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Radical Halogenation
a. Go back to 4.3 to review this reaction
Allylic Bromination
b. Allylic positions are those which are next to a carbon-carbon double
bond
c. Highly selective, only the most stable radical is formed through
resonance
d. Zaitsevs rule says that the most substituted product is the most stable
e. Common reagent/solvent: NBS
f.
Sn2
g. Nucleophilic substitution, bimolecular, one step, transition state exists,
in the transition state, a bond is partially formed with the nucleophile
(backside attack) and a bond is partially broken with the leaving group
(no intermediate), STRONG nucleophile needed
h. Reactivity: CH3X>1>2
i.
j.
k. Factors affecting Sn2:
i. Strength of nucleophile (secondary factor)
1. Trends in nucleophilicity
a. A species with a negative charge is a stronger
nucleophile than a similar neutral species. In
particular, a base is a stronger nucleophile than its
conjugate acid.
b. Nucleophilicity decreases from left to right in the
periodic table, following the increase in
electronegativity from left to right. The more
electronegative elements have more tightly held
nonbonding electrons that are less reactive toward
forming new bonds.
n.
Sn1
o. Substitution, nucleophilic, unimolecular in rate determining step,
nucleophile does not play a role in rate determining step, solvolysissolvent acts as the nucleophile
p. Multistep process
i. First step is a slow ionization to form a carbocation, leaving
group leaves
ii. Second step is a fast nucleophilic attack on the carbocation
q. Weak nucleophile usually used
i. If the nucleophile is an uncharged molecule then the positively
charged product must lose a proton to get final uncharged
product
r.
s. Carbocation stability 3>2>1>CH3X, also correlates to Sn1 reactivity
t. If nucleophile has multiple sites it can use to attack use the site that
will result in the most resonance stabilization
u. Leaving group stability that of Sn2
v. Carbocation resonance structures can make even secondary and
primary halides react as fast as tertiary halides, you dont necessarily
have to make a tertiary stabilized cation, and ALSO allylic resonance
stabilization helps
w. Solvent effects polar protic solvents like alcohols and water are good
for Sn1, polar protic solvents solvate ions
x. Stereochemistry: racemization occurs since the carbocation is planar
and achiral, both enantiomers are formed (retention and inversion),
normally the inversion product is formed in greater percentage since
the leaving group slightly hinders a front side attack, making a back
side attack more preferable
y. CARBOCATION REARRANGEMENTS: done to create more stable
carbocations with hydride and methyl shifts, ring expansion is an
option too
Sn1 vs Sn2
E1
z. Elimination involves the loss of two atoms and the formation of a pi
bond
aa.Slow step of this reaction is the same as that of Sn1
ab.
ac. NOTE: the solvent acts as a base (to remove a hydrogen) rather than a
nucleophile
ad.IMPORTANT: E1 and Sn1 are COMPETITIVE reactions, both happen
normally
ae.Carbocation rearrangements occur, only the solvent acts as a base
instead of a nucleophile, when comparing to Sn1, dont forget ring
expansion as a possibility for cyclobutane and below
ai.
aj. Reactivity 3>2>>1
E2
ak. Elimination, bimolecular, happens with strong BASES, note that strong
nucleophiles tend to be strong bases
al. Reactivity: 3>2>1
am.
an.E2/Sn2 compete in secondary alkyl halide reactions
ao. ZAITSEVS RULE STILL APPLICABLE
ap.STEREOCHEMISTRY IS APPLICABLE: SYN-COPLANAR (0) AND ANTICOPLANAR (180) arrangement of halogen to hydrogen/alkyl group
necessary for this reaction to occur, syn-coplanar corresponds to
eclipsed conformation while anti-coplanar corresponds to staggered
conformation, ALSO anti-coplanar corresponds to trans-diaxial on
cyclohexane chairs
aq.
ar. NOTE: If you want E1 over Sn1, use a strong acid OR HINDERED BASE,
weak nucleophile, and heat, if you want Sn1 over E1 use an acid like
HCl, HI, HBr
E1 and E2 summary
au.
av.
aw.
ax.
ay. Reactivity rate of type of alcohol: 3>2>1, E1
az. Special case of alcohol dehydration to form ETHERS
ba.
bb.
Lecture (XVII) has some practice problems at the end, pg. 316 of Chapter 7 has nice
problem solving strategy for the reactions up to this point
bc.
bd.*NOT A STEREOSELECTIVE reaction because planar carbocation is
formed, the halogen can attack from either side for syn or anti addition
resulting in cis/trans stereoisomers, see problem 8-16 from Wade 8 th
edition for details
be.SOME HBr addition is Antimarkovnical, only exception, it adds as a
radical due to light or peroxide presence, radical adds to the more
substituted carbon, stability of radicals: 3>2>1>radical CH3
bf. The peroxide effect, which is reversal of orientation in the presence of
peroxide, occurs in HBr addition only, you get BOTH Markovnical and
Antimarkovnical products
bg.
bk.
bm.
Markovnikov addition
bn.Reagent is Mercuric acetate
bo.Oxymercuration involves an electrophilic attack on the double bond by
the positively charged mercury species. The product is a mercurinium
ion, an organometallic cation containing a three-membered ring
bp.In the second step, water from the solvent attacks the mercurinium ion
to give (after deprotonation) an organomercurial alcohol. A subsequent
reaction is demercuration, to remove the mercury. Sodium borohydride
(a reducing agent) replaces the mercuric acetate fragment with a
hydrogen atom.
bq.
br. If this reaction is done in an alcohol it is alkoxymercurationdemercuration (convert alkenes to ethers)
i. When mercuration takes place in an alcohol solvent, the alcohol
serves as a nucleophile to attack the mercurinium ion. DRAW
THE ION IN THE MECHANISM. The solvent attacks the
mercurinium ion at the more substituted end of the double
bond (where there is more charge), giving Markovnikov
orientation of addition. The Hg(OAc) group appears at the less
substituted end of the double bond.
ii.
iii. Anti-addition occurs with this
iv.
bt.
bu.
bv. *syn addition: on same side, both in front or behind plane,
stoichiometry: 3 alkenes for 1 BH3 to form 3 alcohols
bw.
Enantiomers form (diastereomers) (racemization)
bx.***ALKENESTRAINED RINGOPENING
by.
bz. ANTI-ADDITION, the electrophilic carbon double bond attacks the X2
(X2=Cl2 or Br2, sometimes I2), forms three membered transition state
with one of the X, and the other X anion is nucleophile attacking
backside to result in formation of enantiomers
ca. Some cases that can be true, but best to draw products out and check
i. If addition of X2 with a compound W/O cis or transtrans
product (racemic)
ii. If addition of X2 with compound W/ cis both enantiomers form
iii. If addition of X2 with compound W/ transmeso-compounds
form
cb. ***ALKENESTRAINED RINGOPENING
ce.
cf. ***ALKENESTRAINED RINGOPENING
ci.
cj. Another (homogeneous) catalyst
ck.
co.
cp.
cq. Epoxide is then protonated by the acid and then a backside attack by
water opens the ring and the water attaches to the more substituted
carbon (MARKOVNIKOV), the end result is an ANTI-ADDED GLYCOL
cr.
cs. Since this reaction is ANTI, there is a possibility for certain isomers to
form based on the stereochemistry of the starting material, see
halogenation of alkenes for details
ct. Might be extra info: Epoxidation reagents can be chosen to favor either
the epoxide or the glycol. chiral diols. Peroxyacetic acid is used in
strongly acidic water solutions. The acidic solution protonates the
epoxide and converts it to the glycol. Peroxybenzoic acids are weak
acids that can be used in nonnucleophilic solvents such as carbon
tetrachloride. m-Chloroperoxybenzoic acid in generally gives good
yields of epoxides. Figure 8-8 compares the uses of these reagents.
cu. ***ALKENESTRAINED RINGOPENING
Dihydroxylation (2 rxns, electrophilic addition) (Synhydroxylation - special) of alkenes to form glycols (XIX)
cv. SUB-REACTION: Osmium tetroxide dihydroxylation, SYN-ADDITION to
alkenes to give GLYCOL, concerted (lots of shifting happens at once like
with epoxidation) ester formed
i. Oxidizing agents like peroxides and tertiary amine oxides used
to reoxidize osmium
ii.
cw.SUB-REACTION: Potassium permanganate dihydroxylation
i. Again, SYN-ADDITION to give GLYCOL, concerted ester formed
ii.
cx. ***ALKENESTRAINED RINGOPENING
cz.
da.
dc. Step 2: Molozonide is formed from the addition of the ozone to the
double bond. Molozonide quickly rearranges into ozonide. But even
that is unstable.
dd.Step 3: A reducing agent, like Dimethyl sulfide is used to get final
products. Note that DMSO is formed (used in SN2 reactions!).
de.To predict the products from ozonolysis of an alkene, erase the double
bond and add two oxygen atoms as carbonyl groups where the double
bond used to be. And to go backward given the products of ozonolysis,
pretend like youre about to smash the double bonded oxygens on
each product together (align them like youre about to do that), but
then erase the double bonded oxygens and form a double bond
between the carbons remaining.
df.
Lecture XIX is the end of alkenes acid-base reactions with alkenes occur with
NaNH2 as the base, result in formation of ammonia and some form of an acetylenic
proton, this only happens with terminal alkynes.
Acetylide Formation
v.
vi.
viii.
dh.Note use of hetero/homogenous catalysts
di.
dm.
dn.HBr addition in the presence of a peroxide (radical, antimarkovnical)
do.
Enols are unstable species that can be turned into ketones and aldehydes through
acids or bases
i.
ii.
iii.
iv.
v.
dq.
3.
a.
SEE PG. 454 of PDF (416 in book) for PROBLEM SOLVING STRATEGY FOR MULTISTEP
SYNTHESIS!
Lecture XXII covers general information about alcohols-might want to look at acidity
of alcohols (PDF PG. 473, section 10-6)
c.
d. Grignard reagents cannot be made from any compounds with acidic
groups meaning HMgX doesnt exist
f.
g. Organolithium reagents are more reactive than Grignard reagents
i.
iv.
v.
h.
i.
i.
Just in case:
k.
l.
Thiols can be prepared through Sn2 also
n.
p.
types
Alcohol Oxidation (XXIV)
q.
r.
s. Oxidation of secondary alcohols, ketone is product, Na2Cr2O7
(oxidizing agent) in H2SO4, this is one possibility for forming a double
bond with oxygen to create only a carbonyl group without any
hydrogens attached to the carbon
u.
v. Using PCC as the oxidizing agent, the reaction can be stopped at the
aldehyde, and instead of using something in H2O, use an ether
w.
x. Tertiary alcohols cant be oxidized (maybe use KMNO4/HNO3?)
z.
ac.
ad.
ae.Another path this could take is dehydration of the alcohol and then use
hydrogenation of alkene to give the final product
ah.
ai.
aj.
ak. Alcoholalkyl halide
al. Reaction occurs normally with PBr3 or the 2P/3I2 combo (PI3)
am.
Works well with primary and secondary alcohols, kinda like Sn2,
meaning no rearrangements occur
an.
aq.
at.
2.
2.
3.
4.
2.
3. The main problem with this reaction is that is reversible so acyl chlorides are
used to drive it forward
4.
Sulfate Esters
1.
Nitrate Esters
1.
2. Examples (first two from left are NITROBENZENE derivatives, PETN is nitrate
ester):
Phosphate Esters
1.
1.
2.
5.
6.
9.
11.
12.A good question
13.