Download Chem 314 Preorganic Evaluation

Organic Reaction Guide
Chem 316 / Beauchamp
Reactions Review Sheet
Beauchamp
1
Name
SN2 Reactions
special features: biomolecular kinetics Rate = kSN2[RX][Nu-], single step concerted reaction, E2 is a competing reaction
relative order of reactivity: CH 3X > 1oRX > 2o RX >> 3oRX (based on steric hinderance, no SN2 at 3o RX)
allylic & benzylic RX are very reactive, adjacent pi bonds help stabilize transition state and lower TS energy (Ea)
complete substitution at Cα (3o RX) or Cβ (neopentyl pattern) almost completely inhibits SN2 reactions
vinyl & phenyl are very unreactive, bonds are stronger and poor backside approach
leaving group ability: OTs = I > Br > Cl in neutral or basic conditions (just like E2, SN1 adn E1), and neutral
molecule leaving groups are good from protonated, cationic intermediates in acid conditions,
-OH2+, -ORH+, -OR2+, -NR3+, etc.
we will consider all anions, ammonia, amines, thiols and sulfides to be strong nucleophiles (favors SN2 and
E2 reactions)
in our course some electron pair donors are mainly nucleophiles (sulfur, azide, cyanide, carboxylates) and
some are mainly bases (t-BuO - K+, Na+ H2N -, Na+ H -)
polar, aprotic solvents work best for SN2 reactions because nucleophiles are relatively unencombered for electron
doantion (dimethyl sulofoxide = DMSO, dimethylformamide = DMF, acetonitrile = AN, acetone, etc.)
in our course some electron pair donors are mainly nucleophiles (sulfur, azide, cyanide, carboxylates) and
we will consider neutral solvent molecules such as water, alcohols and acids to be weak nucleophiles (favors SN1 and E1)
stereoselectivity: 100% inversion of configuration from backside atack
regioselectivity: reacts at carbon with leaving group, completely unambiguous
chemoselectivity: N/A
The following list is designed to emphasize SN2 reactions. Other possibilities (E2) are not listed.
a. primary RX (X = Cl, Br, I, OTs)
X
N C
C
N
nitrile
X
R C
R
C
(from alkyne + NaNH2)
alkyne (terminal or internal)
X
H O
OH
alcohol
X
R O
OR
(from alcohol + NaH)
ether
Possible additional steps
1. make amide (HCl/H2O)
2. make acid (H2SO 4/∆)
3. make aldehyde (DIBALH)
4. make ketone (RMgBr)
5. make 1o amine (LiAlH4)
Limitations
SN2 at Me, 1o and 2o RX
Possible additional steps
1. make cis alkene (Pd/H2/quinoline)
2. make trans alkene (Na/NH3)
3. make alkane (Pd/H2)
4. make ketone (H2SO4/Η2Ο)
5. make aldehyde (a.R2BH, b.H2O2)
6. zipper reaction (NaNR2)
Limitations
SN2 at Me and 1o RX
Possible additional steps
1. make RX (SOCl 2,PBr 3,HI)
2. make tosylate (TsCl/py)
3. make aldehyde (PCC/no H2O)
4. make acid (Jones/Η2Ο)
5. make alkoxide (NaH)
Limitations
SN2 at Me and 1o RX
Possible additional steps
1. protonate in acid
2. stable in base
Limitations
SN2 at Me and 1o RX
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
2
O
R
O
X
O
(from acid + NaOH)
R
ester
O
Possible additional steps
1. hydrolyze in acid or base
2. reduce with LiAlH4
3. react twice with organometallics
Limitations
SN2 at Me, 1o and 2o RX
Possible additional steps
1. make thiolate with NaOH
(good nucleophile)
X
H
S
SH
(from NaSH)
Limitations
SN2 at Me, 1o and 2o RX
thiol
X
R
Possible additional steps
1. can oxidize ro sulfoxide or
sulfone
S
SR
(from thiol + NaOH)
Limitations
SN2 at Me, 1o and 2o RX
sulfide
O
O
Possible additional steps
1. hydrolyze to 1o amine with
NaOH/H 2O
(or hydrazine, H2NNH2)
imide
N
N
X
NaOH/H2O O
O
NH2
1o amine
(from phthalimide + NaOH)
N3
N N N
X
azide
2
N N N
Pd/H2
(from NaN 3)
sodium azide
P
Ph
Ph
Ph
X
= Ph3P
triphenylphosphine
Possible additional steps
1. azides can by hydrogenated
(reduced) to a 1o amines with
Pd/H 2
Limitations
NH2
o
o
o
1 amine SN2 at Me, 1 and 2 RX
P
X
Limitations
SN2 at Me, 1o and 2o RX
alkyltriphenylphosphonium
halide, this salt is used in
Wittig reactions
Possible additional steps
1. make carbanion nucleophile
with n-BuLi and react with
aldehydes and ketones to make
very specific alkenes
Limitations
SN2 at Me, 1o and 2o RX
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
3
Possible additional steps
1. makes RX center into
alkane functionality
H
H Al H Li
H
X
lithium aluminium hydride
(LAH)
Limitations
SN2 at Me, 1o and 2o RX
Possible additional steps
1. makes RX center into
alkane functionality
H
X
H B H
H
Na
Limitations
SN2 at Me, 1o and 2o RX
Cu
X
Li
organocuprate (from
organolithium from
RX compound)
Possible additional steps
1. Couples two "R" parts from two
different RX starting structures,
one is made into an alkyl lithium,
then a cuprate and coupled to
another RX compound, cuprates
are needed because this reaction
We will view cuprate + RX
does not work with Mg or Li
as an SN2 reaction, eventhough
reagents.
Limitations
free radicals may be involved
SN2 at Me, 1o and 2o RX
O
R
X
CH2 Li
R
enolates from carbonyl
compounds + lithium
diisopropyl amide (LDA),
at very low temperatures,
many variations possible
O
Possible additional steps
1. LDA is made from diisopropyl
amine and n-BuLi, usually in
THF at room temperature and
the alkylation reaction run at
-78oC
Limitations
SN2 at Me, 1o and 2o RX
special RX (allyl, benzyl, vinyl, phenyl, neopentyl)
X
X
X
allyl RX
X
X
benzyl RX
exceptionally good electrophiles in SN2 reactions
vinyl RX
phenyl RX
neopentyl RX
very poor electrophiles in SN2 reactions
A good exercise would be to write out each reaction
above with allyl and benzyl RX compounds.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
b. secondary RX (X = Cl, Br, I, OTs)
Beauchamp
X
4
N C
C
N
Limitations
SN2 at Me, 1o and 2o RX
nitrile
mainly E2 reaction
X
R C
C
2-E and 2-Z and 1- alkenes
OH
H O
X
alcohol
2-E and 2-Z and 1- alkenes
OR
R O
X
alcohol
2-E and 2-Z and 1- alkenes
O
R
X
O
Possible additional steps
1. see 1o RX, cyanide is not
too basic for mainly SN2 at
2o RX, acid's pKa = 9
O
R
O
ester
Possible additional steps
1. not useful at 2o RX, see
1o RX reactions, acdtylides
are too basic for mainly SN2 at
2o RX, acid's pKa = 25
Limitations
SN2 at Me and 1o RX
Possible additional steps
1. not useful at 2o RX, see
1o RX reactions, messy
product mixture (SN2
and E2), acid's pKa = 16
Limitations
SN2 at Me and 1o RX
Possible additional steps
1. not useful at 2o RX, see
1o RX reactions, messy
product mixture (SN2
and E2), acid's pK a = 16-18
Limitations
SN2 at Me and 1o RX
Possible additional steps
1. see 1o RX, less basic carboxylates
are better behaved nucleophiles
and give good yields for SN2 at
2o RX centers, conjugate acid's
pKa = 9
Limitations
SN2 at Me, 1o and 2o RX
Possible additional steps
1. see 1o RX reactions
X
H
S
SH
thiol
Limitations
SN2 at Me, 1o and 2o RX
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
5
Possible additional steps
1. see 1o RX reactions
R
X
S
SR
Limitations
SN2 at Me, 1o and 2o RX
sulfide
O
O
N
N
X
O
Possible additional steps
1. see 1o RX reactions
O
NaOH/H 2O
NH2
o
1 amine
N3
N N N
Possible additional steps
1. see 1o RX reactions
azide
X
2
N N N
(from NaN 3)
sodium azide
Pd/H2
NH2
o
1 amine
Ph
P
Ph
P
Ph
Limitations
SN2 at Me, 1o and 2o RX
Possible additional steps
1. see 1o RX reactions
Ph Ph
X
Limitations
SN2 at Me, 1o and 2o RX
X
Ph
triphenylphosphine
H
H Al H
X
Li
H
lithium aluminium hydride
(LAH)
H
H B H
X
H
Na
sodium borohydride
alkyltriphenylphosphonium
halide, used in the Wittig
reaction,
Limitations
SN2 at Me, 1o and 2o RX
Possible additional steps
1. see 1o RX reactions, We
use LAH as nucleophilic
hydride in this book. If
we need basic hydride, we'll
use sodium hydride, NaH.
Limitations
SN2 at Me, 1o and 2o RX
Possible additional steps
1. see 1o RX reactions, We
use NaBH4 as nucleophilic
hydride in this book. If
we need basic hydride, we'll
use sodium hydride, NaH.
Limitations
SN2 at Me, 1o and 2o RX
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
6
Possible additional steps
1. see 1o RX reactions
Cu
X
Li
Limitations
SN2 at Me, 1o and 2o RX
organocuprate
O
R
Possible additional steps
1. see 1o RX reactions
CH2 Li
X
R
O
enolate chemistry
Limitations
SN2 at Me, 1o and 2o RX
Br
O
Intramolecular SN2 reaction.
O
O
O
special RX (allyl, benzyl, vinyl, phenyl, neopentyl)
X
X
X
X
X
allyl RX
benzyl RX
exceptionally good electrophiles in SN2 reactions
vinyl RX
phenyl RX
neopentyl RX
very poor electrophiles in SN2 reactions
SN reactions of epoxide electrophiles are shown in a later table.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
7
E2 Reactions are emphasized in this section
special features: biomolecular kinetics (Rate = kE2[RX][B-], single step concerted reaction, competing reaction is SN2
favored reactivity: 3oRX > 2o RX > 1oRX (none at CH3X, need Cβ-H),
1oRX will produce mainly SN2 product excet for mostly E2 with the sterically hindered and highly basic potassium
t-butoxide and generally more E2 occurs from the less hindered side of the RX
allylic & benzylic RX are very reactive if a conjugated pi bond can form
complete substitution at Cα (3o RX) shuts down SN2 and makes E2 the only choice, but there maay be many
possible E2 products
a completely substituted Cβ makes E2 impossible from that position, but if other Cβ's are present with a hydrogen
present, then E2 can occur from those atoms
vinyl & phenyl are fairly unreactive, but with really stong bases (R2N ) E2 can form an alkyne, or if the alkyne pi bond
becomes conjugated, the reaction can occur more easily with less basic ROleaving group ability: OTs = I > Br > Cl in neutral or basic conditions (just like SN2/E2 reactions)
anions whose conjugate acids have high pK a's (weaker acids have stronger bases) generally produce more E2 relative to
SN2, the two examples we will emphasize at 2o RX centers are carboxylates (SN2 > E2) vs hydroxide and
alkoxides (E2 > SN2) and cyanide (SN2 > E2) vs terminal acetylides (E2 > SN2)
we will consider neutral solvent molecules such as water, alcohols and acids to be weak nucleophiles (favors SN1 and E1)
stereoselectivity: mainly anti Cβ-H and Cα-X elimination since parallel orbital overlap of the favored staggered conformation allows
formation of pi bonds with lower Ea , syn elimination can occur in rigid systems that lock in the required ecliplsed
conformation, there can be a lot of possibilities to consider with up to three beta atoms with hydrogen atoms,
also each hydrogen of a C-beta CH 2 will often be different, producing E or Z stereoisomer alkenes depending on
the anti conformations present, also a chiral 3o RX Cβ-H may have R
(E or Z) and S
(Z or E).
regioselectivity: anti C-beta atoms (or syn in rigid systems) having a hydrogen are required relative to the C-alpha with the leaving group
chemoselectivity: N/A
Two different perspectives to show either SN2 or E2 reactions. Additional features need to be drawn in. The three templates can
work for 1o, 2o and 3o RX compounds. A cyclohexane template is also provided. The anti requirement for E2 reactions requires
that X be in an axial position in cyclohexanes, which also works better for SN2 reactions.
1o RX template
H
E2
target
B
Nu
H
Cβ
SN 2
target
H
Cα
H
Nu
H
B
H
H
Cβ
B
Cα
H
X
Cβ
Nu
= B
3o RX template
X
perspective 2
Nu
H
H
H
Cβ
Cβ
Cβ
Cβ
Cα
perspective 1
Nu
H
H
Cβ
H
B
Cα
At 1o RX SN2 is usually
favored over E2, except
if the sterically large and
very basic potassium
t-butoxide is used.
perspective 2
Nu
Nu
perspective 1
X
= B
2o RX template
B
Nu
Cβ
Cα
X
H
perspective 1
B
H
X
Cβ
H
H
Cβ
Cβ
Cα
Nu
=
B
perspective 2
At 2o RX SN2 and E2, are in
competition, less basic electron
pair donors tend to favor SN2
and more basic electron pair
donors tend to favor E2 reactions,
any feature that adds sterically
large groups pushes the reaction
towards E2.
Only E2 reactions are expected
at 3o RX when reactied with
strong electron pair donors.
X
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
8
Templates for both cyclohexane chair possibilities with a carbon substituent present. The leaving group, X, can be added at any
blank bond position and needs to be in an axial position to be anti in the ring (not true for carbon branch).
4
6
5
2
1
C
interconvert in
fast equilibrium
3
C
possible
reactions
an axial "X" is necessary for a succesful
E2 reaction and also works better for SN2
possible
reactions
?
?
An example of some possible choices for SN2 versus E2 in reactions at a secondary RX center having a chiral Cα, chiral Cβ and a beta CH2.
SN 2
CH2CH3
OCH 3
Cβ
H
Nu
Ha
Nu
Hb
Cβ
C
Cβ
Ha
CH3
CH2CH 3
OCH 3
Cβ
H
B
Cα
H
Ha
Cβ
CH2CH3
OCH 3
Cβ
H
B
H
Hb
Hb
CH3
Cα
H
Ha
H
H
C
C
I
CH2CH3
OCH3
C
Hb
Cβ
CH3
(3R,4S)
(3S,4S)
E2
CH2CH3
Cβ OCH 3
I
Cα
H
E2
H
CH3
CH3
H
(2E,4S)-3-methoxy-2-hexene
E2
CH3CH2
C
I
H
B
C
H
CH2CH 3
OCH 3
Cβ
OCH 3
CH2CH3
Cα
H
Hb
Cβ
H
C
I
C
CH2CH3
OCH 3
C
CH3
H
Ha
(3Z)-3-methoxy-3-hexene
H
CH3
(2Z,4S)-3-methoxy-2-hexene
a. primary RX (X = Cl, Br, I, OTs), typically see mostly SN2 and do not consider the E2 product, unless the base is potassium
t-butoxide, then E2 is the major product
OH
X
H O
or
or
OR
R O
Contrast with the reaction
below.
mainly SN2
BUT
O
K
X
mainly E2
Contrast with the reaction
above.
a big, bulky, very strong base
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
9
o
b. secondary RX (X = Cl, Br, I, OTs), SN2 and E2 products are both competitive at 2 RX, less basic anions are often good nucleophiles
and produce more SN2 product, while more basic anions are better at plucking off a Cβ−Η producing more E2 product, any feature
that introduces steric hindrance will favor E2 product (hindrance at Cα, Cβ or in the electron pair donor = base/nucleophile)
similar looking base/nucleophiles (used in this book) that react differently with 2oRX structures
less basic, mainly SN2 reaction
more basic, mainly E2 reaction
R C
N C
pKa of conjugate acid = 9
C
pKa of conjugate acid = 25
less basic, mainly SN2 reaction
O
R
O
pKa of conjugate acid = 5
more basic, mainly E2 reaction
H O R O
pKa of conjugate acid = 16-18
E2 reactions of 2o RX (and a few 3o RX) compounds
X
H O
or
R O
E2 products
E2 requires Cβ-H and Cα-X
bonds to be in anti conformation
OH (or OR)
SN2 product
Possible additional steps
1. many additional alkene reactions,
are possible although in this
reaction these would not be
productive because too many
different products are obtained
Limitations
SN2 and E2 products obtained
Possible additional steps
1. alkene reactions
H O
X
or
R O
only one hydrogen can be anti
or three Cβ-H's
Limitations
mainly E2 product
CH3
H 3C
C O
only E2 reaction, t-butoxide is
too big and bulky for SN2
reactions, an anti Cβ -H is
possible on either side when
the Br is axial
K
CH3
Br
enantiomers
CH3
H 3C
Br
C O
K
CH3
6
1
2
Br
R 3N
(DBU or DBN)
No
reaction
High pKa , sterically bulky base,
should be only E2, but Br cannot
significantly rotate to an axial
position since the very large
t-butyl group locks the ring into
confromation having t-but yl
equatorial.
Only E2 at a 3o RX with a strong
base/nucleophile. There are three
Cβ's but only C6 and the methyl
carbons allow the necessary anti
conformation for E2 reactions. C2
cannot rotate its hydrogen anti.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
10
Only E2 at a 3o RX with a strong
base/nucleophile. All three Cβ's
can rotate a hydrogen anti and
form E2 product.
6
1
F
Br
3
6
A Cβ carbon is fully substituted
so SN2 reaction is greatly
inhibited. There is an anti
Cβ-H possibility on the other
side so E2 can occur there.
C N
Br
H Br
5
4
3
2
1
H CH3
H
H
SN2 and E2 reactions possible,
this is a good example for showing
why you need o be able to draw
and understand 3D drawings, this
example is comprehensively viewed
below.
CH3O
See choices below.
Br
CH3
(3S,4S)
H
SN2 reaction
H
CH3O
OCH3
H
H
SN 2
S Br
H
R H
Br
S
H
S
H
E2 reactions
H
H
S Br
H
S
H
C-C
rotation
CH3O
H
CH3
H
H
H
H
CH3
CH3O
C-C
rotation
H
H
H
Br
E2a
H
CH3O
H
C-C
rotation
H
H
CH3
Br
Br
E2c
E2b
H
CH3 CH3
CH3 H
H
H
H
H
"Z" configuration
H
H
"E" configuration
CH3
H
"E" configuration
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
11
SN1 and E1 Reactions (they share a common carbocation intermediate)
special features: unimolecular kinetics ( Rate = kSN1[RX] or Rate = kE1[RX], the relative rates depend on the k's ), multi step reaction,
SN1 and E1 are c ompeting reactions (usually SN1 dominates)
favored reactivity: 3oRX > 2o RX and we say none at a 1o RX or CH3X because those carbocations are too unstable
to form
allylic & benzylic RX are reactive because of resonance stabilization of carbocation (even if 1o RX)
the number of R gourps at Cβ is not especially important in our course, because the key step in either SN1 or E1
is the first step involving ionization of the Cα-X bond, but highly substituted Cβ positions mean there will
probably be rearrangements
there is no anti Cβ-H requirement for E1 because the carobcation is so reactive and any Cβ-H can be rotated parallel
to the empty p orb ital, generally the more substituted, more stable alkene forms to the greatest extent
vinyl & phenyl are completely unreactive because the sp2 bonds are generally too strong to break and the sp
carbocation is too unstable in the case of vinyl and the empty sp2 orbital is too unstable in the case of phenyl
leaving group ability: OTs = I > Br > Cl in neutral or basic conditions (same for all of the reactions),
and neutral molecule leaving groups are good from protonated, cationic intermediates in acid conditions,
-OH2+, -ORH+, -OR2+, -NR3+, etc.
only weak base/nucleophiles (usually the same molecule: H-B: = H-Nu:) will be used in these reactions, usually it is
the solvent molecule (H2O, ROH or RCO2H in this book)
the solvent is usually a polar, protic solvent that is capable of stabilizing charged intermediates
the only synthetically useful E1 reaction in this book will be dehydration of alcohols, ROH, in concentrated H2SO4
with heating (∆) which distills out the alkene and shifts the equilibrium towards E1
whenever carbocations are formed, rearrangements must be considered and are likely if similar or more stable
carboncations can form (we will usually only emphasize rearrangements to more stable carbocations),
but the ultimate two leading to stable products reactions are add a nucleophile or lose a beta hydrogen
stereoselectivity: any Cβ-H can be lost in an E1 reaction because any Cβ-H can be rotated parallel to the empty p orbital allowing
formation of pi bonds, generally the most stable, more substituted (or E over Z) alkene forms to the greatest
extent, SN1 reactions lead to racemization of chiral RX centers
regioselectivity: any Cβ hydrogen atom can be lost in E1 reactions, in SN1 reactions the nucleophile will add to either face of the
Cα carbon unless there rearrangement occurs
chemoselectivity: N/A
In this book SN1 reactions attack will occur from either side of the flat Cα carbon. This will result in racimization of configuration at chiral
centers or cis/trans products in rings.
i. (R
racemization) or (S
racemization)
2
X
2
C
H Nu
X
C
H Nu
4
3
ii. (cis ring
Nu H
R
H
H Nu
3
3
"R" configuration
leads to racemization (50/50 mixture for our course)
R
R
Nu H
R
X
Br
proton
transfer
Nu
trans ring
H
H
CH3
only one anti Cβ-H
"IF" E2 reaction.
"IF" RO
SN2/E2
H
H
H
first step for
SN1/E1 reactions
ROH
Nu
cis ring
attack can occur from top or bottom of carbocation
Nu H
Br
=
4
"S" configuration
H
H
C
cis/trans ring)
X
trans ring
Nu
4
3
attack can occur from either
face of the flat carbocation
cis/trans ring) or (trans ring
2
C Nu
4
"S" configuration
X
2
proton
transfer
H
H
H
H
H
CH3 H
conformation changes of two chairs
allows any beta hydrogen to be lost
from the carbocation
CH3
1. rearrange 2. add Nu
(likely in this reaction
because a 3o R+ can form)
3. lose beta-H
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
12
via
Br
Our general rules are SN1 > E1,
except for high temperature, acid
dehydration of alcohols.
Rearrnagement here is not a
E1 (minor) problem because nothing
changes. No stereochemistry or
regiochemistry to consider.
H2O
OH
SN1 (major)
via
Br
ROH
E1 (minor)
OR
SN1 (major)
via
O
OH
Br
E1 (minor)
O
O
SN1 (major)
Our general rules are SN1 > E1,
except for high temperature, acid
dehydration of alcohols.
Rearrnagement here is not a
problem because nothing
changes. No stereochemistry or
regiochemistry to consider.
Our general rules are SN1 > E1,
except for high temperature, acid
dehydration of alcohols.
Rearrnagement here is not a
problem because nothing
changes. No stereochemistry or
regiochemistry to consider.
via
E1
(minor)
Br
H 2O
enantiomers
OH
SN1 (major)
diastereomers
Rearrangement of 2o
OH carbocation is possible,
but not shown in this
problem.
via
E1
(minor)
enantiomers
ROH
Br
OR
SN1 (major)
diastereomers
Rearrangement of 2o
OR carbocation is possible,
but not shown in this
problem.
via
E1
(minor)
O
Br
enantiomers
OH
O
O
ester on top
and bottom
SN1 (major)
diastereomers
Rearrangement of 2o
carbocation is possible,
but not shown in this
problem.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
13
via
Br
H2O
E1 (minor)
Rearrangement is likely because a 3o
OH carbocation can form from the
originally formed 2o carbocation.
SN1 (major)
via
ROH
Br
E1 (minor)
SN1 (major)
OR
Rearrangement is likely because a 3o
carbocation can form from the
originally formed 2o carbocation.
via
O
OH
Br
E1 (minor)
O
SN1 (major)
via
Br
H 2O
OH
SN 1
Rearrangement is likely because a 3o
carbocation can form from the
originally formed 2o carbocation.
O
Rearangement is likely since a 3o
carbocation can form, normally
SN1 dominates over E1, with
racimization of a chiral center
(stereogenic centers are drawn with
a wiggly lines), however significant
E1 is expected because the alkene is
E1 tetrasubstituted.
via
Br
ROH
OR
SN 1
E1
via
O
Br
OH
O
O
SN 1
E1
Rearangement is likely since a 3o
carbocation can form, SN1 will
dominate over E1, racimization
of chiral center is expected
(stereogenic centers are drawn with
a wiggly line, only the most stable
E1 alkene is shown.
Rearangement is likely since a 3o
carbocation can form, normally
SN1 dominates over E1, with
racimization of a chiral center
(stereogenic centers are drawn with
a wiggly lines), however significant
E1 is expected because the alkene is
tetrasubstituted.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Br
Beauchamp
14
OH
H 2O
SN1, very good at benzylic even
though primary can still occur
because of resonance stabilization
of carbocation, E1 is not possible
here because there is no Cβ-H to
lose a hydrogen.
O
Br
Br
OR
or
ROH
Br
kinetic
product
H2O
Phenyl carbocation is VERY
difficult to form in sp2 orbital.
No reaction
OH
SN1, very good at allylic R+
common intermediate via
resonance, two different
products formed from a
commonintermediate having
OR partial positive charge at two
thermocynamic sites as shown by the
product
resonance structures
Vinyl carbocation is VERY difficult
to form in p orbital of sp hybridized
carbon. Carbocations that we typically
see are empty p orbitals of a sp2
hybridized carbon.
No reaction
Br
SN1, acid protonates OH and makes
OH
-OH2+. Water is a good leaving group
HI
cis or trans
and when at 2o or 3o forms a carbocation.
Mainly SN1 with HX acids. Nucleophile
adds from top and bottom.
I
cis and trans
OH
SOCl 2
cis or trans
Cl
SO2 leaving group, HCl also
formed. View reaction as SN1
at 2o and 3o ROH.
cis and trans
OH
PBr3
cis or trans
Br
cis and trans
O
S Cl = TsCl
OH
OTs
O
N = pyridine
cis goes to cis
and
trans goes to trans
Oxygen first does SN2 at phosphorous
and then HOPBr 2 is the leaving group
in second step (repeated two more
times). View reaction as SN1 at 2o and
3o ROH and SN2 at methyl or 1o ROH.
Substitution reacton is at the sulfur
and represents another way to make
the OH into a good leaving group, as
a tosylate (inorganic sulfur ester).
Pyridine added to sponge up (neutralize)
the HCl generated in the reaction.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
OH
Beauchamp
15
Dehydration of alcohols in
strong acid, with heat, represents
our main E1 conditions.
Rearrangement is possible, but
not shown.
H2SO4 / ∆
enantiomers
cis or trans
OH
OH
OH
OH would protonate, but -OH2+
cannot leave from a phenyl carbon.
the empty sp2 orbital (NOT a p
orbital!) is too unstable.
HBr
No Reaction
Just a reminder at 1o ROH, OH
would protonate, but -OH2+
HBr
Br
H2SO4 / ∆
cannot leave from a 1o carbon.
It needs to be pushed off via
SN2 by the bromide.
E1, initial carbocation
rearranges and then eliminates
at high temperature. The alkene(s)
distill out. Tetrasubstitution is the
most stable alkene shown.
major
E1
E1 product. The most stable
alkene is shown due to more
substituted, trans and conjugated.
H2SO4 / ∆
HO
OH
Br
PBr3
1. TsCl, pyridine
2. NaBr
OH
Br
SOCl 2
OH
Cl
Oxygen first does SN2 at phosphorous
and then HOPBr2 is the leaving group
in second step (repeated two more
times). View reaction as SN1 at 2o and
3o ROH and SN2 at methyl or 1o ROH.
1. makes tosylate (good leaving group)
reaction occurs at sulfur, not carbon
so no change in chiral center
2. SN2 by bromide at carbon, chiral
center inverts
SO2 leaving group, HCl also
formed. View reaction as SN1
at 2o and 3o ROH and SN2 at
methyl and 1o ROH.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Reactions of Alkenes (and Alkynes) -
Beauchamp
16
Stereoselectivity (cis vs trans, E vs Z, R vs S) and Regioselectivity (reacts at C1 vs C2), it is sometimes possible to see these
features in the product structures which can be achiral, enantiomers, diasteromers and/or meso. Reagents generally can
attack from either face. Sometimes the approaches are equivalent and sometimes one face is preferred over the other.
In the reactions below, if "Stereo = Y" is written, then the reaction can be stereoselective even if not all products will show it.
If "Regio = Y" is written, the reaction can be regioselective even if not all products will show it.
Br
1
Stereo = N
Regio = Y
HBr
racemic
2
a. Hg(OAc) 2
H2O (or ROH)
b. NaBH4
3
OH
Stereo = N
Regio = Y
Markovnikov addition,
intermediate carbocation
does not rearrange because of
mercury bridge, NaBH4 reduces
off mercury to hydrogen
Stereo = N
Regio = Y
Markovnikov addition,
intermediate carbocation
can rearrange if more stable
carbocation can form, if heated
the E1 alkene is the product
racemic
OH
H 2SO4 / H 2O
racemic
4
OH
a. BH3
b. H2O2 / HO
5
Br
a. BH3
b. Br2 / CH3O
6
Br
Br
Br2
Stereo = Y
(syn)
Regio = Y
Stereo = Y
(syn)
Regio = Y
Stereo = Y
(anti)
Regio = N
racemic
7
OH
Br
Br2 / H2O
Stereo = Y
(anti)
Regio = Y
racemic
8
a. Br2 / H 2O
b. NaOH
O
racemic
Markovnikov addition,
intermediate carbocation
(can rearrange, add a
nucleophile or lose a
beta hydrogen.
Stereo = Y
(anti, SN2)
Regio = N
(overall)
anit-Markovnikov addition,
borane forms trialkylborane,
second step oxidizes boron
position to an OH
Same as above, but instead of
boron becoming an OH, it
becomes a Br
Bromonium bridge prevents
rearrangement, bromide adds
anti to first bromine at more
partial postive carbon.
Bromonium bridge prevents
rearrangement, hydroxide adds
anti to first bromine at more
partial positive carbon. Similar to
above reaction.
Product from #7 forms an
epoxide. Oxgen attacks from
backside in anti conformation.
Can also be made directly from
alkene with mCPBA.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
17
9
Stereo = Y
(syn)
Regio = N
O
mCPBA
10
11
a. mCPBA
b. H3O / H2O
or
b. HO / H2O
OsO4
or
KMnO4
racemic
Stereo = Y
(anti)
OH Regio = N
OH
racemic
Stereo = Y
(syn)
OH Regio = N
OH
racemic
Stereo = Y
(syn)
Regio = N
12
H2 / Pd
13
o
1. O 3, -78 C
2. CH3SCH3 or Zn
achiral
H
O
O
H
14
o
1. O3, -78 C
2. NaBH 4
OH
15
1. O 3, -78oC
2. H 2O2
16
1. Br2
2. NaNH 2
3. WK
OH
O
Reaction occurs in a single
step via concerted mechanism.
Net result of epoxidation followed
by opening the epoxide in acid or
base is anti addition of two vicinal
alcohol groups. This is opposite to
the next reaction (syn addition).
Dioxygenation occurs in a single
concerted step via syn addition,
followed by aqueous hydrolysis to
form a vicinal diol. This is opposite
to the above reaction (anti addition).
The metal activates the hydrogen
and two hydrogen atoms add to
the pi bond in a cis or syn manner.
Stereo = N
Regio = N Ozone cuts pi bond in two and
workup leaves a carbonyl bond
H
at each carbon (aldehydes and/or
ketones are the products).
Stereo = N
Regio = N Ozone cuts pi bond in two and
workup reduces carbonyl bonds
HO
CH3
at each carbon to alcohol groups.
Stereo = N Ozone cuts pi bond in two and
Regio = N workup oxidizes carbonyl bonds
O
OH
at each carbon to carboxylic
= CO2 acids or ketones if the alkene
carbon is geminally substituted.
OH
Stereo = N Bromine adds as in reaction 6 above.
Regio = N Sodium amide performs two E2
reactions and then deprotonates the
alkyne. Workup with acid protonates
the sp carbanion to form an alkyne.
H2 / Pd
Stereo = Y The metal activates the hydrogen
Regio = N and two hydrogen atoms add to the
first pi bond in a cis or syn manner
to form an alkene, which then
reduces to the alkane.
H2 / Pd / quinoline
Stereo = Y The metal activates the hydrogen
Regio = N and two hydrogen atoms add to the
first orbital in a cis or syn manner.
The quinoline poisons the catalyst
so that alkenes do not react further.
17
18
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
18
Stereo = Y An electron from sodium adds to
Regio = N the LUMO orbital. the resulting
anion protonates. Another electron
adds and the resulting anion protonates
to form the more stable E alkene.
19
Na / NH3
Stereo = N Markovnikov addition, intermediate
Regio = Y carbocation (can rearrange, add a
Br
nucleophile or lose a beta hydrogen.
achiral, but cis/trans diastereomers
20
HBr
21
a. Hg(OAc) 2
H2O (or ROH)
b. NaBH4
24
a. BH3
b. Br2 / CH3O
Stereo = N
Regio = Y
Markovnikov addition,
intermediate carbocation
can rearrange if more stable
carbocation can form, if heated
the E1 alkene is the product
OH
H 2SO4 / H 2O
a. BH3
b. H2O2 / HO
Markovnikov addition,
intermediate carbocation
does not rearrange because of
mercury bridge, NaBH4 reduces
off mercury to hydrogen
OH
22
23
Stereo = N
Regio = Y
OH Stereo = Y
anit-Markovnikov addition,
Regio = Y
boron and hydrogen add syn,
OH borane forms trialkylborane,
second step oxidizes boron
position to an OH
Br Stereo = Y
Regio = Y
Same as above, but instead of
Br boron becoming an OH, it
becomes a Br
Br
25
Br
Br2
Br
Br
26
Br
Br2 / H 2O
OH
Stereo = Y, Regio = Y
27
a. Br2 / H 2O
b. NaOH
Stereo = Y
Regio = N
Bromonium bridge prevents
rearrangement, bromide adds
anti to first bromine.
Bromonium bridge prevents
rearrangement, hydroxide adds
anti to first bromine at more
partial positive carbon. Similar
OH to above reaction.
Br
Product from #7 forms an
epoxide. Oxgen attacks from
O
O
backside in anti conformation.
Can also be made directly from
alkene with mCPBA.
Stereo = Y, Regio = N
28
O
mCPBA
Reaction occurs in a single
O step via concerted mechanism.
Epoxide oxygen adds syn.
Stereo = Y, Regio = N
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
29
30
Beauchamp
a. mCPBA
b. H3O / H2O
or
b. HO / H2O
OsO4
or
KMnO4
19
OH
Net result of epoxidation followed
by opening the epoxide in acid or
base is anti addition of two vicinal
alcohol groups. This is opposite to
OH the next reaction (syn addition).
OH
OH
Stereo = Y, Regio = N
OH
OH
Stereo = Y, Regio = N
31
Dioxygenation occurs in a single
OH concerted step via syn addition,
followed by aqueous hydrolysis to
OH form a vicinal diol. This is opposite
to the above reaction (anti addition).
The metal activates the hydrogen
and two hydrogen atoms add to
the pi bond in a cis or syn manner.
H2 / Pd
Stereo = Y, Regio = N
O
32
o
1. O 3, -78 C
2. CH3SCH3 or Zn
O
OH
33
o
1. O3, -78 C
2. NaBH 4
OH
O
34
1. O 3, -78oC
2. H 2O2
35
H
Ozone cuts pi bond in two and
workup leaves a carbonyl bond
at each carbon (aldehydes and/or
ketones are the products).
1. Br2
2. NaNH2
3. WK
36
H2 / Pd
37
H2 / Pd / quinoline
O
OH
Ozone cuts pi bond in two and
workup reduces carbonyl bonds
at each carbon to alcohol groups.
Ozone cuts pi bond in two and
workup oxidizes carbonyl bonds
at each carbon to carboxylic
acids or ketone if the alkene
carbon is geminally substituted.
Bromine adds as in reaction 6 above.
Sodium amide performs two E2
reactions and then deprotonates the
alkyne. Workup with acid protonates
the sp carbanion to form an alkyne.
The metal activates the hydrogen
and two hydrogen atoms add to the
first pi bond in a cis or syn manner
to form an alkene, which then
reduces to the alkane.
The metal activates the hydrogen
and two hydrogen atoms add to the
first pi bond in a cis or syn manner.
The quinoline poisons the catalyst
so that alkenes do not react further.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
20
An electron from sodium adds to
the LUMO pi bond. the resulting
anionprotonates. Another electron
adds and the resulting anion protonates
to form the more stable E alkene.
38
Na / NH3
39
Zipper reaction, tautomer-like
proton exchanges that move pi
bonds to the terminal position where
anion is most stable (in sp orbital)
as: R
1. Na NR2
2. workup
40
1. Na NR2
2. O
Zipper reaction, R
opens epoxide, workup
protonates the alkoxide.
3. workup
OH
41
1. Na NR2
2.
Br
3. workup
1. Na NR2
2. H 2C=O
3. workup
42
H
1.
43
H
Zipper reaction, R
does SN2 on R-Br.
OH
Na NR2
O
OH
2.
H
3. workup
44
H
O
H2SO4 / H2O
HgSO4
O
45
2-hexanone
H 2SO4 / H 2O
HgSO4
O
3-hexanone
46
O
H2SO4 / H 2O
HgSO4
47
H
a. R2BH
b. H2O2 / HO
O
H
Step one forms terminal sp carbanion
nucleophile. Step 2 adds methanal
(formaldehyde) as a one carbon
electrophile. Workup protonates the
alkoxide anion.
Similar to above except a generic
aldehyde is used as the carbon
electrophile. Workup protonates the
alkoxide anion.
Markovnicov addition of water (H
and OH) via most stable carbocation.
Forms enol which tautomerizes to
methyl ketone when a terminal alkyne
reacts.
If a nonterminal alkyne is used,
reaction could occur from either
side, possibly producing different
ketones probably in similar amounts.
If some special feature makes
one side preferred (e.g. resonance)
then a single ketone might be
preferred.
Anti-Markovnikov addition of dialkylborane to
a terminal alkyne. Two large R groups are used
(9-BBN is common) so the addition only occurs
once to the skinny alkyne. Workup with H2O2
oxidizes carbon with boron to an enol-like structure
which when released protonates to form an aldehyde
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
21
O
48
2-hexanone
a. R2BH
b. H2O2 / HO
O
3-hexanone
If a nonterminal alkyne is used,
reaction could occur from either
side, possibly producing different
ketones probably in similar amounts.
Miscellaneous alkenes and alkynes to consider.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
Reactions of Alcohols (SN, E, oxidation, esterification, acetal/ketal formation, acid/base...)
22
There is methanol and there are primary, secondary, tertiary, allylic, benzylic alcohols. Phenols (aromatic alcohols)
are considered separately.
R
R
H
OH
R
C
R
C
OH
OH
OH
OH
R C OH
H3C OH
H
R
H
o
o
o
methanol
phenols
allylic alcohols
benzylic alcohols
1 ROH
2 ROH
3 ROH
1
HI
No carbocations at primary
carbon. Mechanism is SN2.
I
OH
2
OH
SOCl 2
Carbocations form at secondary
carbon. Mechanism is SN1.
Cl
3
OH
Br
PBr3
Carbocations form at secondary
carbon. Mechanism is SN1.
4
OH
H 2SO4 / ∆
E1 conditions, alkene would
distill out and shift equilibrium
towards products. Rearrangements
are expected.
major
5
OH
H 2SO4 / ∆
E1 conditions, alkene would
distill out and shift equilibrium
towards products. Rearrangements
are expected.
H2SO4 / ∆
E1 conditions, alkene would
distill out and shift equilibrium
towards products. Rearrangements
are expected.
6
OH
major
minor
7
OH
Na H
Na(s) metal can also be used
O
Na
a strong base/nucleophile
8
OH
Na H
Na(s) metal can also be used
O
Na
a strong base/nucleophile
Sodium hydride is only basic in
our course. It is very useful for
pulling off very weakly acidic
protons. LAH and NaBH4
can be nucleophilic in our course.
Sodium hydride is only basic in
our course. It is very useful for
pulling off very weakly acidic
protons. LAH and NaBH4
can be nucleophilic in our course.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
23
9
OH
Na(s) metal can also be used
10
11
The first reaction is acid/base
and the second reaction is SN2.
This reaction would work in
either direction of alcohol and RX
compound.
2.
O
Br
The first reaction is acid/base
and the second reaction is SN2.
If the reaction were tried the other
way around there would be
consideralbe E2 product
1. NaH
OH
OH
O
2.
Br
1. NaH
2.
OH
The first reaction is acid/base
and the second reaction is SN2.
If the reaction were tried the other
way around there would only
be E2 product
O
Br
O
13
tosyl
S Cl chloride
O
pyridine = proton sponge
The OH of an alcohol can be made
into a toslyate (an inorganic ester).
OTs
Tosyl group is a very good leaving
group in SN and E chemistry (similar
1o tosylate, good leaving group to iodides).
O
14
OH
15
a strong base/nucleophile
1. NaH
OH
12
Na
O
Na H
tosyl
S Cl chloride
OTs
O
2o tosylate, good leaving group
pyridine = proton sponge
Ts-Cl = tosyl chloride
N
pyridine = proton sponge
The OH of an alcohol can be made
into a toslyate (an inorganic ester).
Tosyl group is a very good leaving
group in SN and E chemistry (similar
3o tosylate, good leaving group to iodides). Susceptible to E1.
O
TsOH (cat.)
OH (remove H2O)
OH
O
O
Fischer esterification
O
17
OH
The OH of an alcohol can be made
into a toslyate (an inorganic ester).
Tosyl group is a very good leaving
group in SN and E chemistry (similar
to iodides).
OTs
OH
16
Sodium hydride is only basic in
our course. It is very useful for
pulling off very weakly acidic
protons. LAH and NaBH4
can be nucleophilic in our course.
TsOH (cat.)
OH (remove H2O)
O
O
Removing water shifts equilibrium
to the right and adding water shifts
equilibrium to the left. Toluene
sulfonic acid is a common catalyst.
Removing water shifts equilibrium
to the right and adding water shifts
equilibrium to the left. Toluene
sulfonic acid is a common catalyst.
Fischer esterification
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
24
O
18
TsOH (cat.)
OH (remove H2O)
OH
19
OH
Removing water shifts equilibrium
to the right and adding water shifts
equilibrium to the left. Toluene
sulfonic acid is a common catalyst.
E1 possible at 3oRX, reducing yields.
O
Fischer esterification
O
CrO3 / pyridine / no H2O
PCC
O
H
aldehyde at 1o ROH
20
OH
CrO3 / pyridine / no H2O
PCC
O
ketone at 2o ROH
21
OH
CrO 3 / pyridine / no H2O
PCC
No reaction at 3o ROH
OH
CrO3 / H2O / acid
Jones reagent
OH
acid at 1o ROH
23
OH
CrO3 / H2O / acid
Jones reagent
Need OH and H on the same carbon
atom. Highly oxidized chromium strips
electrons from oxygen and base removes
proton in E2 reaction to form pi bond
between the carbon and the oxygen.
In acid the aldehyde hydrates and OH
and H are on the same carbon atom again.
The second oxidation forms a carboxylic
acid.
O
22
Need OH and H on the same carbon
atom. Highly oxidized chromium strips
electrons from oxygen and base removes
proton in E2 reaction to form pi bond
between the carbon and the oxygen.
Need OH and H on the same carbon
atom. Highly oxidized chromium strips
electrons from oxygen and base removes
proton in E2 reaction to form pi bond
between the carbon and the oxygen.
No further reaction is possible on a
ketone because there is no hydrogen
atom to allow the E2 reaction to occur.
O
ketone at 2o ROH
24
OH
25
diol = ethylene glycol
OH
O
H
aldehyde
26
CrO3 / H2O / acid
Jones reagent
ketone
27
O
O
O
(remove H2O)
DHP = dihydropyran
O
ketal
(remove H2O)
TsOH
O
H
acetal
HO
toluene sulfonic acid = TsOH
enol ether
OH
O
HO
toluene sulfonic acid = TsOH
(remove H2O)
diol = ethylene glycol
OH
O
No reaction at 3o ROH
O
acetal
OTHP
THP = tetrahydropyran
Tertiary alchols do not react because
there is not hydrogen atom to allow
the E2 reaction to occur.
Acetals are used to protect aldehydes.
They are stable in neutral and basic
solution, but reactive in acid solution.
Removing water shifts equilibrium to
the right, adding it shifts to the left.
Ketals are used to protect ketones.
They are stable in neutral and basic
solution, but reactive in acid solution.
Removing water shifts equilibrium to
the right, adding it shifts to the left.
Alcohols can be protected with DHP
forming a THP acetal. There is a
disquised carbonyl and second OH
hidden in the DHP and THP groups.
THP acetals are stable in neutral and
basic solution, but reactive in acid
solution. Removing water shifts
equilibrium to the right, adding it shifts
to the left.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
25
Reactions of Epoxides (mainly SN2-like reactions, E2-like reactions are possible but not emphasized in our course)
Epoxides are unusual ethers. Because of their large ring strain (26 kcal/mole) they can open in acid or base conditions. In
base the attack of the strong nucleophile is at the less hindered position as one would expect in an SN2-like reaction. But in
acid the attack of the weak nucleophile is at the more hindered position because it carries more of the partial positive charge
which more strongly attracks the weak nucleophile. In both reaction attack is forced to occur from the opposite side of the
epoxide bridge. In the second compound below, no inversion is observed at the more hindered position in base and inversion
is observed there in acid.
1R
1R
H
O
O
O
O
O
4S
4S
2S
2R
2S
ethylene oxide (2R)-propylene oxide cyclohexene oxide (1R,2S,4S)-methylcyclohexene oxide (1R,2S,4S)-2,4-dimethylethenoxirane (2R)-propenoxirane cyclohexenoxirane (1R,2S,4S)-methylcyclohexenoxirane
cyclohexenoxirane
Opens trans or anti from backside
attack. Cannot tell in this simple
epoxide.
1
H2O / H3O+
O
OH
HO
2
H
O
H 2O / H3O
+
OH
HO
2R
2S
OH
3
Opens trans or anti from
backside attack at the more
substituted, more partial
positive carbon. Chiral
center does invert, becomes S.
H
OH
H 2O / H3O+
O
OH
OH
50/50 mixture of enantiomers
OH
4
5
O
HO
/ H2O
a strong base/nucleophile
6
H
OH
H 2O / H3O+
O
HO
In strong base/nucleophile conditions
attack is at the less hindered positon
as expected in SN2-type reactions.
A chiral center at the more
substituted position is not inverted.
/ H2O
2R
HO
2R
7
OH
O
HO
Similar to #1. Opens trans or
anti from backside attack.
Diasteromers are formed in
unequal amounts.
OH
OH
unequal mixture of diasteromers
In strong base/nucleophile conditions
attack is at the less hindered positon
HO
as expected in SN2-type reactions.
OH
A chiral center at the more
substituted position is not inverted.
H OH
O
Similar to #1. Opens trans or
anti from backside attack.
Enantiomers are formed in
equal amounts (a racemic
mixture).
/ H 2O
OH
racemic mixture of enantiomers
Similar to #5. Opens trans or
anti from backside attack.
Enantiomers are formed in a
50/50 racemic mixture.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
8
O
9
HO
/ H 2O
2. workup
Grignard, lithium or
cuprate organometallic
H
HO
H OH
CH2 (MgBr)
O
2. workup
Grignard, lithium or
cuprate organometallic
2R
11
2. workup
Grignard, lithium or
cuprate organometallic
12
OH
13
2. workup
Grignard, lithium or
cuprate organometallic
H
O
OH
H
H
O
Na
2. workup
terminal acetylides
2R
Similar to #8.
OH
unequal mixture of diasteromers
SN2 reaction at less hindered
center. The acetylide is made
from a terminal alkyne + NaNH2.
Na
2. workup
terminal acetylides
Similar to #7.
racemic mixture of enantiomers
CH2 (MgBr)
O
Similar to #6.
2R
CH2 (MgBr)
O
14
Similar to #5. Mg and Li reagents are
formed from the metals and an RX
compound. Cuprates are made from
lithium reagents and cuprous bromide
(CuBr). Workup is necessary
CH2 (MgBr)
O
10
26
OH
OH Similar to #5. Opens trans or
anti from backside attack.
Diasteromers are formed in
OH
OH unequal amounts.
unequal mixture of diasteromers
HO
HO
H
Similar to #6.
2R
OH
15
O
H
Similar to #7.
Na
2. workup
terminal acetylides
racemic mixture of enantiomers
OH
16
O
H
Na
2. workup
terminal acetylides
Similar to #8.
OH
unequal mixture of diasteromers
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
27
Reactions of Aldehydes and Ketones (mainly carbonyl addition reactions in strongly acidic or strongly
basic conditions)
1. Carbonyl groups in strong acid (weak base/nucleophile conditions)
a. Always begin by protonating the carbonyl oxygen lone pair.
b. Protonation on oxygen generates a resonance stabilized carbocation with reactions of
carbocations
1. add nucleophile = first step of carbonyl addition and substitution reactions
2. lose beta hydrogen = tautomer reactions
3. no rearrangements because of resonance.
C O
H X
C O
H Cα
C O
addition could produce enantiomers, if the
carbon with the OH group is the only chiral
center...or could lead to diasteromers, if
there is one or more other chiral centers
H
H
C O
C O
H Cα
X
addition
product
H Cα
top/bottom or syn/anti addition is not relevant in our course, but
could lead to R/S stereochemistry (loss of "β H" is also possible)
resonance shows that the positive charge is spread over the carbon
and oxygen atoms, the first resonace structure is better with full
octets and an extra bond, but the second resonance structure is
very informative about the ultimate fate of the intermediate
competing pathway, redrawn from
above (keto/enol tautomerization)
H
C O
X
H Cα
H Cα
The addition is totally
regioselective. Use a
lone pair for electron
donation. In our course,
begin every carbonyl
reaction in acid this way.
X
H
H
Cα
enol structure
2. Carbonyl groups in strong nucleophile/base conditions (weak acid or nonacidic conditions).
Two sites of attack are possible by strong electron pair donation (recall SN2 at carbon and E2 at hydrogen).
a. Nucleophilic attack at carbon (C=O) or
b. Basic attack at an adjacent hydrogen (Cα-H)
Remember a similar competition about where to donate the
electrons in SN (carbon) versus E (hydrogen) reactions.
a. Nucleophilic attack is possible at electrophilic carbon using strong electron pair donation. Often all acidic
protons are excluded to avoid quenching the strong electron pair donor.
H X
Nu
C O
H Cα
often all acidic protons are excluded
to avoid protonating the nucleophile
Nu
Nu
C O
C O H
H Cα
H Cα
addition
product
neutralize, often as a
second workup step
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
28
b. Basic attack is possible at the “relatively acidic” Cα-H. Often all acidic protons are avoided to avoid
quenching the strong electron pair donor.
reaction with
an electrophile,
usually at carbon
C O
Cα
C O
C
E α
Eδ
B
C O
C
H α
carbon electrophiles
often add at Cα
carbonyl with
electrophile
"keto"
tautomer
reaction with a proton,
can occur at carbon or
oxygen (tautomers)
C O
Cα
Cα-H's to carbonyl groups are more
acidic than typical C-H bonds due to
resonance stabilization by oxygen in
the enolate conjugate base.
hydrogen usually
C O H equilibrates among
Cα
all basic positions,
preferred location
depends on thermo"enol"
dynamics though
tautomer
less stable contributors
may be more reactive
H X
enolate
intermediate
tautomerization
further reactions
at C or O
are possible
pKa (CH in alkane) = 50
pKa (CH α to C=O) = 20
Reactions of Aldehydes and Ketones (mainly carbonyl addition reactions)
O
O
O
H
H
propene
O
O
2S-methylbutanal
2-butanone 2R-methylpentan-2-one 4-methylcyclohexan-1-one 3R-methylcyclohexan-1-one
Hydration of a carbonyl.
Equilibrium favors the keto
form. Very fast in acid or
base and very slow in neutral
water. Keto/enol tautomeriztion
is also possible.
1
O
H2O / H3O+
H
2
HO OH
H
Same as #1.
O
H2O / H3O
+
HO OH
3
Same as #1.
O
4
OH
H 2O / H3O +
O
HO
/ H 2O
H
5
O
OH
HO OH
H
O
HO
/ H 2O
HO OH
Hydration of a carbonyl.
Equilibrium favors the keto
form. Very fast in acid or
base and very slow in neutral
water. Keto/enol tautomeriztion
is also possible.
Same as #2.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
29
6
OH
O
7
O
Same as #2.
OH
OH
Li
1.
H
8
/ H 2O
HO
Organometallic (from RX
compound) adds to carbonyl
electrophile. Racemic (R/S)
2o benzylic ROH forms in
this reaction.
2. workup
1. CH3CH2 (MgBr)
O
Organometallic (from RX
compound) adds to carbonyl
electrophile. Achiral 3o ROH
forms in this reaction.
OH
2. workup
1.
9
Na
Terminal acetylide adds to top
and bottom of carbonyl face.
Cis/trans diastereomers form.
O
OH
2. workup
"OH" on top and bottom
10
O
1. Na
OH
CN
2. workup
H
C
N
1o RNH2 + aldehyde or ketone forms
imines. Removing water shifts
equilibrium to right and adding water
shifts it to left. Many 1o RNH2
derivatives react similarly. E/Z
stereochemistry is possible but not shown.
11
O
H 2N
TsOH
pH = 5 (-H2O)
N
12
O
H N
N
TsOH
pH = 5 (-H2O)
13
O
H
14
O
CrO3, H2O, H3O+
(Jones)
Pyrolidine (2o amine) forms enamines
with carbonyl compounds. Removing
water shifts equilibrium to right and
adding water shifts it to left. Makes Cα
into a neutral nucleophilic carbon.
Oxidizes via carbonyl hydrate.
O
OH
OH
Zn, HCl
Clemmenson Reduction
Cyanide nucleophile forms
cyanohydrin with carbonyls and
slow addition of acid. Aldehydes
and less substituted ketones work
best. R/S is possible here.
H
OH
Reduces C=O to CH2 in acid.
Zn supplies the electrons and
HCl supplies the protons
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
15
O
16
Beauchamp
H2NNH2, KOH, ROH
(Wolff -Kishner Reduction)
O
O
TsOH
(-H2O)
O
H
O
TsOH
(-H2O)
O
O
OH
HO
18
O
1. NaBH4
2. workup
H
Acetals form (via hemiacetals). Removing
water shifts equilibrium to right and
adding water shifts it to left. Makes
carbonyls unreactive under neutral and
basic conditions (protects them), but are
reactive in acid to break down back to the
carbonyl.
OH
HO
H
17
30
Reduces C=O to CH2 in base.
A hydrazone forms, there are a
number of proton transfers, some
resonance structures and loss of
nitrogen.
OH
19
20
H
1. LiAlH4
2. workup
O
OH
1.
H
Ph
2. workup
21
O
1. Ph
Ph P
HO
O
(diol)
HO
TsOH, (-H2O)
23
O
O
O
H N
H
Lithium aluminium hydride
reduces all carbonyl compounds,
nitriles and opens epoxides. Workup
protonates intermediate anion. A
ketone forms a 2o ROH. Cis/trans
diastereomers form in this example.
Wittig reaction. Wittig salt
formed via RX + Ph3P. Carbanion
generated with nBuLi.
Ph
2. workup
22
Sodium borohydride only reduces
aldehydes and ketones and opens
epoxides. Workup protonates
intermediate anion. An aldehyde
forms a 1o ROH.
Wittig reactions form really specific
alkenes. The Wittig salt is formed
via RX + Ph3P. Nucleophilic carban
is generated with nBuLi.
Ph
Ph P
O
Similar reaction with ketones.
Ketals form (via hemiketals) and are
used to protect ketones. Removing
water shifts equilibrium to right
and adding water shifts it to left.
TsOH
pH = 5 (-H2O)
N
Ketal formation (remove water).
Hydrolyze ketal to ketone under
same conditions, but add water.
Protecting group for carbonyls.
Pyrolidine (2o amine) forms enamines
with carbonyl compounds. Removing
water shifts equilibrium to right and
adding water shifts it to left. Makes Cα
into a neutral nucleophilic carbon.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
1.
H2N
24
31
pH = 5 (-H2O)
H
O
N
2. Na H3BCN
H
1.
25
1o amines form imines with carbonyl
compounds, which can be reduced to
2o amines by NaBH3CN. 2o amines react
in an analogous way to form 3o amines
(see next example).
pH = 5 (-H2O)
H N
O
2o amines form iminium ions with
carbonyl compounds, which can be
reduced to 3o amines by NaBH3CN.
(See examples above.)
N
2. Na H3BCN
26
β
1.
O
Li
α
H
α,β-unsaturated carbonyl
27
β
α
Li and Mg organometallics prefer
1,2 attack of α,β-unsatruated c arbonyls.
Cuprates prefer attack at Cβ, called
conjugate addition or 1,4-addition.
Allylic/benzylic OH probably unstable
in this example.
OH
2. workup
O
1.
O
α,β-unsaturated carbonyl
28
O
α
β
α,β-unsaturated carbonyl
Li and Mg organometallics prefer
1,2 attack of α,β-unsatruated c arbonyls.
Cuprates prefer attack at Cβ, called
conjugate addition or 1,4-addition.
Carbonyl group is retained in this example.
Cu
Li
2. workup
Na
O
CN
H2O/ROH
C
N
More stable nucleophiles, like
cyanide, prefer attack at Cβ, forming
the more stable, thermodynamic
product, also called conjugate addition
or 1,4-addition. Stabilized enolates,
discussed later, react in a similar
manner in the Michael reaction.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
Reactions of Carboxylic Acids and their derivatives (typically acyl substitution reactions, because there is a
leaving group at the acyl carbon, as opposed to typically addition reactions at aldehydes and ketones)
O
O
O
O
O
O
Cl
propanoyl chloride propanoic anhydride
OH
propanoic acid
O
O
ethyl propanoate
C
NH2
propanamide
32
N
propanenitrile
Which C=O groups are most reactive? Why? (The answers are found in steric, inductive and resonance effects.) Thiol esters
(structure C, below) are not usually emphasized in organic chemistry, but are very important for living organisms (biochemistry).
Acetyl CoA is a well known example. One might say that thioesters are nature's acid chlorides. In carboxylic acids and their
derivatives, the third resonance structure is a strong contributor when the contributing lone pair comes from a 2p orbital (oxygen
and nitrogen) that overlaps well with the 2p orbitals of the C=O pi bond (the third resonance structure is more important than the
second resonance structure). However, resonance donation from chlorine and sulfur is not as good becasue the 3p orbital is larger
and electron delocalization is not as efficient. Because chlorine and sulfur are somewhat electronegative there is increased partial
positive character on the carbonyl carbons from an inductive effect, with little return of electron density via resonance. Additionally,
chloride and sulfides are stable anions and good leaving groups which leads to high reactivity in acyl substitution reactions. The
middle oxygen of anhydrides has good overlap with the carbonyl carbons, but is split between two carbonyls, which reduces its
resonance effect, while the electron withdrawing inductive effect is even larger than that found in an ester. The carboxylate group of
an anhydride is also a good leaving group. Aldehydes and ketones do not have a stabilizing third resonace contributor which makes
them more reactive than those functional groups that do, where resonance donation is important (esters and amides). Aldehydes are
more reactive than ketones because they have a sterically small hydrogen substituent and aldehydes do not have the extra "R" group
of a ketone which is inductively donating and reduces the parital positive of the carbonyl carbon and thereby reducing their reactivity
with nucleophiles. Esters (we will consider carboxylic acids and esters equivalently) and amides are less reactive than any of the
previously discussed groups, because the third resonance structure below significantly reduces the partial positive at the carbonyl
carbon. Amides are less reactive than esters because nitrogen is many orders of magnitude better at donating electrons than oxygen
on the basis of electronegativity. Normally, we would never even think of a negatively charged carboxylate as being an electrophile,
however, even the carboxylate will react that way with an excess of organolithium compounds, the most pushy electron pair donors
that we enounter. Thus, the typical order of reactivity is that shown below (A>B>C>D>E>E>F>G>H)
A
B
O
1
C
R
O
Cl
R
O
2
R
C
R
C
O
O
Cl
R
O
3
C
O
C
-7 (-10)
pKa (∆G)
of HCl
R
C
R
R
O
O
O
Cl
C
C
C
D
E
F
G
H
O
O
O
O
O
O
C
SR
R
R
R
C
SR
R
C
H
R
R
C
C
R
R
H
R
C
SR
C
OR
R
O
O
R
R
no additional
resonance
O
R
C
O
O
O
O
C
C
C
NR2
R
O
OR
R
O
R
C
C
R
C
O
O
NR2
R
O
OR
C
C
O
O
NR2
R
C
O
+5 (+7)
+25 (+35)
+7 (+10)
+40 (+56)
+18 (+25)
+37 (+52)
+50 (+70)
The first number represents the pK a of LG part of acyl group when protonated (the corresponding ∆G in
parentheses in kcal/mole). This provides a measure of how stable the leaving group is on its own.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
33
O
1
O
Cl
Cl
OH
Cl
thionyl chloride
O
O
2
OH
There are a variety of ways to
transform a carboxylic acid into
an acid chloride. Two of these are
shown and use thionyl chloride or
oxalyl chloride.
O
S
O
Cl oxalyl
chloride
Cl
Cl
O
O
3
O
O
Carboxylates are even better
nucelophiles and are easily
formed by neutralizing the acid.
O
HO
O
anhydride
Cl
O
4
O
O
Cl
OH
See #1. Acid chlorides are at the
top of the reactivity hill and all
of the other acid derivatives can
be made from them by using the
appropriate nucleophile.
O
O
anhydride
5
O
SH
Cl
O
This would probably be a pretty
stinky reaction.
S
ethanethiol
O
O
6
Cl
Ester synthesis. Adding a 3o amine
will neutrialize the HCl that also
forms and protect an organic molecule
that has other sensitive functionality.
HO
O
pyridine (proton sponge)
7
O
HO
O
Ester synthesis.
O
Cl
pyridine (proton sponge)
8
O
O
Cl
9
H 2O
O
OH
Generally, we are doing
everything in our power to
avoid this reaction. It undoes
the first two reactions above
that made the acid chlorides.
NH2
Reaction with ammonia
will form 1o amides. An extra
equivalent is needed to neutralize
the HCl formed.
O
Cl
NH3
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
34
10
o
O
O
Reaction with 1 amines
will form 2o amides. An extra
equivalent is needed to neutralize
the HCl formed.
H 2N
N
Cl
11
H
O
O
Reaction with 2o amines
will form 3o amides. An extra
equivalent is needed to neutralize
the HCl formed.
HN
Cl
13
O
N
Reaction with diisobutyl aluminium
hydride (DIBALH) at very low
temperature will form aldehydes,
after acidic workup. Nitriles and
esters also form aldehydes with
DIBALH.
O
1. H Al
-78oC
Cl
H
DIBALH
2. workup
O
14
O
Cu
Li
Cl
cuprates
-78oC
O
15
O
Reaction with cuprates at very low
temperature will form ketones.
O
O
A more complex anhydride is prepared
from a simpler anhydride. Ethanoic
anhydride (acetic anhydride) is readily
available and commonly used in this
manner.
O
HO
O
O
16
O
O
O
17
O
Ester synthesis. A carboxylic acid
also forms. If the molecule has other
sensitive functionality then an amine
base may be needed to neutrialize the
acid.
O
HO
O
O
Ester synthesis. DMAP is a
common catalyst in these reactions.
O
HO
O
O
(CH 3)2N
N
N,N-dimethylaminopyridine (DMAP)
18
O
O
O
H 2O
O
19
OH
2
O
O
O
H2N
N
O
pyridine (proton sponge)
H
Generally, we are doing
everything in our power to
avoid this reaction.
1o, 2o or 3o amide synthesis is possible
in a manner similar to the acid chlorides
above from ammonia, 1o amines or
2o amines. Excess amine is needed to
neutralize the carboxylic acid.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
20
O
Beauchamp
1. LiAlH4
2. workup
O
21
35
Lithium aluminium hyhdride, (LAH)
OH
reduces all carbonyl functional groups,
as well as nitriles. LAH supplies
discarded nucleophilic hydride and workup
OH
in workup supplies acidic (electrophilic) hydrogen.
isolated
O
O
O
OH
O
TsOH (cat.), (-H2O)
O
22
OH
23
1. LiAlH4
2. workup
1. NaOH
2. Br
O
OH
24
Fischer ester synthesis. Uses a catalytic
amount of acid and water is removed,
which shifts the equilibrium to the ester
side. Adding water under the same
conditions would hydrolyze the ester
back to an alcohol and a carboxylic acid.
HO
OH
Hydroxide neutralizes the carboxylic
acid. The carboxylate acts as a well
behaved nucleophile to do SN2
reactions at methyl, 1o and 2o RX
compounds.
O
O
Amides are pretty hardy and require
pretty harsh acid or base conditions
to hydrolyze them to carboxylic acids.
In base the formation of a carboxylate
drives the reaction and in acid complete
protonation of the amine drives the
reaction (no longer nucleophilic). The
target molecule could be either part (the
acid or the amine) or both of them. To
extract the neutral acid into an ether layer
a low pH extraction would be necessary,
while to get the amine into an ether layer
a high pH extraction would be needed.
O
O
H2SO4 / H2O / ∆
N
OH
H
H3N
O
25
O
1. NaOH / H2O / ∆
2. neutralize with acid
N
OH
H
H N
after acidic workup
26
O
1. LiAlH4
2. workup
N
26
A 3o amide generally forms
a 3o amine when reduced with
LAH.
N
O
N
H
1. LiAlH4
2. workup
N
H
H
27
Lithium aluminium hyhdride
reduces all carbonyl functional
groups, as well as nitriles.
H
A 1o, 2o or 3o amide generally
forms a 1o, 2o or 3o amine when
reduced with LAH, followed by
acidic workup.
O
N
H
1. LiAlH 4
2. workup
N
H
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
28
Beauchamp
36
O
1. LiAlH4
2. workup
N
29
N
O
O
3o amindes + Grignard reagents
lead to ketones after hydrolytic
workup.
1.
(MgBr)
N
2. workup
30
O
O
H
N
Cl
H
S
Cl
N
NH2
C
HCl / H2O / ∆
O
32
C
N
OH
H2SO4 / H2O / ∆
C
1. NaOH / H2O
2. workup
C
N
H Al
34
C
N
As with amides, nitriles require
harsh acid or base conditions to
hydrolyze them to first amides,
then carboxylic acids. In base the
formation of a carboxylate drives
the reaction and in acid complete
protonation of the ammonia
drives the reaction (no longer
nucleophilic).
O
33
C
1o amindes can be dehydrated
with thionyl chloride to form
nitriles.
thionyl chloride
31
C
N
C
OH
O
H
-78oC
O
DIBALH
Reaction with diisobutyl aluminium
hydride (DIBALH) at very low
temperature will form aldehydes,
after acidic workup. Acid chlorides
and esters also form aldehydes with
DIBALH.
Esters should have been placed up above carboxylic acid reactions.
35
O
O
O
H2SO4 / H2O / ∆
OH
HO
36
O
O
O
NaOH / H2O / ∆
OH
HO
Esters are hydrolyzed back to a
carboxylic acid and an alcohol in
aqueous acid. Either compound
could be the desired target. Overall
this is the reverse of Fischer ester
synthesis.
Esters can also be hydrolyzed back
to a carboxylic acid and an alcohol
in aqueous base. Either compound
could be the desired target. This is
sometimes called saponification
(soap making).
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
37
from reduced carbonyl,
desired target
O
37
OH
O
1. LiAlH4
2. workup
discarded
in workup HO
from reduced carbonyl,
discarded in workup
38
1. LiAlH4
2. workup
O
O
39
HO
O
1. H Al
O
-78oC
desired O
target
H
DIBALH
2. workup
40
desired
target
OH
O
OH
O
1. CH3CH2 Li
2. workup
LAH reduces esters to 1o alcohols
after acidic workup. Either product
alcohol could be the desired target.
While NaBH4 will reduce aldehydes
and ketones, it will not reduce esters
(no reaction).
LAH reduces esters to 1o
alcohols after acidic workup.
Either product alcohol could
be the desired target.
Reaction with diisobutyl aluminium
discarded hydride (DIBALH) at very low
in workup temperature will form aldehydes,
after acidic workup. Acid chlorides
and nitriles also form aldehydes with
HO
DIBALH.
Esters react twice with Mg and Li organometallics
forming 3o ROH after acidic workup. Two of the R
groups of the 3o ROH are the same, being added
from the organometallic. Benzylic, 3o ROH would
be sensitive to substitution (SN1) or elimination
(E1) in the workup in this example.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Reactions of Aromatic Compounds
Beauchamp
38
1. Electrophilic aromatic substitution reactions
a. (activating substituents)
Common ortho / para directing substituents: any alkyl substituent, any group with a lone pair next to the aromatic ring that can be
used in resonance with the intermediate carbocation. This could include the following commonly encountered groups in our course.
R
R
OH
OR
O
N
NR2
O
R = alkyl
phenols
ethers
esters
R
amides
amines (except in
strong acid where
they are protonated)
1
HNO3 / H2SO4
faster than
benzene
NO2
2
SO3 / H2SO4
SO3H
faster than
benzene
3
FeCl3 / Cl 2
Cl
faster than
benzene
4
AlCl3 /
Cl
O
AlCl3 /
faster than
benzene
Cl
Nitration conditions (HNO3/H2SO4) make
nitroaromatic compounds. Here with an
ortho/para activating substituent. Ortho
product expected, but not shown. A small
amount of meta product is also likely.
Sulfonation conditions (H2SO4/SO3, oleum),
makes aromatic sulfonic acids. Mainly
ortho/para product with methyl substituent.
Halogenation (FeX3/X2), (Cl 2 and Br2),
halogenates (chlorine or bromine)
aromatic compounds. Mainly
ortho/para product with methyl
substituent.
Friedel Crafts alkylation (RX/AlX3),
forms carbocations and rearrangements
are likely, adds alkyl groups to aromatic
ring, which makes the aromatic ring more
activated and likely to react again.
faster than
benzene
5
R
X
O
halogen comounds (X = F,
Cl, Br, I), while ortho/para
directing, these substituents
are deactivating
O
Friedel Crafts acylation (RCOCl/AlCl 3),
forms a resonance stabilize carbocation
(an acylium ion) so no rearrangement is
expected, makes aromatic ketones, which
deactivate the ring and make it less likely
that another reaction will occur
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
39
b. Electrophilic aromatic substitution reactions (deactivating substituents)
Common meta directing substituents: any strongly electron withdrawing substituent by resonance or inductive effect. They often have an
atom with a double bond to oxygen next to the aromatic ring (can be carbon, nitrogen, sulfur and others). The attached group is destabilizing
to the positively charged aromatic substitution intermediate when they are directly facing one another which occurs with ortho/para attack, so
electrophiles prefer the meta position for attack in substitution reactions and the reaction is always slower than benzene. Some commonly
encountered groups in our course are shown below.
O
C
O
S
X
O
X
O
sulfonic acids, amides,
esters, X = OH, NR2, OR
NR3
N
nitro groups
slower than
benzene
NO2
Nitration conditions (HNO3/H2SO4) make
nitroaromatic compounds. Here with an
meta deactivating substituent. Meta is the
main product expected and a slow reaction
is likely.
SO3H
Sulfonation conditions (H2SO4/SO3, oleum),
makes aromatic sulfonic acids. Mainly
meta product with a nitro substituent.
O 2N
7
SO3 / H2SO4
slower than
benzene
O 2N
8
O 2N
X
sp3 carbon with
strongly withdrawing
groups attached
positively charged
groups, like
ammonium ions
HNO3 / H2SO4
O 2N
C X
O
6
O 2N
Br
FeCl3 / Cl 2
slower than
benzene
O 2N
9
O 2N
AlCl3 /
Cl
No reaction
does not typically work with
deactivated aromatic rings
O
10
O 2N
AlCl3 /
NR2
amides
esters
acids
ketones
aldehydes
C
OR
OH
R
O
C
C
C
H
O
O
O
Cl
does not typically work with
deactivated aromatic rings
No reaction
Halogenation (FeX3/X2), (Cl2 and Br2),
halogenates (chlorine or bromine)
aromatic compounds. Mainly
metal product with a nitro substituent.
Friedel Crafts alkylation (RX/AlX3),
forms carbocations and rearrangements
are likely, but the reaction is rarely
successful with only deactivating
substituents present.
Friedel Crafts acylation (RCOCl/AlCl 3),
forms a resonance stabilize carbocation so
no rearrangement is expected, but the reaction
is rarely successful with only deactivating
substituents present.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
2. Nucleophilic reactions (addition/elimination),
diazonium chemistry (Ar-N2+) from following sequence:
HNO3
H 2SO4
nitro Æ amino Æ diazonium salts
NaNO2 / HCl
(makes HONO)
Fe / HCl
O2N
40
H2N
reduce
nitro
group
N N
diazonium salt, stable below
5oC, decomposes to carbocation
(or free radical ) above 5oC,
see reactions below
O
possible reactions
at meta position(s)
T > 5oC
Cl
O
aromatic ring is
the electrophile !
reactions are more controlable with
less activating amide than amine,
possible reactions at ortho/para position(s),
can hydrolyze amide back to the amine
to continue the reaction sequence towards
the diazonium chemistry
N
H
1
HNO 3 / H2SO4
First step to diazonium salt is
nitration of an aromatic ring.
O 2N
2
Fe / HCl or
SnCl2/HCl
O 2N
reduce nitro
group
3
H 2N
O
O
H 2N
Meta groups might be added at this
stage before the nitro group is reduced
to an amine. A metal in a reduce state
donates electrons and an acid donates
the protons.
Cl
N
H
4
O
N
H
H3O+ / H 2O
or
NaOH / H 2O
H 2N
5
H 2N
NaNO2 / HCl
(makes HO-N=O)
N N
6
N N
T > 5oC
aromatic ring is
the electrophile !
7
T > 5oC
N N
CuCl
Cl
If additional substitution at this stage is
desired, the amine group is usually
protected as an amide to reduce its basicity
and activating power. All available positions
(o + p) might be substituted or the amine
might be protonated and turned into a meta
director. If the amine is protected as an amide
it must be hydrolyzed in acid or base to get
back the amine functionality
Nitrous acid is the electrophile and the
aromatic amine group is the nucleophile,
which joins two nitrogen atoms together,
followed by some proton transfers, loss
of water and resonance.
diazonium salt is stable below 5oC, it
decomposes to an unusual carbocation in
that the empty orbital is sp2, (some reactions
may proceed by a free radical intermediate),
a variety of nucleophiles can be added at
this point, see reactions below
Ipso substitution (same position), Copper
reactions are called Sandmeyer reactions,
the chlorine put on in this reaction is
backwards to the way it was put on above,
nucleophilic chloride adds here.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
41
8
Ipso substitution (same position), Copper
reactions are called Sandmeyer reactions,
the bromine put on in this reaction is
backwards to the way it was put on above,
nucleophilic bromide adds here.
T > 5oC
N N
Br
CuBr
9
T > 5oC
N N
Ipso substitution (same position), Copper
reactions are called Sandmeyer reactions,
cyanide is nucleophilic in this reaction,
the aromatic ring is the electrophile.
NC
CuCN
10
T > 5oC
N N
Ipso substitution (same position), iodide
is the nucleophile.
I
KI
11
T > 5oC
N N
Ipso substitution (same position),
water is the nucleophile.
HO
H 2O
12
T > 5oC
N N
Ipso substitution (same position), a
fluoride from tetrafluoroborate is the
nucleophile.
F
BF4
13
Ipso substitution (same position),
hypohphosphorous acid is a very
unusual ACID hydride donor. A
possible reaction sequence is shown
below.
T > 5oC
N N
H
H 3PO2
H
H
O
P
OH
H
Electrophile
H
Electrophile
O
P
OH
OH2
lose
proton
H
O
P O
H
OH
Hypohphosphorous acid is a very unusual ACID hydride donor. The hydride reduces something and the phosphorous gets oxidized.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
42
Nucleophilic reactions (addition / elimination), similar to conjugate substitution at an α,β-unsaturated
carbonyl having a leaving group, except followed by elimination to reform the aromatic compound
Electron poor aromatic rings with a good leaving group attached allow nucleophiles to add at the carbon with the leaving group,
followed by rearomatization when the good leaving group leaves. The leaving group has to be ortho or para to the electron
withdrawing group so that the substituent can stabilize the negative charge in the intermediate. It is similar to the diazonium
intermediate in that the aromatic ring is the electrophile.
1
O2N
Cl
2
OH
H2O
O2N
Br
OH
CH3O
OCH3
CH3OH
O 2N
O
O 2N
O
N
N
O
Br
The nitro substituent is electron
withdrawing and can stabilize
negative charge by resonance and
chloride is a good leaving group,
attack by a nucleophile can displace
the chloride, the reaction is somewhat
like a substitution reaction on a
vinylogous acid halide.
O
N
O
Br
Nu
O
Nu
Nu
O
O
O
analogous nucleophilic substitution
reaction on a vinylogous acid chloride
Cl
Cl
Nu
Nu
Nu
3.
Benzyne (elimination / addition), uses a very strong base, sodium amide (NaNH2)to force a 1,2
elimination beta to good leaving group forming highly reactive benzyne. A nucleophile can add to
the “pseudo” triple bond on either side, after which the aromatic ring protonates at the other position.
Benzyne forms in an E2-like reaction requirering a very strong base (often some sort of sodium amide, NaNR2), except because of
the rigid, flat nature of the aromatic ring, no real pi bond can form. The parallel sp2 orbitals are angled away from one another making
for a very unstable and highly reactive arrangement of orbitals. An electron pair donor in the vacinity of either sp2 ortibal will add its
electrons to form a sigma bond and isolate the pseudo pi electrons in a highly basic sp2 orbital which quickly protonates in an acid/base
reaction to regenerate a neutral aromatic ring. If an unchanged substituent is present on the ring, it is easily seen that either carbon of the
pseudo pi bond can be attacked by a nucleophile, because isomeric products are obtained.
1
Br
N(CH3) 2
Nu: adds at
either position
HN(CH3)2
benzyne intermediate
2
N
meta and para
products obtained
Nu: adds at
either position
Cl
N(CH3) 2
N
N
ortho and meta
products obtained
HN(CH 3)2
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
N
Organic Reaction Guide
Beauchamp
4. Miscellaneous side chain reactions
1
O
R
2
CH2
HCl / Zn
CH2
R
CH2
R
H2NNH2/RO /∆
O
R
Clemmenson reduction (HCl/Zn),
reduces aromatic ketone to methylene
carbon (CH2) under acid conditions.
The Zn supplies the electrons and the
HCl supplies the protons.
R
O
R
3
43
Pd / H2
Wolff Kishner reduction (H2NNH2/RO /∆),
reduces aromatic ketone to methylene
carbon (CH2), under base conditions.
Imine-like structure forms, acid/base
proton transfers, tautomer-like changes
and ultimately loss of nitrogen gas.
Pd/H2 reduction, reduces aromatic ketone
to methylene carbon (CH2) because it's
benzylic, reduces, reaction occurs under
neutral conditions unlike Clemmenson's
(acidic) or Wolff-Kishner (basic).
4
CrO3/∆
HO2C
CO2H
6
KMnO4/∆
HO2C
CrO3/∆ or KMnO 4/∆ oxidations, very
harsh conditions, no sensitive groups
tolerated, oxidizes any carbon side chain
with a benzylic hydrogen to a carboxylic
acid, a quaternary benzylic carbon will
either not react or if really pushed the
aromatic ring is oxidized away, leaving
a carboxylic acid in place of the ring.
7
KMnO4/∆
forcing
conditions
HO2C
8
Br
Br2 / hν
+
Free radical substitution (Cl 2 or Br2
HBr and light, hν), chain reaction mechanism
prefers benzylic position because of
weaker C-H bond
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
44
Synthesis of Functional Groups – most of the reactions listed below have been listed above, but are listed
here by the common theme of functional group preparation so you can consider a variety of possibilities
when considering the synthesis of a particular functional group.
1.
Synthesis of RX compounds
RX compounds from free radicals substitution of sp3 C-H bonds - the weakest C-H bond is attacked
fastest
Typical range of sp3 C-H bonds
CH4
H3C
CH3
Typical free radical substitution mechanism
1. initiation
Br
hν and/or ∆
Br
Br
Br
2 propagation
a. abstraction of H - bromine atom abstracts hydrogen atom from weakest C-H bond fastest (3o > 2o > 1o > methyl).
H
H
Br
H
H
2o > 1o
Br
∆Hrxn depends on
difference in C-H
and H-Br bond
energies.
b. abstraction of Br - carbon free radical abstracts Br from Br2 molecule (very weak bond).
∆Hrxn is always
favorable because
Br
Br
Br-Br bond is so
Br
Br
weak.
3 termination - two free radicals diffuse near one another and quench each other in bond formation.
H
H
H
H
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
45
a. Synthesis of RX compounds from alcohols
1
OH
2
Br
HBr
Use of HX acids (HCl, HBr, HI).
Cl
OH
SOCl 2
3
OH
4
OH
Use of thionyl chloride.
Br
PBr3
a.
Use of phosphorous trichloride
(PCl3, PBr3 or P/I2).
b.
O
S
Cl
O
a.
Na I
OTs
b.
Make tosylate followed by an SN2
reaction (Me, 1o, 2o RX) with a
sodium halide salt
I
N
b. Synthesis of RX compounds from alkenes
5
HBr
a.
6
b.
1. BH3
2. Br2 / CH3O
HX acids (Markovnikov addition)
Br
a.
CH3
b.
H
B
CH3
H
R
Br
R
i. BH3 ii. H2O2/HO
(anti-Markovnikov &
"syn" addition)
2. Synthesis of alcohols
a. Synthesis of alcohol compounds from RX compounds
1
Br
2
Br
NaOH
1. CH3CO2Na
2. NaOH
OH
OH
(via ester)
3
Br
OH
H 2O
SN2 at Me, 1o with NaOH
SN2 at Me, 1o , 2o with CH3CO2Na,
followed by base hydrolysis to form
the alcohol and acetate which is
discarded.
SN1 at 2o, 3o RX with H2O,
possible rearrangements,
reasonable if rearrangement
is not a problem
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
46
b. Synthesis of alcohol compounds from alkenes
OH
1
Mercury bridge of cation intermediate
minimizes rearrangement. Borohydride
reduces mercury off and substitutes
hydrogen on.
1. HgX 2 / H2O
2. NaBH4
2
OH
Aqueous acid forms carbocation
intermediate which can rearrange
H3O+ / H2O
1. O 3 / -78oC
2. NaBH 4
3
4
1. BH3
2. H2O2 / HO
CH3OH
OH
lost in
aqueous
workup
Ozonolysis cuts double bond in
two forming carbonyls and sodium
borohydride workup reduces
carbonyls to alcohols.
Anti-Markovnikov and "syn" addition
of borane, BH3, followed by oxidation
with perioxide to form an alcohol,
OH
c. Synthesis of alcohol compounds from RMgX & RLi organometallics reacted with aldehydes, ketones, esters (twice) and epoxides
(all followed by acid workup)
1. Mg
Organomethallics + aldehydes and
1
2. O
ketones makes 1o (from CH2=O),
Br
2o (from RCH=O) or 3o (from R2C=O)
H
OH
3. WK
alcohols.
1. Mg (2 eqs.)
2. O
2
Organomethallics + esters (react
twice) makes 3o alcohols.
Br
3. WK
OCH3
OH
1. Li
2. O
3
Br
3. WK
OH
Organomethallics + epoxides, SN2-like
reaction at less hindered side of the
epoxide, workup protonates the
alkoxide.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
47
d. Synthesis of alcohol compounds from metal hyrides, LiAlH4 or NaBH4 reacted with aldehydes, ketones, esters and acids (twice &
only with LAH) and epoxides (all followed by acid workup)
1
O
H
2
O
OCH 3
1. NaBH4
2. workup
OH
1. LiAlH4
2. workup
OH
Sodium borohydride (or LAH) +
aldehydes and ketones makes
1o or 2o alcohols after workup.
Only lithium aluminium hydride
works on esters, reacts twice to make
1o alcohols after workup.
(+ CH 3OH, discarded)
3
O
OH
4
O
1. LiAlH4
2. workup
OH
NaBH4 or LiAlH4 + epoxides, SN2-like
reaction at less hindered side of the
epoxide, workup protonates the
alkoxide.
OH
1. NaBH4
2. workup
(R)
Only lithium aluminium hydride
works on esters, reacts twice to make
1o alcohols after workup.
(R)
e. Acid or base hydrolysis of esters forms a carboxylic acid and an alcohol (either or both could be the desired result).
O
1
O
OCH 3
2
1. H2O / HO
2. WK
OH
CH3OH
(discard ?)
O
O
+
H3O / H2O
O
3.
OH
(discard ?)
HO
Base hydrolysis of esters is often
called saponification (soap making)
Acid hydrolysis of esters is the
reverse of Fischer ester synthesis.
Water is added instead of removed.
Synthesis of ethers from alcohols and alkenes
1
2
OH
OH
3
1. NaH
2.
Make an alcohol into a stronger
nucleophile by removing proton
with hydride (strong base). SN2 works
OK at methyl and primary RX centers.
O
Br
conc.
H 2SO4
cold
An SN1 reaction at 2o adn 3o ROH
(could have E1 complications), and
an SN2 reaction at 1o ROH.
O
1. HgX2
OH
2. NaBH 4
O
Markovnikov addition of an alcohol
at an alkene. Rearrangement is
minimized by bridging mercury atom,
which gets reduce off with hydride
(free radical intermediate). Note that
the alcohol used in this reaction could
have been made by a similar procedure
between and alkene and water.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
4. Synthesis of epoxides from alkenes
48
Br
1
1. Br2
H2O
H
OH
First, a halohydrin is made from an
alkene. Products in this example are
enantiomers.
(d / l)
2
H
Br
NaOH
H
O
OH
(d / l)
CH3
H
3
mCPBA
O
H
5.
In a second reaction, the alkoxide is
formed and does an SN2 on the
vicinal bromide to form the epoxide.
Products in this example are
enantiomers.
meta-chloroperoxybenzoic acid
(mCPBA) accomplished the same
transformation in a single step.
The products in this example is
meso (achiral with chiral centers).
Synthesis of alkenes
1
OH
These are E1 conditions.
Rearrangements are possible.
H 2SO4 / ∆
(dehydration)
2
O
K
Br
3
4
5
(major)
This represents our only productive
conditions for E2 at a primary center
and is due to the sterically bulky and
very basic potassium t-butoxide.
Br
NaOH
Strong base/nucleophile and a 3o RX
mean an E2 reaction. Only the more
stable alkene is shown.
O
1. Ph3P=CH2
(from CH3X)
2. WK
Wittig reaction, generally the best bet
to get the exact alkene you are looking
for.
Pd / H2
quinoline
Poisoned Pd catalyst stops at the cis
alkene.
(Lindlar's cat.)
6
Na / NH3(l)
Birch reduction of alkyne mostly
forms E (trans) alkene.
(Birch)
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
7
Beauchamp
49
(Birch)
Birch reduction of aromatic ring puts
two pi bonds opposite one another.
If an electron donating substituent is
present, it will be at one of the sp2
positions.
Pd / H 2
Complete reduction of an alkyne
to an alkane for comparison.
Na / NH3(l)
ROH
8
6.
Synthesis of alkynes
1
1. NaNH 2
Terminal acetylide carbanion works
well at methyl and primary RX.
Br
2.
SN 2
2
Br
Double elimination product (plus loss of
terminal sp C-H under the reaction
conditions. Workup protonates or an
electrophile could be added. The starting
dibromide can be made from an alkene + Br2.
1. excess
NaNH2
2. WK
Br
3
7.
The Zipper reaction moves a triple
bond through any number of CH2's until
the termial position is found, where the
sp C-H is lost, forming the most stable
anion in the pot.
1. excess
NaNH2
2. WK
Synthesis of amines
O
O
1. NaOH
1
N H
O
N
Br
2.
SN 2
O
NaOH
NH2
Gabriel amine synthesis, starts with
phthalimide, removes proton on
nitrogen, does an SN2 reaction on an
RX and hydrolyzes off the two
carbonyl portions to obtain a 1o RNH2.
O
2
N
1o amines
O
3
O
1.
H
4
NH2
2. NaBH 3CN
3. WK
1.
O
H
1o amines
H
Reductive alkylation of imine with
sodium cyanoborohydride to make
o
o
3o amines 2 or 3 amines.
N
H
N
H
2. NaBH 3CN
3. WK
N
3o amines
Reductive alkylation of imine with
sodium cyanoborohydride to make
2o or 3o amines.
H
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
5
O
NH2
Beauchamp
50
1. LiAlH4
2. WK
NH2
LAH reduction of 1o, 2o and 3o amides
makes 1o, 2o and 3o amines.
1. LiAlH4
2. WK
NH2
LAH reduction of nitriles makes
1o amines after workup.
6
C
8.
N
Synthesis of ketones
1
OH
O
CrO3
(no H2O or H2O)
PCC or Jones at 2o ROH.
2
C
N
O
Li
Nitriles + RLi compounds, followed by
hydrolysis form ketones.
2. WK
3
O
H3O+ /Hg+2
H2O
4
5
1. O3, -78o
2. CH3SCH 3
O
(CH 3)2Cu
Cl
6
S
S
1. nBuLi
2. CH3Br
3. WK
1. nBuLi
2. CH3CH2Br
3. WK
S
8
O
2
O
Li
S
7
Hydration of an alkyne. Markovnikov
additon, forms enol, which tautomerizes
to ketone.
S
S
S
Ozonolysis of alkene, DMS workup.
Many other workup conditions are
possible. For best results here, it would
be nice to have a symmentrical alkene.
Cuprates + acid chlorides form
ketones. Cuprates come from
organolithium compounds which
come from RX compounds.
Dithiane alkylation (twice), then
hydrolysis to the carbonyl compound.
If hydrolyzed after one alkylation, then
an aldehyde is obtained.
S
S
O
Hg+2 / H2O
S
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
9
Beauchamp
51
2 eqs.
O
2 eqs.RLi + carboxylic acid, forms a
double alkoxide because of the power
of the organolithium nucleophile, which
hydrolyzes to a ketone in the workup.
O
CH3 Li
OH
2. WK
10
O
O
Friedel Crafts Acylation, makes aromatic
ketones, deactivating substituents inhibit
the reaction. Only reacts one time because
keto group is a deactivating, meta director.
Cl
AlCl3
9.
Synthesis of aldehydes
1
OH
2
N
C
3
O
CrO3
(no H2O)
PCC
H
Nitriles + DIBALH, followed by
hydrolysis form aldehydes.
O
1. DIBAH
-78oC
2. WK
H
hydroboration of an alkyne, then H2O2/HO
O
1. BH3
2. H 2O2./ HO
H
4
5
1. O3, -78o
2. CH3SCH3
O
Cl
6
S
7
2
H
1. DIBAH
-78oC
2. WK
1. nBuLi
2. CH3CH2Br
3. WK
S
O
S
O
H
Cuprates + acid chlorides form
ketones. Cuprates come from
organolithium compounds which
come from RX compounds.
Dithiane alkylation (once) , then
hydrolysis to the carbonyl compound.
An aldehyde is obtained.
S
S
O
Hg
+2
/ H2O
H
S
8
Ozonolysis of alkene, DMS workup.
Many other workup conditions are
possible. For best results here, it would
be nice to have a symmentrical alkene.
O
O
1. DIBAH
-78oC
2. WK
O
H
DIBAH + ester at low temperature
makes aldehydes after hydrolysis.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
52
O
9
C O
HCl
AlCl3
H
Vilsmeier reaction on activated aromatics
(many variations) to make aromatic
aldehydes.
10. Protection of aldehydes and ketones
1
O
N
HO
OH
TsOH (-H2O)
C
N
2
N
3
O
O
C
O
O
O
1. CH3Li
2. mild WK
O
O
O
O
O
O
C
O
Protection of aldehyde or ketone
with ethylene glycol. Acid catalysis
and removal or water forms acetal
or ketal. Carbonyl becomes inert
to many strong nucleophiles that
would otherwise react with it.
Run the desired reaction, an organometallic reaction here. It is possible
to do a mild workup and not hydrolyze
the ketal, or a more vigorous workup,
as in the next frame could deptrotect
the ketal at the same time as the other
reaction is worked up.
+
H 3O / H 2O
11. Synthesis of acids
1
O
OH
2
CrO3
(H2O)
i. O 3 / -78oC
ii. H2O2 /HO
3
C
N
4
C
5
N
O
H2SO4
H2O / ∆
1. H 2O/HO
∆
2. WK
aqueous
acid or base
OR
OH
2
O
OH
O
Jones conditions oxidize 1o ROH to
carboxylic acids and 2o ROH to
ketones.
Ozonolsis with oxidative workup,
using H2O2, forms acid if alkene
carbon has a hydrogen and ketones
if alkene carbon is geminally
disubstituted.
Full acid hydrolysis of a nitrile.
OH
O
Full base hydrolysis of a nitrile.
OH
O
Aqueous hydrolyisis of acid derivatives.
OH
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
6
O
O
O
53
O
aqueous
acid or base
Cl
7
Beauchamp
Aqueous hydrolyisis of acid derivatives.
OH
O
aqueous
acid or base
8
O
O
H2SO4
H2O / ∆
NH2
9
Full acid hydrolysis of a amide.
OH
1. Mg
2. CO2
3. WK
Br
Aqueous hydrolyisis of acid derivatives.
OH
O
Grignard reagent reacted with carbon
dioxide, then workup.
O
OH
12. Synthesis of acid chlorides
1
O
OH
A few ways to make an acid chloride
from a carboxylic acid: thionl chloride,
oxalyl chloride and phosphorous
trichloride.
O
SOCl 2
Cl
thionyl chloride
O
2
O
Cl
OH
O
Cl
O
Cl
oxalyl chloride
3
O
O
PCl3
OH
Cl
phosphorous trichloride
13. Synthesis of anhydrides
O
O
1
O
OH
O
O
O
2
O
O
OH
Cl
O
O
A couple ways to make an
unsymmetrical anhydride from
a carboxylic acid and either
another anhydride or an acid
chloride.
O
O
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
14. Synthesis of esters
1
Beauchamp
54
1. NaOH
2. Br
O
O
OH
2
O
O
OH
O
TsOH
(-H2O)
OH
3
O
OH
O
O
O
O
5
O
O
A tertiary amine is sometimes used
to make the reaction work faster and
better.
O
OH
Fischer ester synthesis, acid catalysis
and remove water to from ester. Use
opposite conditions to hydrolyze ester
(acid catalysis and lots of water).
A tertiary amine is sometimes used
to make the reaction work faster and
better.
O
Cl
4
Make a good carboxylate nucleophile
then ract with a methyl, 1o or 2o RX
compound.
O
O
Cl
O
O
O
O
Another use of mCPBA is to oxidize
ketones to esters. Called the
Baeyer Villegar Rxn.
NH2
Milder conditions hydrolyze nitriles
to amides, harsher conditions
hydrolyze nitriles to carboxylic acids.
H
mCPBA
15. Synthesis of amides
1
C
2
N
O
HCl
H2O
Acid chlorides + ammonia, 1o or 2o
amines makes 1o, 2o or 3o amides.
O
O
Cl
NH3
NH2
O
3
N
Anhydrides + ammonia, 1o or 2o
amines makes 1o, 2o or 3o amides.
N
Anhydrides + ammonia, 1o or 2o
amines makes 1o, 2o or 3o amides.
O
N
Cl
4
H
O
O
O
O
N
H
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
16. Synthesis of nitriles
1
Beauchamp
Br
55
Na
N
C
SN2 reactions of cyanide with
methyl, 1o or 2o RX compounds
N C
2
O
SOCl 2
NH2
C
N
Dehydration of primary amide with
thionyl chloride.
(-H2O)
17. Enamine Chemistry
1
Start with carbonyl, make enamine,
alkylate enamine, hydrolyze back
to carbonyl compound with extra
R group added (methyl, allyl or
benzyl in our course).
N H
O
N
pH = 5
(-H2O)
Hydrolyze alkylation product
via this intermediate
2
1.
N
Br
O
2. WK = aq. hydrolysis
H 2O
N
18. Synthesis of β-hydroxycarbonyl and α,β-unsaturated carbonyl
O
1
α
O
H
O
H
Na RO
β OH
β-hydroxy carbonyl
H
O
2
O
α
α
H
H
β OH
acid. hydrolysis
H3O+ / H2O / ∆
β
α,β-unsatruated carbonyl
Aldol reaction of two carbonyls,
usually the same one. Base is used to
make an enolate which then attacks
another carbonyl to form a β-hydroxy
carbonyl structure that can be isolated
or dehydrated to an α,β-unsatruated
carbonyl shown in the next frame. this
often done with acid, but in this book
we will indicate the next step with the
symbol for heat, ∆.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
Beauchamp
19. Malonic ester synthesis (produces mono and di- substituted acetic acids)
1
O
1. CH3CH2O
2.
Br
O
O
O
O
O
O
O
O
O
H3O+ / H2O
(-CO2)
product from 1
O
O
3. WK
O
2
OH
monoalkylated acetic acid
O
3
O
O
product from 1
O
4
O
1. CH3CH2O
2.
Br
O
O
O
O
56
Malonic ester synthesis. Remove
acidic proton with alkoxide base
then alkylate with electrophile
(RX, epoxide or another carbonyl).
Can hydrolyze ester at this point,
decarboxylate (-CO2) to obtain a
monoalkylated ethanoic acid
(acetic acid), or repeat the reaction
a second time and then decarboxylate
to obtain a dialkylated ethanoic acid
(acetic acid). It's also possible to do
similar chemistry by using the dianion
of ethanoic acid or using a simple
ethanoate ester and LDA to generate
the ester enolate and perform an
alkylation at low temperature (-78oC)
3. WK
O
O
O
O
H3O+ / H2O
(-CO2)
OH
dialkylated acetic acid
product from 3
20. Ethyl acetoacetate synthesis (produces mono and di- substituted acetones)
1
O
O
O
O
1. CH3CH2O
2.
Br
O
O
3. WK
O
O
2
O
+
H 3O / H 2O
(-CO2)
O
product from 1
O
monoalkylated acetone
O
1. CH3CH2O
2.
Br
3
O
product from 1
O
O
O
Acetoacetic ester synthesis. Remove
acidic proton with alkoxide base
then alkylate with electrophile
(RX, epoxide or another carbonyl).
Can hydrolyze ester at this point,
decarboxylate (-CO2) to obtain a
monoalkylated 2-propanone (acetone),
or repeat the reaction a second time
and then decarboxylate to obtain a
dialkylated 2-propanone (acetone).
It's also possible to do similar
chemistry by using a simple
ketone and LDA to generate
the ketone enolate and perform an
alkylation at low temperature (-78oC)
O
3. WK
O
O
4
O
product from 3
H3O+ / H2O
(-CO2)
dialkylated acetone
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
21. Cuprate chemistry
Beauchamp
57
1
Br
Organolithium reagents come
from RX compounds + Li metal.
Li
Li
RX compound
organolithium reagent
Cu
Cuprates are prepared from organolithium reagents + CuBr (cuprous
salt) in a 2 to 1 ratio.
Li
organocuprate
There are three choices for a cuprate
in our course.
2
Li
0.5 eq CuBr
O
3
4
Cu
α
Li
organocuprate
β
α,β-unsaturate
carbonyl
Cu
2. Cuprate coupling reaction with an
RX compound. Remember the cuprate
comes from an organolithium, which
comes from another RX compound. It
hard to tell which bond was formed
and in what direction the atoms were
used because there are a lot of possibilities
Br
Li
organocuprate
5
1. conjugate addition to an
α,β-unsaturate carbonyl
O
RX compound
O
Cu
3. Cuprate substitution of chlorine in
an acid chloride to make a ketone.
There are two possible ways you could
consider joining the acid chloride and
cuprate.
O
Cl
Li
organocuprate
acid chloride
22. Conjugate addition – stable anions often add at the C-β carbon
O
O
O
O
Na
N C
O
O
H3O+ / H2O
(-CO2)
O
C
O
N
23. Dithiane Chemistry – see aldehydes and ketones above
1
S
S
2
1. nBuLi
2. CH3CH2Br
3. WK
S
Dithiane alkylation (once) , then
hydrolysis to the carbonyl compound.
An aldehyde is obtained.
S
S
O
Hg
+2
/ H2O
H
S
3
S
S
1. nBuLi
2. CH3Br
3. WK
S
S
Dithiane alkylation (twice), then
hydrolysis to the carbonyl compound.
If hydrolyzed after one alkylation, then
an aldehyde is obtained.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
4
Beauchamp
58
1. nBuLi
2. CH3CH 2Br
3. WK
S
S
S
S
S
5
O
Hg+2 / H2O
S
24. Dianion Chemistry
1
O
O
O
O
1. NaH or LDA
2. nBuLi
O
O
O
O
O
2
O
O
Br
O
workup
O
O
O
3
O
O
O
O
O
4
O
5
O
H3O+ / H2O
(-CO2)
O
1. NaOH
2. LDA
O
O
OH
7
A second alkylation can be
performed using the normal ethyl
acetoacetate synthesis, alcylating
the position in between the two
carbonyl groups. After ester
hydrolysis and decarboxylation
a disubstituted acetone is obtained
with a alkylation on both sides
of the carbonyl.
O
O
CH3Br
O
O
1.
O
2. workup
Br
The reaction can be run once,
worked up and decarboxylated
(shown in the next frame). In
this case the same product could
have been obtained using the
normal ethyl acetoacetate synthesis.
The same product as using the
normal ethyl acetoacetate synthesis.
O
O
O
6
O
1.
2.
O
O
H3O+ / H2O
(-CO2)
To make dianion requires very strong
bases. To simplify our reaction we will
write 2 eqs of LDA to show formation
of dianion. The second acidic site is the
more reactive site in the alkylation.
OH
Dianions from carboxylic acid can
be formed using a strong, nonnucleophilic base for the Cα-H
position. The carbanionic site is the
more reactive site and alkylation
occurs there. The product will be an
alkylated carboxylic acid, which
can be esterified by making the
carboxylate and doing an SN2 on
an RX compound, as discussed
earlier.
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc
Organic Reaction Guide
59
O
O
8
Beauchamp
1. NaOH
OH
OH
Br
2.
25. Robinson Annelation
1
O
O
O
O
O
O
HO
O
2
O
i. Base makes enolate
O
O
O
O
ii. conjugate addition to
α,ß-unsaturated carbonyl
O
O
2. workup
O
OH
2
O
3
3
O
4
3
O
6
5
HO
6
O
4
O
1
5
iii. aldol condensation (-H2O),
1,6 atoms join together
1
O
2
O
O
β-hydroxycarbonyl
(aldol product)
OH
4
-H2O
O
O
O
β-hydroxycarbonyl
5
α,β-unsaturatedcarbonyl
O
O
H3O
O
O
O
α,β-unsaturatedcarbonyl
6
-H2O
∆
HO
O
O
- CO2 followed by
tautomerization of enol
HO
O
O
O
If ester group is hydrolyzed
the acid will decarboxylate
(-CO2) forming a cyclic ketone.
(annelation = ring forming)
O
C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc