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Mechanism
P.282
As a general rule, the formation of a new chirality center by the reaction of a chiral reactant leads to unequal amounts of
diastereomeric products. If the chiral reactant is optically active because only one enantiomer is used rather than a
racemic mixture, then the products are also optically active.
Summary Ch 8
Kap. 9 Alkynes
HydroborationOxidation of Alkynes
Internal alkyne
Terminal alkyne
Skillnad:
keton
Aldehyde
Mek:
The alkylation reaction is limited to the use of primary alkyl bromides and alkyl iodides because acetylide ions are
sufficiently strong bases to cause elimination instead of substitution when they react with secondary and tertiary alkyl
halides.
The Nucleophile
Any species, either neutral or negatively charged, can act as a nucleophile as long as it has an unshared pair of electrons; that
is, as long as it is a Lewis base.
Para-toluenesulfonyl chloride
The Solvent
Protic solvents those that contain an OH or NH group are generally the worst for SN2 reactions, while polar aprotic
solvents, which are polar but dont have an OH or NH group, are the best.
Acetonitrile (CH3CN), dimethylformamide [(CH3)2NCHO, abbreviated DMF], dimethyl sulfoxide [(CH3)2SO, abbreviated
DMSO], and hexamethylphosphoramide {[(CH3)2N]3PO, abbreviated HMPA} are particularly useful.
SN1
The Nucleophile
The nature of the nucleophile plays a major role in the SN2 reaction but does not affect an SN1 reaction. Because the SN1
reaction occurs through a rate-limiting step in which the added nucleophile has no part, the nucleophile cant affect the
reaction rate.
The Solvent
SN1 reactions take place much more rapidly in strongly polar solvents, such as water and methanol, than in less polar
solvents, such as ether and chloroform.
E2
A mines
Carbon yl Co m pounds
Degreeof unsaturation(HDI )=
2 C +2+ NH X
2
Kap 14
14.2 Electrophilic Additions to Conjugated Dienes: Allylic Carbocations
The DielsAlder reaction is that it is stereospecific, meaning that a single product stereoisomer is formed.
Cis-alken cis-produkt
Trans-alken trans-produkt
Kap 15
15.3 Aromaticity and the Huckel 4n+2 Rule
(4n + 2) electrons aro matisk
(4n ) electrons anti- aro matisk
Imidazole, both nitrogens are sp2-hybridized, but one is in a double bond and contributes only one electron to the aromatic
system while the other is not in a double bond and contributes two electrons from its lone pair.
Aromatic Nitration
Jrn, tenn (Sn) eller SnCl2 kan anvndas som reagens fr att reducera nitrobensen till anilin:
Tin(II) chloride (SnCl2) is particularly mild and is often used when other
reducible functional groups are present.
Nucleophilic aromatic substitution occurs only if the aromatic ring has an electron-withdrawing substituent in a position
ortho or para to the leaving group to stabilize the anion intermediate through resonance.
Note the differences between electrophilic and nucleophilic aromatic substitutions. Electrophilic substitutions are favored
by electron-donating substituents, which stabilize a carbocation intermediate, while nucleophilic substitutions are favored
by electron-withdrawing substituents, which stabilize a carbanion intermediate. Thus, the electron-withdrawing groups
that deactivate rings for electrophilic substitution (nitro, carbonyl, cyano, and so forth) activate them for nucleophilic
substitution. Whats more, these groups are meta directors in electrophilic substitution but are orthopara directors in
nucleophilic substitution. And finally, electrophilic substitutions replace hydrogen on the ring, while nucleophilic
substitutions replace a leaving group, usually halide ion.
16.8 Benzyne
Carboxylic acid and ester reductions are usually carried out with the more reactive reducing agent LiAlH4. All carbonyl
groups, including acids, esters, ketones, and aldehydes, are reduced by LiAlH4.
Carboxylic acids dont give addition products with Grignard reagents because the acidic carboxyl hydrogen reacts with the
basic Grignard reagent to yield a hydrocarbon and the magnesium salt of the acid.
The reactions of primary and secondary alcohols with SOCl2 and PBr3 take place by SN2 mechanisms.
One of the most important reasons for using tosylates in S N2 reactions is stereochemical. The SN2 reaction of an alcohol via
an alkyl halide proceeds with two inversions of configurationone to make the halide from the alcohol and one to substitute
the halideand yields a product with the same stereochemistry as the starting alcohol. The S N2 reaction of an alcohol via a
tosylate, however, proceeds with only one inversion and yields a product of opposite stereochemistry to the starting alcohol.
Mekanism:
Alcohol dehydrations carried out with POCl3 in pyridine take place by an E2 mechanism
Mechanism:
Secondary and tertiary alcohols
Oxidation of a primary or secondary alcohol KMnO4, CrO3, and Na2Cr2O7, (1*alcohol Dess-Martin
periodinane)
Chlorotrimethylsilane (Cl-TMS) is often used, and the reaction is carried out in the presence of a base, such as
triethylamine, to help form the alkoxide anion from the alcohol and to remove the HCl by-product from the reaction
Ta bort TMS:
Unfortunately, the method is limited to use with primary alcohols because secondary and tertiary alcohols dehydrate by an
E1 mechanism to yield alkenes.
The Williamson Ether Synthesis
Unsymmetrical ethers should therefore be synthesized by reaction between the more hindered alkoxide partner and less
hindered halide partner rather than vice versa.
Alkoxymercuration of Alkenes
Alken + 1. Hg(OAc)2,H2O 2.NaBH4 alcohol
Alken + 1. (CF3CO2)2Hg, CH3OH 2.NaBH4 Eter
Mekanism:
Ethers with only primary and secondary alkyl groups react by an SN2 mechanism, in which I2 or Br2 attacks the protonated
ether at the less hindered site.
Ethers with a tertiary, benzylic, or allylic group cleave by either an SN1 or E1 mechanism because these substrates can
produce stable intermediate carbocations.
Mechanism:
Dihydropyran
In organic synthesis, the 2-tetrahydropyranyl group is used as a protecting group for alcohols. Reaction of the alcohol with
dihydropyran forms a tetrahydropyranyl ether, protecting the alcohol from a variety of reactions. The alcohol can later be
restored readily by acidic hydrolysis with formation of 5-hydroxypentanal.
OBS!
When both epoxide carbon atoms are either primary or secondary, attack of the
nucleophile occurs primarily at the less highly substituted sitean SN2-like result. When one of the epoxide carbon atoms is
tertiary, however, nucleophilic attack occurs primarily at the more highly substituted site an SN1-like result.
The reaction often works poorly unless an excess of the nucleophile is used because the product thiol can undergo a second
SN2 reaction with alkyl halide to give a sulfide as a by-product. To circumvent this problem, thiourea, (NH 2)2C P S, is often
used as the nucleophile in the preparation of a thiol from an alkyl halide.
Unlike dialkyl ethers, dialkyl sulfides react rapidly with primary alkyl halides by an SN2 mechanism to give sulfonium ions
(R3S+).
Another difference between sulfides and ethers is that sulfides are easily oxidized. Treatment of a sulfide with hydrogen
peroxide, H2O2, at room temperature yields the corresponding sulfoxide (R2SO), and further oxidation of the sulfoxide with
a peroxyacid yields a sulfone (R2SO2).
Mechanism
Mechanism
Certain carboxylic acid derivatives can be partially reduced to yield aldehydes. Diisobutylaluminum hydride (DIBAH, or
DIBAL-H)
Preparing Ketones
Either the DessMartin periodinane or a Cr(VI) regent such as CrO3 is a common choice.
Mekanism; basisk
Mechanism; sur
Mekanism:
19.9 Nucleophilic Addition of Hydrazine: The WolffKishner Reaction: reduction of an aldehyde or ketone
to yield an alkane.
Mechanism Wolff-Kishner
PCl5 will convert carboxylic acids to the corresponding acyl chloride. It also converts alcohols to alkyl chloride. SOCl2 is
more commonly used in the laboratory because the SO2 is more easily separated from the organic products than is POCl 3.
The net effect is addition of the nucleophile to the C=C bond, with the carbonyl group itself unchanged. In fact, of course,
the carbonyl group is crucial to the success of the reaction. The C=C bond would not be activated for addition, and no
reaction would occur, without the carbonyl group.
Reaktionen ovan sker under termodynamisk kontroll och inte kinetisk kontroll. Drfr bildas endast den mest stabila
konjugat additionsprodukt.
Conjugate Addition of Alkyl Groups: Organocopper Reactions
Only ketones, not aldehydes
Mechanism:
Hydrolysis of Nitriles
Note that the product acid has one more carbon than the starting alkyl halide.
Exempel
Preparation of Nitriles
The simplest method of nitrile preparation is the S N2 reaction of CN with a primary or secondary alkyl halide, as discussed
in Section 20.5.
Primary amide, RCONH2 + SOCl2 eller POCl3 nitriles
Mechanism:
Reactions of Nitriles
Step 4 (21.7)
NH2
Mechanism:
Mechanism:
Mechanism:
Amides are difficult to prepare by direct reaction of carboxylic acids with amines because amines are bases that convert
acidic carboxyl groups into their unreactive carboxylate anions. Thus, the OH must be replaced by a better, nonacidic
leaving group. Dicyclohexylcarbodiimide (DCC) is used.
Alternatively, borane in tetrahydrofuran (BH3/THF) is a useful reagent for reducing carboxylic acids to primary alcohols.
Reaction of an acid with BH3/THF occurs rapidly at room temperature, and the procedure is often preferred to reduction with
LiAlH4 because of its relative ease and safety.
Jmf
Because HCl is formed during the hydrolysis, the reaction is often carried out in the presence of a base such as pyridine or
NaOH to remove the HCl and prevent it from causing side reactions.
Conversion of Acid Halides into Anhydrides
Because HCl is formed during the reaction, 2 equivalents of the amine must be used.
Mechanism:
Ex 2
Reactions of Esters
Esters undergo the same kinds of reactions that weve seen for other carboxylic acid derivatives, but they are less reactive
toward nucleophiles than either acid chlorides or anhydrides. All their reactions are applicable to both acyclic and cyclic
esters, called lactones.
Mechanism:
Ester aldehyde
Reactions of Amides
Conversion of Amides into Carboxylic Acids: Hydrolysis
Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine on heating in either aqueous acid or aqueous
base.
Syra-katalys:
Bas-katalys:
Mechanism:
Ex
Uppg 21.21
Solution
Note that only the hydrogens on the -position of carbonyl compounds are acidic. Hydrogens at , , , and so on, arent
acidic and cant be removed by base because the resulting anions cant be resonance- stabilized by the carbonyl group.
22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions
Mekanism:
Uppg 22.5 Show how you might prepare 1-penten-3-one from 3-pentanone.
Mekanism:
Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted
into enolate ions by reaction with LDA.
Haloform Reaction
The product of a malonic ester alkylation has one acidic hydrogen remaining, so the alkylation process can be repeated to
yield a dialkylated malonic ester.
On heating with aqueous hydrochloric acid, the alkylated (or dialkylated) malonic ester undergoes hydrolysis of its two ester
groups followed by decarboxylation (loss of CO2) to yield a substituted monocarboxylic acid.
Only substituted malonic acids and -keto acids undergo loss of CO2 on heating (decarboxylation).
Exempel:
The malonic ester synthesis can also be used to prepare cycloalkanecarboxylic acids.
Ex:
Decarboxylation:
Problem 23.1
Predict the aldol reaction product of the following compounds:
On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base rather than a
full equivalent so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound.
The real value of aldol dehydration is that removal of water from the reaction mixture can be used to drive the aldol
equilibrium toward product.
On the other hand, mixed aldol reactions can lead cleanly to a single product if either of two conditions is met:
If one of the carbonyl partners contains no hydrogens, and thus cant form an enolate ion to become a donor, but does
contain an unhindered carbonyl group and so is a good acceptor of nucleophiles, then a mixed aldol reaction is likely to
be successful.
Example:
If one of the carbonyl partners is much more acidic than the other and so is transformed into its enolate ion in preference
to the other, then a mixed aldol reaction is likely to be successful.
Example:
Solution:
Mekanism:
The only difference between the aldol condensation of an aldehyde or ketone and the Claisen condensation of an ester
involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is
protonated to give an alcohol product exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The
tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution
product exactly the behavior previously seen for esters (Section 21.6).
Problem 23.12
As shown in Figure 23.4, the Claisen reaction is reversible. That is, a -keto ester can be cleaved by base into two fragments.
Using curved arrows to indicate electron flow, show the mechanism by which this cleavage occurs.
Solution:
The cyclic -keto ester produced in a Dieckmann cyclization can be further alkylated and decarboxylated by a series of
reactions analogous to those used in the acetoacetic ester synthesis (Section 22.7).
The overall sequence of (1) Dieckmann cyclization, (2) -keto ester alkylation, and (3) decarboxylation is a powerful method
for preparing 2-substituted cyclopentanones and cyclohexanones.
(2)
(22.7 Alkylation of Enolate Ions
(3)
(1) Enamine formation from a ketone (sid 50 word). (2) The enamine adds to the ,-unsaturated ketone in a Michael
reaction (ovan p denna sida). (3) Enamine hydrolysis back to a ketone (sid 50).
Tin(II) chloride (SnCl2) is particularly mild and is often used when other reducible functional groups are present.
SN2 Reactions of Alkyl Halides
Unfortunately, these reactions dont stop cleanly after a single alkylation has occurred. Because ammonia and primary
amines have similar reactivity, the initially formed monoalkylated substance often undergoes further reaction to yield a
mixture of products.
Ex:
Azide ion ()
A better method for preparing primary amines is to use azide ion, N3-, as the nucleophile rather than ammonia for SN2
reaction with a primary or secondary alkyl halide. The product is an alkyl azide, which is not nucleophilic, so overalkylation
cant occur.
Mechanism:
Ammonia adds to the ketone carbonyl group in a nucleophilic addition reaction to yield an intermediate carbinolamine.
The carbinolamine loses water to give an imine.
product.
NB: Its usually better to choose the combination with the simpler amine component methylamine in this case and to use an
excess of that amine as reactant.
Hofmann and Curtius Rearrangements
Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann
rearrangement and the Curtius rearrangement. Although the Hofmann rearrangement involves a primary amide and the
Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms.
Hofmann Mechanism:
(1) Base abstracts an acidic N-H proton, yielding an amide anion. (2) The anion reacts with bromine in an alpha-substitution
reaction to give an N-bromoamide. (3) Abstraction of the remaining NH proton by base gives a resonance-stabilized
bromoamide anion . . . (4) . . . which rearranges when the R group attached to the carbonyl carbon migrates to nitrogen at the
same time the bromide ion leaves. (5) The isocyanate formed on rearrangement adds water in a nucleophilic addition step to
yield a carbamic acid. (6) The carbamic acid spontaneously loses CO2 to give an amine.
Curtius mechanism
Ex:
Hofmann Elimination
Like alcohols, amines can be converted into alkenes by an elimination reaction. But because an amide ion, NH 2-, is such a
poor leaving group, it must first be converted into a better leaving group.
Silver oxide acts by exchanging iodide ion for hydroxide ion in the quaternary salt, thus providing the base necessary for
elimination. The actual elimination step is an E2 reaction (Section 11.8) in which hydroxide ion removes a proton at the same
time that the positively charged nitrogen atom leaves.
Unlike what happens in other E2 reactions, the major product of the Hofmann elimination is the less highly substituted
alkene rather than the more highly substituted one.
Ex p Hofmann elimination:
1.
2.
Another drawback to the use of amino-substituted benzenes in electrophilic aromatic substitution reactions is that Friedel
Crafts reactions are not successful (Section 16.3). The amino group forms an acidbase complex with the AlCl3 catalyst,
which prevents further reaction from occurring. Both drawbacks can be overcome, however, by carrying out electrophilic
aromatic substitution reactions on the corresponding amide rather than on the free amine.
Ex:
Ex:
Arenediazonium salts are useful because the diazonio group (N2) can be replaced by a nucleophile in a substitution reaction.
Many different nucleophileshalide, hydride, cyanide, and hydroxide among othersreact with arenediazonium salts,
yielding many different kinds of substituted benzenes. The overall sequence of (1) nitration, (2) reduction, (3) diazotization,
and (4) nucleophilic substitution is perhaps the single most versatile method of aromatic substitution.
Sandmeyer reaction
Aryl chlorides and bromides are prepared by reaction of an arenediazonium salt with the corresponding copper(I) halide,
CuX. Aryl iodides can be prepared by direct reaction with NaI without using a copper(I) salt.
Nitriles:
Similar treatment of an arenediazonium salt with CuCN yields the nitrile, ArCN, which can then be further converted into
other functional groups such as carboxyl.
OH
Mechanism:
The compound with its newly generated OH group at C1 cis to the OH at the lowest chirality center in a Fischer
projection is called the anomer; its full name is -D-glucopyranose. The compound with its newly generated OH group
trans to the OH at the lowest chirality center in a Fischer projection is called the anomer; its full name is -Dglucopyranose.
Note that in -D-glucopyranose, all the substituents on the ring are equatorial. Thus, -D-glucopyranose is the least sterically
crowded and most stable of the eight D aldohexoses.
Glycoside Formation
Reduction of Monosaccharides
Oxidation of Monosaccharides
In general, the triene cyclohexadiene equilibrium favors the cyclic product, whereas the diene cyclobutene equilibrium
favors less strained open-chain product.
Amino groups are often protected as their tert-butyloxycarbonyl amide (Boc) or fluorenylmethyloxycarbonyl amide (Fmoc)
derivatives. The Boc protecting group is introduced by reaction of the amino acid with di-tert-butyl dicarbonate in a
nucleophilic acyl substitution reaction and is removed by brief treatment with a strong acid such as trifluoroacetic acid,
CF3CO2H. The Fmoc protecting group is introduced by reaction with an acid chloride and is removed by treatment with
base.
Bases
When determining the basicity of two bases, evaluate the relative stabilities of the bases themselves.
Evaluate which of the two or more bases is better able to donate its lone pair of electrons?
Electronegativity; the more electronegative atom will hold on its electrons more tightly than the atom that is less e-negative.