396 CHAPTER 10 Substitution Reactions of Alkyl Halides
S-ADENOSYLMETHIONINE:
A NATURAL ANTIDEPRESSANT
S-Adenosylmethionine is sold in many health
food and drug stores as a treatment for depression and arthritis.
It is marketed under the name SAMe (pronounced Sammy). Al-
though SAMe has been used clinically in Europe for more than
two decades, it has not been rigorously evaluated in the United
States and is not approved by the FDA. It can be sold, however,because the FDA does not prohibit the sale of most naturally
occurring substances, as long as the marketer does not make
therapeutic claims. SAMe has also been found to be effective in
the treatment of liver diseases—diseases caused by alcohol and
the hepatitis C virus. The attenuation of liver injuries is accom-
panied by increased levels of glutathione in the liver. Glu-
tathione is an important antioxidant (Section 23.8). SAM is
required for the synthesis of cysteine (an amino acid), which, in
turn, is required for the synthesis of glutathione.Summary
Alkyl halides undergo two kinds of nucleophilic substitu-
tion reactions: and In both reactions, a nucle-
ophile substitutes for a halogen, which is called a leaving
group. An reaction is bimolecular—twomolecules are
involved in the rate-limiting step; an reaction is unimol-
ecular—onemolecule is involved in the rate-limiting step.
The rate of an reactiondepends on the concentration
of both the alkyl halide and the nucleophile. An reaction
is a one-step reaction: The nucleophile attacks the back side
of the carbon that is attached to the halogen. The reaction
proceeds in the direction that allows the stronger base to dis-
place the weaker base; it is reversible only if the difference
between the basicities of the nucleophile and the leaving
group is small. The rate of an reaction depends on steric
hindrance: The bulkier the groups at the back side of the car-
bon undergoing attack, the slower is the reaction. Tertiary
carbocations, therefore, cannot undergo reactions. An
reaction takes place with inversion of configuration.
The rate of an reactiondepends only on the concen-
tration of the alkyl halide. The halogen departs in the first
step, forming a carbocation that is attacked by a nucleophile
in the second step. Therefore, carbocation rearrangements
can occur. The rate of an reaction depends on the ease
of carbocation formation. Tertiary alkyl halides, therefore,
are more reactive than secondary alkyl halides since tertiary
carbocations are more stable than secondary carbocations.
Primary carbocations are so unstable that primary alkyl
halides cannot undergo reactions. An reaction
takes place with racemization. Most reactions are
solvolysisreactions: The solvent is the nucleophile.
The rates of both and reactions are influenced
by the nature of the leaving group. Weak bases are the best
leaving groups because weak bases are best able to accom-
SN 2 SN 1SN 1SN 1 SN 1SN 1SN 1SN 2
SN 2SN 2SN 2SN 2SN 1SN 2SN 2 SN1.modate the negative charge. Thus, the weaker the basicity
of the leaving group, the faster the reaction will occur.
Therefore, the relative reactivities of alkyl halides that dif-
fer only in the halogen atom are
in both and reactions.
Basicityis a measure of how well a compound shares its
lone pair with a proton. Nucleophilicityis a measure of
how readily a compound is able to attack an electron-defi-
cient atom. In comparing molecules with the same attack-
ing atom or with attacking atoms of the same size, the
stronger base is a better nucleophile. If the attacking atoms
are very different in size, the relationship between basicity
and nucleophilicity depends on the solvent. In protic sol-
vents, stronger bases are poorer nucleophiles because of
ion–dipole interactionsbetween the ion and the solvent.
Methyl halides and primary alkyl halides undergo only
reactions, tertiary alkyl halides undergo only reac-
tions, vinylic and aryl halides undergo neither nor
reactions, and secondary alkyl halides and benzylic and al-
lylic halides (unless they are tertiary) undergo both and
reactions. When the structure of the alkyl halide allows
it to undergo both and reactions, the reaction
is favored by a high concentration of a good nucleophile in
an aprotic polar solvent, while the reaction is favored
by a poor nucleophile in a protic polar solvent.
Protic solvents( ROH) are hydrogen bond donors;
aprotic solvents(DMF, DMSO) are not hydrogen bond
donors. The dielectric constantof a solvent tells how well
the solvent insulates opposite charges from one another. In-
creasing the polarity of the solvent will decrease the rate of
the reaction if one or more reactants in the rate-determining
step are charged and will increase the rate of the reaction if
none of the reactants in the rate-determining step is charged.H 2 O,SN 1SN 2 SN 1 SN 2SN 2SN 1SN 2 SN 1SN 2 SN 1SN 2 SN 1RI 7 RBr 7 RCl 7 RFSummary of Reactions
- reaction: a one-step mechanism
Relative reactivities of alkyl halides:
Only the inverted product is formed.CH 3 X 71 ° 72 ° 73 °.−
Nu + C XXC Nu + −SN 2AU: OK two and one bold face?