 1010 centuries!

In order to study the kinetic acidity of extremely weak acids (pKa's = 30 to 50) it is necessary to use
much stronger bases, which of course have much weaker conjugate acids. Amide anions (pKa's = 26
to 36) have been used for this purpose.

By comparing the rates of hydrogen exchange for different compounds under identical conditions,
tables of relative kinetic acidities may be assembled. An interesting example of such a study has
been reported for a group of nitroalkanes having acidic α-hydrogens. Compared with the terminal
alkyne discussed above, such nitroalkanes are relatively strong C-H acids. Removal of an α-
hydrogen by a base generates a conjugate base called an aci-anion, as shown here.

R2CH-NO2 + B:(–) M(+) R2C=NO2(–) M(+) + B-H

nitro compound aci-conjugate base

Since the nitroalkanes used in this study are stronger acids Compound pKa Relative Rate
than water, the kinetic exchange experiments must be of Exchange
conducted under milder conditions than those used for the
terminal alkyne. This is achieved by using smaller base
CH3NO2 10.2 120
concentrations and lowering the temperature of the exchange
reaction. Accurate pKa's of 2-nitropropane, nitroethane and
nitromethane may be measured directly in aqueous solution. CH3CH2NO2 8.5 20
These kinetic and equilibrium acidities are listed in the table
on the right. Note that for these three compounds, kinetic (CH3)2CHNO2 7.7 1.0
acidity changes in an opposite fashion to equilibrium acidity.
The kinetic order seems to reflect steric hindrance and
carbanion stability; whereas, the equilibria favor increased substitution of the aci-anion double
bond.

Base-catalyzed isotope exchange studies of compounds incorporating more than one set of acidic
hydrogens provides additional insight concerning the creation and use of nucleophilic conjugate
bases. Ketones provide many examples of regioisomeric enolate base formation, and the following
diagram shows two such cases. As noted in the nitroalkane study, hydrogens on an α-methyl group
are exchanged more rapidly than those on more substituted α-carbon atoms. The equations in the
 53

diagram show only the initial product from a single exchange. These products have additional α-
hydrogens which are also exchanged by subsequent reactions of this kind, so that complete
replacement of all α-hydrogens by deuterium takes place in a short time.
The relative stability of the resulting enolates increases with substitution of the enolate double bond.
Equations showing the equilibrium concentrations of these isomeric enolates will be displayed by
clicking the Toggle Equations button. In order to determine enolate anion equilibria for these
ketones, the bulky strong base sodium hexamethyldisilazide (pKa = 26) was used.

By clicking the Toggle Equations button a second time, the relative rates of α-hydrogen exchange for
some substituted cyclohexanones will be displayed above. Once again, less substituted α-carbons
exchange more rapidly, but more highly substituted enolates are found to predominate under
equilibrium conditions. A third click of the Toggle Equations button will display an energy profile
for the 2-methylcyclohexanone case, which should clarify the distinction between kinetic and
equilibrium acidity. Two other examples are also shown. These displays may be cycled repeatedly.

Most carbon acids yield conjugate bases that are stabilized by charge delocalization onto
neighboring heteroatoms. This resonance stabilization requires significant structural reorganization
of the initial compound, which in turn imposes an energy barrier that retards the rate of proton
abstraction. For example, the alpha-carbon of a ketone or ester must undergo rehybridization as the
enolate anion is formed. The stereoelectronic demands of this change have been described , and it is
not surprising that enolate anion formation is much slower than equivalent proton transfers
between alcohols and other hydroxylic compounds. Deprotonation rates of phenol and
nitromethane, compounds with nearly identical pKa's (10.0), provide an instructive example of this
structural reorganization factor. The acidic proton in phenol is bound to oxygen, so deprotonation
requires little structure change and is very fast. Nitromethane is a carbon acid. Deprotonation to an
aci-anion involves considerable structural change, and is a million times slower than phenolate
formation. These structural changes are illustrated in the following diagram.
 54

Note that the O-H electron pair in phenol remains largely on oxygen in the corresponding conjugate
base, whereas the C-H electron pair in nitromethane is predominantly shifted to oxygen in its
conjugate base (colored blue).

The trends outlined here are a bit oversimplified, since solvent and cation influences have been
ignored. For a discussion of these factors, and practical applications of enolate anion intermediates
in synthesis Click Here.

Carbon Oxidation States

Assigning Oxidation State Numbers to Carbon

The qualitative rules repeated below may be used to create a carbon atom redox number that reflects
its oxidation state.

1. If the number of hydrogen atoms bonded to a carbon increases, and/or if the number of
bonds to more electronegative atoms decreases, the carbon in question has been
reduced (i.e. it is in a lower oxidation state).
2.
2. If the number of hydrogen atoms bonded to a carbon decreases, and/or if the number
of bonds to more electronegative atoms increases, the carbon in question has been
oxidized (i.e. it is in a higher oxidation state).
3.
3. If there has been no change in the number of such bonds, then the carbon in question
has not changed its oxidation state. In the hydrolysis reaction of a nitrile shown above,
the blue colored carbon has not changed its oxidation state.

We begin by noting that elemental carbon has a zero oxidation state by definition. A carbon atom
bonded only to other carbon atoms, as in the structures on the right below, is therefore assigned an
oxidation number of zero. If one of the carbon substituents is replaced by a hydrogen atom this
oxidation number changes by -1; whereas, if the carbon substituent is replaced by a more
electronegative substituent (O, N, F, Cl, Br etc.) the oxidation number changes by +1. Further
examples of this simple system are shown in the diagram.
 55

Stereoelectronic Effects

Stereoelectronic Effects

Factors that influence the properties or reactivity of molecular species as a consequence of the
spatial orientation of filled or unfilled orbitals are termed stereoelectronic. In many cases,
electron pairs in atomic or molecular orbitals that are involved in the making or breaking of bonds
have an optimal geometrical alignment that is critical for a reaction to occur. This alignment
provides the best overall bonding of participating species during the course of a reaction, and
reflects the fact that transition states having the greatest bonding energy have lower potential
energies than transition states with less bonding.
Two relatively simple examples of stereoelectronic effects are found in SN2 and E2 reactions. The
mechanisms of these reactions were described earlier in our discussion of alkyl halide chemistry, but
a more extensive examination of these common transformations will provide a helpful introduction
to this subject.

1. SN2 Reactions

Nucleophilic substitution reactions of alkyl halides take place by a continuum of mechanisms,

defined by SN2 behavior at one extreme and SN1 behavior at the other. The essential characteristics
of the SN2 process include inversion of configuration at the reaction site, sensitivity to steric
hindrance in the alkyl group, and second order kinetic behavior. The orbital interactions that take
place in a successful SN2 reaction are shown in the following diagram. The bonding and antibonding
sigma molecular orbitals composing the C-X bond are drawn in the yellow box at the top of the
diagram. As a nucleophile approaches the rear side of the carbon, the orbital containing the non-
bonded electron pair (light blue) begins to overlap with the empty antibonding C-X sigma orbital
(pink colored), shown on the left of the bottom line. As electrons occupy this antibonding orbital, the
C-X bond is weakened. In the transition state partial bonds exists between the carbon and both the
nucleophile and the halogen (the carbon orbital is essentially sp2 and is colored orange here).
Finally, a full C-Nu sigma bond develops and the halogen leaves as an anion.
 56

Other substitution reactions also proceed by the SN2 pathway, as illustrated by the stereoisomeric
cyclohexyl tosylates in the following diagram. The bulky tert-butyl group on C-4 serves to lock the
chair conformation in the configuration shown, so one isomer has an equatorial tosylate function,
and the other an axial tosylate. On reaction with sodium thiophenolate, both isomers undergo
bimolecular substitution with inversion, the axial isomer reacting about thirty times faster than its
equatorial epimer. Steric hindrance to rear side nucleophile approach by the red colored hydrogen
atoms is present for each isomer, but the relief of steric crowding of the axial tosylate leaving group
helps to facilitate substitution of the that isomer.

SN2 reactions may be intermolecular, as in these examples, or intramolecular. By clicking on the

above equations, an example of two sequential substitutions, the first intermolecular and the second
intramolecular, will be displayed. Note that the intramolecular substitution shown here proceeds via
the same orbital alignment described above. The reacting moieties in intramolecular reactions are
incorporated in the same molecule; consequently, such reactions exhibit first order kinetic behavior
instead of the usual second order kinetics. Because enolate alkylation reactions are irreversible, the
strained four-membered ring product is stable under the reaction conditions.
In general, intramolecular forms of bimolecular reactions are faster than their
intermolecular counterparts, since the reactive sites are held close together (their relative
concentrations are as high as possible). The rapid lactonization of gamma and delta-hydroxy acids
compared with corresponding intermolecular esterifications is another example of this principle,
 57

which is associated with a favorable entropy change. Note, however, that ring size has a profound
influence on the intra- vs. intermolecular dichotomy.

Maximum overlap of the electron orbital of the nucleophile with the antibonding sigma orbital of the
carbon substituent requires an approach from the rear side of the carbon, ideally 180º from the
leaving group. The importance of this orientation, which is shown in previous diagrams, was made
clear by an experiment conducted by A. Eschenmoser over 25 years ago. The results of
Eschenmoser's experiment are presented in the following illustration. Initially, two equations are
written. The first describes the intermolecular methylation of a sulfone anion by methyl tosylate, a
typical SN2 reaction. The second is a very similar reaction which many would consider to be
intramolecular, since a methyl sulfonate moiety is positioned ortho to the sulfone function.
By clicking on these equations, evidence against the intramolecular mechanism will be displayed.
Although intramolecular reactions are often favored, this case requires a significant departure from
the 180º orbital alignment required by an authentic SN2 reaction. Since this reaction was found to be
second order and is not faster than the simple intermolecular analog (reaction 1 on the preceding
slide), it cannot be intramolecular.

2. E2 Reactions

Elimination of vicinal groups, usually called 1,2- or beta-elimination, is the most common type of
elimination reaction. Examples of some typical cyclohexyl halide eliminations are given in the
following illustrations. From the location of the double bond in the elimination products, and the
relative rates of elimination, it is clear that a diaxial orientation of the eliminating atoms or groups
(colored red) is necessary for optimum reaction.
 58

Two views of the characteristic orbital orientations

of this anti-elimination are drawn on the right.
Two planes are defined in the upper drawing. The
light green plane defines the coplanar nature of the
leaving groups (X & Y) and the carbons to which
they are bonded. The light orange plane identifies
the plane of the final double bond. Together with the
lower drawing, the initial display shows the overlap
of participating bonding orbitals. The corresponding
antibonding orbitals of the C-X and C-Y bonds will
appear by clicking on the upper display. This orbital
alignment defines the stereoelectronic character of
these elimination reactions. Note that the "anti"
descriptor for this configuration refers to the
antarafacial relationship of X and Y with respect to
the light orange plane. Also, the E2 designation
refers to the second order kinetics observed for these
reactions.
Although anti-eliminations are favored when
possible, syn-elimination is observed in some cases.
By clicking on the lower display, it will be replaced
by a similar orbital drawing for syn elimination. In
 59

both syn and anti-transition states the X-C-C-Y bonds are coplanar, an alignment that allows facile
conversion of two sigma bonds (colored red) to a pi-bond. Because of the eclipsed configuration of
the syn-transition state, it is less stable than a corresponding anti-transition state. Syn-elimination
is sometimes observed when Y is an ionic species, such as (CH3)3N(+); but it usually occurs when an
anti configuration is unstable or not possible, as in the following example. Isotopic substitution
confirms that this base-catalyzed beta-elimination takes place by a syn mechanism.

The anti-configurational relationship of the leaving groups in E2 reactions is relatively easy to see in
the cyclohexyl compounds shown above, thanks to the chair conformations of these substrates. If
this stereoelectronic feature is general for all E2 reactions, it should also hold for eliminations of
acyclic compounds. The following examples illustrate this behavior. Conformational mobility about
the central C-C bond allows each stereoisomer to adopt an anti alignment of leaving groups (colored
green), and this is reflected in the products.

3. Trans-Addition to Alkenes

Addition reactions to carbon-carbon double bonds show a parallel stereoselectivity to the

elimination reactions. Both syn and anti additions are observed, as noted in an earlier chapter.
Indeed, the trans-addition of halogen reagents provides good examples of the importance of
stereoelectronic control, even in the presence of opposing steric factors. The addition of bromine to
4-tert-butylcyclohexene, shown here, is a simple case. Assuming trans-addition, two stereoisomeric
products are possible. Remarkably, the product having two axial bromines is favored over its
diequatorial isomer. In order to maintain maximum bonding throughout the addition, carbon-
bromine bonds must be aligned perpendicular to the plane of the double bond. This diaxial
 60

orientation mirrors the stereoelectronic demands of the E2 eliminations discussed above, and may
be realized in two ways.

By clicking on the equation, the first and most favored addition will appear above. A half-chair
conformation for the substituted cyclohexene is drawn on the left. The large t-butyl substituent
occupies an equatorial orientation and serves to hold the conformer as shown. Trans-addition in the
manner depicted leads directly to the diaxial product. Clicking on the drawing a second time
displays the alternate trans addition. In order to maintain good orbital alignment throughout this
reaction, the cyclohexane ring must adopt a higher energy twist-boat conformation. This on relaxing
to a chair gives the diequatorial product. As a result, the first addition has a lower activation energy
than the second.
The attentive reader will recall that trans-addition of bromine and other halogen reagents was
attributed to nucleophilic ring opening of a cyclic halonium ion intermediate. It is instructive to
consider this aspect of the stereoelectronic factor using a somewhat more rigid alkene substrate.
This is shown in the following illustration. The trans-fused six-membered rings hold the central
cyclohexene ring in a tight configurational grip. Chair-chair interconversions are not possible, and
even twist-boat conformers are very strained. The initial electrophilic attack of bromine takes place
from the underside of the molecule, due to the steric hindrance of the axial methyl group. The
resulting bromonium ion is written in brackets, and it is apparent that nucleophilic attack from the
top would be less hindered at C-7 than at C-6 (the methyl group again). By clicking on the equation,
a conformational drawing of this reaction will be displayed. The two possible sites of attack are
designated by green (C-6) and red (C-7) arrows. Although bromide ion attack at C-6 is more
hindered, it is favored by the diaxial stereoelectronic factor, and this is the initially observed
product. Subsequent rearrangement of this diaxial dibromide to its diequatorial isomer takes place
slowly.

Stereoelectronic control of epoxide ring opening follows the same principles.

 61

4. Addition of Nucleophiles to Carbonyl Groups

Stereoelectronic factors have been shown to influence the addition of nucleophilic reagents to
carbonyl groups, particularly for aldehydes and ketones. An outline of this stereoelectronic effect is
provided in the following diagram. The essential molecular orbitals are drawn to the left of the
diagram, and the initial bonding with a nucleophile is believed to take place with the empty
antibonding pi-orbital. This would explain the favored bonding alignment, known as the Bürgi-
Dunitz trajectory.

Many carbonyl addition reactions have been analyzed by a combination of steric and
stereoelectronic factors. In the following illustration, two hydride reductions of methyl ketones are
shown. Since each ketone has an existing stereogenic site, and since the reduction creates a new
chiral center, diastereomeric products are possible. These may be designated in several ways, but
the syn-anti notation is generally preferred. When the existing stereogenic center is located next to
the carbonyl group, as in the upper equation, it may influence the proportion of product
diastereomers. Diastereoselectivity of this kind is sometimes called asymmetric induction. This
influence is, of course, the same for both an enantiomerically pure or a racemic reactant. If,
however, the stereogenic center is far away from the carbonyl group, it has a negligible influence on
the reduction, and a 50:50 mixture of diastereomers is produced (lower example).
 62

A number of models have been proposed to explain the diastereoselectivity of the first reduction.
Many conformations about the alpha-C-CO bond may be written, and the challenge is to pick one
that accounts for the observed selectivity. By clicking on the drawing, three of these will be
displayed. For general use, the substituents on the chiral center adjacent to the carbonyl group are
labeled L (large), M (medium) and S (small) to reflect their size. In each model the sterically
preferred Bürgi-Dunitz approach is shown by a pink arrow, and each predicts the correct
configuration of the favored diastereomer. The earliest rationalization was offered by D. Cram and is
shown by the model on the left. A more favored conformation was chosen by G. Karabatsos, as
shown by the center model. The most recent model (on the right) is that proposed by H. Felkin.
These models all require classification of S, M & L substituents, occasionally a tricky process, and
assume a reactant-like transition state for the reduction. Even so, some bonding of hydride to the
carbonyl carbon must take place in the transition state, accompanied by corresponding small
structural changes. Plausible structures for these transition states are given in the orange box. An
important point needs to be made here.
The ratio of products obtained from a a group of equilibrating conformers is
determined by transition state energies, not conformer concentrations.
This generally useful rule is called The Curtin Hammett Principle.

A brief analysis of these models is instructive. The Cram model makes use of an unfavorable
conformer (R & L are eclipsed). Although this strain is slightly relieved in the transition state, the
oxygen and associated metals is moving toward the M group, resulting in increased crowding. The
Karabatsos model starts with a favorable conformer, but the nucleophile trajectory nearly eclipses
the C-S bond (~20º dihedral angle). The oxygen shift in the transition state relieves eclipsing strain
with M, benefiting the transition state energy. Finally, the Felkin-Ahn model seems to offer the best
rationalization. The nucleophile trajectory is roughly 40º away from eclipsing the C-S bond, and
both the oxygen and the R group undergo favorable shifts in the transition state.

Cyclic ketones have fewer low energy conformations than do acyclic ketones, and diastereoselectivity
in nucleophilic addition reactions is often observed. An analysis similar to that used above for the
acyclic compounds has proven useful in explaining and predicting the outcome of such reactions. By
clicking on the drawing a second time, the hydride reduction of 2-methylcyclopentanone will be
displayed. The trans isomer is favored by a 3:1 ratio. Again, steric hindrance to hydride approach on
the Bürgi-Dunitz trajectory rationalizes this finding.
 63

5. Stereoelectronic Modulation of Cyclization

The formation of rings from suitably substituted molecular chains is a common requirement in
synthesis. In general terms this transformation takes place by the bonding together of two reactive
functional groups located at the ends of a chain. In the following diagram these are represented by
an electrophilic group (E), and a nucleophilic group (Nu). Two possible modes of reaction are
outlined here. In order to form a ring, an intramolecular reaction must take place. However, any
significant quantity of reactant contains approximately 1020 molecules, and these may react with
each other in an intermolecular manner to give dimeric and larger products. Controlling the
course of such a reacting system is not a trivial matter, and many factors influence the outcome.
Among these, the thermodynamic functions enthalpy and entropy are especially important.

The enthalpy factor is associated with ring strain, which includes angle and eclipsing strain. Small
three and four-membered rings are destabilized thermodynamically by such strain, and as a rule
cannot be prepared by reversible bond formation. Five and six-membered rings are less strained,
and are often created by reversible bond formation, as in the cases of lactonization of hydroxy acids
and Dieckmann condensations. Medium sized rings (8 to 11 atoms in size) are generally destabilized
by transannular crowding (steric hindrance by groups on opposite sides of the ring).
The entropy factor is related to the concentration of chain conformations in which the ends to be
joined are close together. For a three carbon chain this concentration is nearly 100%, but it drops off
rapidly as the length of the chain increases. The number of different conformers a chain may assume
increases with the length of the chain, and the proportion of conformers having proximate ends
decreases. These thermodynamic factors interact in opposition to each other. Entropy favors small
ring formation, even though this is energetically (enthalpically) unfavorable. Irreversible bond
forming reactions, such as enolate alkylations, are used to achieve this outcome. Five and six-
membered ring formation is favored by both factors, and may be achieved by both reversible and
irreversible bond formation. The often cited principle that intramolecular reactions are
favored over intermolecular reactions has its origin here. Medium and large sized rings, on
the other hand, are difficult to make due to the low probability of suitable conformers in the reaction
mixture. Intermolecular dimerization and polymerization are usually observed unless the reactions
are conducted at high dilution. Remember, the rate of a bimolecular reaction, such as dimerization
is proportional to the square of reactant concentration (2nd order); whereas, the unimolecular
cyclization reaction has a rate proportional to the first power of reactant concentration (1st order).
Thus, at very low reactant concentration, cyclization occurs faster than dimerization.

Because of the structural constraints in a cyclization transition state, stereoelectronic influences may
be anticipated. One example is shown by the following two equations. Conjugate addition of amines
 64

to unsaturated carbonyl reactants is usually rapid and reversible, as demonstrated by the first
equation. At first glance, the reactant in the second equation might be expected to undergo an
intramolecular reaction of the same kind, yielding a five-membered heterocyclic ester (drawn in the
red box). In practice, however, the reaction is slower and takes a different course, producing a five-
membered lactam by direct acylation of the amine by the ester.

To explain this unexpected change in behavior, we must examine the orbital trajectories permitted
in the two transition states (1,4- versus 1,2-addition). By clicking on the drawing a representation of
these transition states will be displayed. Neither achieves a perfect Bürgi-Dunitz approach of the
nitrogen nucleophile to a double bond, but the 1,2-addition comes much closer. Furthermore, the
best 1,4-addition trajectory is unable to occur in a plane orthogonal to the plane of the double bond;
whereas, the 1,2 addition is again much closer to the ideal orientation. For a display of 1,4-
versus 1,2-addition in this example Click Here.

6. The Baldwin Rules

General stereoelectronic constraints on cyclization reactions were recognized by J. Baldwin, and

summarized in a qualitative model now referred to as the Baldwin Rules. The following diagram
illustrates the five major cyclization modes treated by Baldwin. In each case a nucleophilic moiety
bonds to an electrophilic site (usually a carbon atom), designated by a purple dot. The flow of
electrons during bond formation may be encompassed by the developing ring (an endo cyclization),
or may shift away from the ring (an exo cyclization). Furthermore, the electrophilic site may have
different hybridization states. The terminology used to identify a given ring formation consists of
three parts: the ring size, given by n + 3 in the diagram (where n=0 or an integer), the exo / endo
feature, and the hybridization. Since it is unlikely that endo-tet reactions will be useful for making
rings, such reactions are not included here. However, the possibility of a six-membered cyclic analog
of this kind was discussed earlier.

Using this terminology, the previous cyclization of the amino ester to a lactam is a 5-exo-trig
process (the double bond is the carbonyl group). The alternative ring closure by conjugate addition
 65

is 5-endo-trig, with respect to the carbon-carbon double bond, even though the conjugative
shift of electrons to the ester carbonyl is exocyclic.

The stereoelectronically favored trajectories for nucleophilic bonding to carbon atoms of different
hybridization states are summarized below. The tetrahedral and trigonal cases have already been
described. It is clear that these trajectories represent a "least motion" transition state in which
bonding is kept to a maximum throughout the reaction. By applying these trajectories to the five
cyclization categories noted above, Baldwin was able to discern the effect of ring size on an idealized
transition state. In some cases the constraints of a given ring size perturbed the transition state to
such a degree that reaction seemed improbable. Such cases were called unfavorable.

The following table summarizes Baldwin's conclusions. The 3-endo-trig, 4-endo-trig and 5-endo-trig
combinations, together with the 3-exo-dig and 4-exo-dig possibilities (all colored pink in the table)
were classified as "unfavorable". All the other combinations were classified "favorable", and are
colored light green in the table.
Remember, this evaluation is based primarily on stereoelectronic factors. So called favorable
cyclizations may fail for other reasons, and sometimes an unfavorable cyclization may take place
when alternative reactions are even less favored.
 66

Ring Closure Categories

Tetrahedral Closure 3-exo-tet 4-exo-tet 5-exo-tet 6-exo-tet 7-exo-tet

3-exo-trig 4-exo-trig 5-exo-trig 6-exo-trig 7-exo-trig

Trigonal Closure
3-endo-trig 4-endo-trig 5-endo-trig 6-endo-trig 7-endo-trig

3-exo-dig 4-exo-dig 5-exo-dig 6-exo-dig 7-exo-dig

Digonal Closure
3-endo-dig 4-endo-dig 5-endo-dig 6-endo-dig 7-endo-dig

Unfavorable combinations are colored light red

In the examples on the right

the first equation describes a
5-endo-trig cyclization that
fails to take place. The second
equation shows a successful 5-
endo-dig reaction, similar in
many respects to the first.

When an enolate anion serves

as the nucleophilic agent in a
ring closure, a modification of
the Baldwin rules should be used. These rules will be shown on the right by clicking on the drawing.
An example comparing a 5-(enolexo)-exo-tet closure with an isomeric 5-(enolendo)-exo-tet option
will then replace the modified rules by a second click on the drawing. A third click on the drawing
will display a similar 6-(enolendo)-exo-trig example.

7. Rationalizing Conformational Preferences

The following diagram shows two conformational equilibria in which one of the isomers is favored.
Esters generally prefer to adopt a Z-configuration, as shown in the first example. Lactones
incorporated in seven membered and smaller rings are forced into an E-configuration, and
consequently are more reactive.
In the second example, tri-tert-butyl hexahydro-(1,3,6)-triazine exists predominantly in a
configuration having one axial tert-butyl group. Explaining these structural preferences provides an
instructive review of stereoelectronic factors.
 67

The ester equilibrium is most simply analyzed by considering electron and dipole interactions. The
latter will be displayed by clicking on the diagram. In the E-conformer the carbonyl group dipole is
repelled by the similarly oriented ether oxygen dipole, whereas these dipoles have opposite
directions in the Z-conformer. Also, the non-bonded electron pairs of the two oxygens are closer
together in the E-conformer than in the Z-conformer. A similar analysis of the second example
shows a parallel alignment of all three amine dipoles in the all equatorial conformer, and a less
repulsive arrangement in the axial conformer.

A thorough evaluation of these cases should also examine the interaction of a non-bonding electron
pair with neighboring (vicinal) antibonding orbitals that may function as electron acceptors. This
analysis of the ester equilibrium will be shown by clicking on the diagram a second time. The upper
part of the diagram illustrates the p-pi conjugation of one non-bonding electron pair with the
carbonyl group. This conjugation explains the large energy barrier for interconversion of the E & Z
conformers. The remaining electron pair occupies a sp2 orbital (colored pink), and this is the donor
pair that may have a bonding interaction with an acceptor orbital (an anomeric effect). Only the Z-
conformer provides this stabilizing interaction, which involves the antibonding C-O orbital (light
gray) of the carbonyl sigma bond (colored red). A similar donor-acceptor interaction provides
additional stabilization for the axial-tert-butyl conformer in the second example, as illustrated by
clicking on the diagram a third time.

8. The Anomeric Effect

The anomeric effect was first recognized in carbohydrate chemistry, but applies generally to all
organic compounds.
 68

Carbocation Stability

Factors Influencing Carbocation Stability

Carbocation intermediates, sometimes called carbonium ions, have been proposed or identified as
important species in reactions ranging from electrophilic addition to alkenes, to unimolecular
solvolysis of alkyl halides. The relative stability of these cationic intermediates varies markedly with
the presence of substituents on the trivalent charged carbon atom, in a fashion that has led useful
empirical rules for predicting reaction selectivity (summarized elsewhere). This stability order for
simple alkyl alkenyl and aryl substituted carbocations is repeated below, followed by a table of
supportive data.

Carbocation CH2=CH-
CH3(+) < CH3CH2(+) < (CH3)2CH(+) ≈ < C6H5CH2(+) ≈ (CH3)3C(+)
Stability CH2(+)

Carbocation Stabilities Relative to the Ethyl Cation & Tosylate Solvolysis

Rates

Relative Relative Rate of

Cation Tosylate Derivative
Stability Solvolysis in CF3CO2H

CH3CH2 (+) 0 kcal/mole CH3CH2OTs 1.0

CH3CH2CH2 (+) 6 CH3CH2CH2OTs 5.3

(CH3)2CH (+) 22 (CH3)2CHOTs 2.6 * 104

(CH3)3C (+) 40 (CH3)3COTs 6.3 * 1013

 69

A few carbocations, such as tropylium and trityl

(triphenylcarbenium) shown on the right, are
sufficiently stable to form isolable salts with poorly
nucleophilic anions, such as tetrafluoroborate (BF4(–) ).
However, most carbocations are unstable and very
reactive under normal laboratory conditions, so
conventional studies of all but the most stable of these
species have not been possible. Nevertheless, gas phase
ionization energies of alkyl chlorides, hydride affinity
measurements (gas phase), molecular orbital calculations, and low temperature nmr examination of
ionized alkyl halides in mixed solvents composed of SbF5, SO2, SO2F2 & SO2FCl. (referred to as
"super acids") have confirmed the qualitative relationship shown above. At low temperatures, 1H
and 13C nmr spectra of (CH3)3C(+) and (CH3)2CH(+) were obtained and interpreted. The charged
tricoordinate carbon atom exhibited a 13C signal over 300ppm downfield from TMS.

1. Inductive & Resonance Effects

What are the factors that influence carbocation stability? The most common means of stabilizing an
ion is by charge delocalization, either by inherent structural interactions or by solvation. As noted
elsewhere, such structural interactions may usually be classified as inductive or resonance
effects, and these may complement or oppose each other. Examples of both are given in the
following diagram.

Alkyl groups have somewhat lower electronegativities and are more polarizable than hydrogen. If an
alkyl group is bonded to the carbocation center, the electron pair of the C-C sigma bond will shift
toward the positive charge, transferring a small part of that charge to the alkyl group. In the diagram
on the left above, this inductive electron shift is designated by a light blue arrow head. Additional
alkyl groups provide increased inductive charge dispersion, with each group assuming a share of the
charge. Clearly, this analysis supports the stabilizing influence of alkyl substituents on carbocations.
Resonance stabilization by non-bonding electron pairs on adjacent heteroatoms is particularly
strong, as shown on the right above. Such charge delocalization overcomes the potential inductive
destabilization of these electronegative substituents. Similar stabilization is provided by an adjacent
nucleophilic pi-electron function, such as a double bond. A phenyl substituent affords even greater
charge delocalization than a double bond, as reflected by the position of a benzyl cation in the
stability order. Resonance stabilization is generally stronger than inductive effects, and is the
predominant factor stabilizing the tropylium and trityl cations.
 70

2. Hyperconjugation

Another way in which alkyl substituents stabilize carbocations is illustrated in the following
diagram. This conjugative charge delocalization, called hyperconjugation, involves partial pi-
bond formation to alpha-carbon atoms, provided suitably oriented C-H or C-C bonds are present.
The small increase in stability of the 1-propyl cation compared with an ethyl cation, as noted above,
suggests that C-C hyperconjugation provides slightly greater stabilization than does the C-H
hyperconjugation shown here. Hyperconjugation by alkyl substituents also acts to stabilize
unsaturated functional groups, as noted earlier for carbon-carbon double bonds.

Since hyperconjugation and the inductive effect act in the same manner, their relative importance in
carbocation stabilization is a matter of interest. Some insight to this question is found in a group of
novel compounds, bridgehead substituted bicyclic halides. Two examples of these compounds are
shown below. The nomenclature of bridged bicyclic compounds identifies the length of the chains
that connect the bridgehead atoms (colored pink here). Three connecting chains are present in a
bicyclic compound, and the number of atoms in each chain (excluding hydrogen) is given as a
number in brackets. If the chains are of different lengths the longest is listed first. One of the
bridgehead atoms is numbered one, and the longest chain continues the numbering sequence until
the second bridgehead atom is included. Numbering then continues along the next longest chain.
The base name of the bicyclic compound reflects the total number of carbons, and is therefore the
sum of the bridging chains plus two (the bridgehead atoms).
 71

The bridgehead substituted halides shown above will form 3º-carbocations when ionized. Inductive
stabilization of these cations should be similar to that of the tert-butyl cation, so if this were the
predominant stabilizing factor from alkyl substitution, the reactivity of these halides should be
similar to their tert-butyl counterparts. In practice, however, the bridgehead halides were found to
be much less reactive. Indeed, 1-chlorobicyclo[2.2.1]heptane was recovered unchanged from
prolonged treatment with hot ethanolic silver nitrate. The instability of such bridgehead
carbocations has been attributed to the pyramidal shape forced upon the trigonal carbon (sp2
hybridized). However, covalent bonds are generally able to accommodate modest bending
distortions without significant destabilization, and the inductive shift of electron pairs toward the
positively charged carbon atom is unlikely to be impeded by a pyramidal configuration of the
carbocation.
An alternative explanation is that hyperconjugation with the alpha-methylene groups is prohibited
by the rigid configuration of these bridgehead cations. By clicking on the diagram above, an
illustration of one possible C-H hyperconjugative interaction will be displayed. The carbon-carbon
double bond implicit to this occurrence is badly twisted, and could not exist as such in any stable
alkene. Structural prohibitions of this kind are encompassed in an empirical guideline called Bredt's
rule.
On the other hand, C-C hyperconjugation may act to partially stabilize bridgehead carbocations. By
clicking on the diagram a second time, two examples of such hyperconjugation will appear. While
still relatively inert, the bicyclo[2.2.2]octane compound is roughly a million times more reactive
than its bicyclo[2.2.1]heptane analog, shown above. This may be attributed to improved
hyperconjugation, since the appropriate C-C bonds (colored red) are better aligned with a
developing bridgehead carbocation. Furthermore, confirmation of expected changes in bond lengths
resulting from such hyperconjugation has been obtained by X-ray diffraction analysis of a crystalline
SbF6 salt of the adamantane cation. In this study, the red-colored bonds were lengthened and the
green-colored bonds were shortened.

3. Aldehyde Derivatives

Among aldehydes, formaldehyde, H2C=O, has many unique properties. For

example, with ammonia it reacts in a 3:2 ratio to give a tricyclic product,
shown on the right, and known as hexamethylenetetramine. This interesting
compound may function as an ammonia derivative for the synthesis of 1º-
amines, or as a convenient high-melting source of formaldehyde by way of
acid-catalyzed hydrolysis.

An interesting reagent that distinguishes aldehydes from ketones is the hydrazine derivative, 4-
amino-3-hydrazino-5-mercapto-1,2,4-triazole, best known as Purpald (formula shown below).
Although this reagent reacts with both aldehydes and ketones, only the aldehyde product is further
oxidized to a purple, 10 π-electron aromatic heterocycle on exposure to air. Note that the pair of
electrons on the nitrogen atom common to both rings is part of the π-electron system.
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