¯-OH Good Nuc¯, Strong Base
Converts R-L to R-OH for 1° and activated 2° R-L
SN2 conditions, normal 2° R-L leads to E2
(use synth. eq. acetate)
¯-OR Good Nuc¯, Strong Base
Converts R-L to R-OR for 1° and activated 2° R-L
SN2 conditions, normal 2° R-L leads to
E2. Known as Williamson Ether Synthesis
CH3CO2¯ Fair Nuc¯, Weak Base
Is a synth. eq. for ¯OH (unmasked with KOH/H2O)
SN2 conditions, will work fine for any 1°
or 2° R-L
Na (also Na•) Sodium metal acts as a base,
removing H+ from ROH to create RO¯ (alkoxide)
Harsh conditions that require p/p alcohol as the solvent (the CA of RO¯)
K2CO3 Weak base used to
deprotonate (remove H+) from
phenols
Will not work for normal alcohols, only phenols
H2SO4 Strong acid which can
protonate alcohols, allowing SN1 ether formation
The CB of H2SO4 is not a Nuc¯ or a
strong base
RCO2- Fair Nuc¯, Weak Base (E2
competition minimized)
SN2 conditions, will work well for 1° and
any/all 2° R-L
HBr, HI Strong acids which convert OH
into X (Br or I)
Can be used on 1° (SN2), or 2° and 3°
(both SN1) alcohols
HCl Strong acid which converts OH
into Cl
Can be used only on 3° alcohols. Must add ZnCl2 for 1° or 2° ROH
SOCl2 Converts OH into Cl All three work well for 1° and 2° alcohol
conversion. If 3° ROH, H-X is the best reagent.
PBr3 Converts OH into Br
PI3 Converts OH into I
Converts a leaving group into an NH2. This reagent is a
synthetic equivalent for NH3,
used to make 1° amines.
Known as the Gabriel Synthesis. Avoids the problem of multiple alkylations.
LiAlH4 Gives an ‘H¯’ which replaces a
leaving group with H
Very reactive, cannot be used around water or alcohols
NaBH4 Gives an ‘H¯’ which replaces a
leaving group with H
Less reactive, compatible with water or alcohols
¯-CN Fair nucleophile, weak base S
N2 reagent, works well with both 1° and
2° R-L ¯-C=C—H
Acetylide
Good nucleophile, strong base SN2 reagent, works with 1° only, if 2°, E2
is the major product
NaNH2 or ¯-NH2 Very strong base Can remove H from R--C=C--H
¯SR or Ph3P Fair nucleophiles, weak bases SN2 reagents, works well with both 1°
and 2° R-L
HBr or HI Strong acids that cleave ethers 1° (SN2) and 2° & 3° (SN1)
¯-OH or ¯-OR Strong bases, Good Nuc¯ Lead to S
N2 when 1° or 2° (aprotic); but
E2 when 2° (p/p solvent) or 3° (regardless of solvent)
t-BuO-¯ or LDA Sterically hindered base Poor Nuc, leads to E2 for 1°, 2°, 3°
(Hofmann product) ¯-OH, or NaNH∆
2 Very strong basic conditions Used to prepare alkynes (E2 twice)
H2SO4, or H∆ 3PO4, ∆ Dehydration reaction E1 mechanism (Zaitsev product), Watch
out for rearrangements Na2Cr2O7
K2Cr2O7 in H2SO4
CrO3
H2CrO4 (Jones Reagent)
KMnO4 (often hot with H+ or OH-)
1° ROH --> carboxylic acid 2° ROH --> ketone
Strong Oxidizing Agent
1° ROH --> aldehyde 2° ROH --> ketone
Ag2O aldehyde-->carboxylic acid Incompetent Oxidizing Agent
NaOCl Only does 2° ROH --> ketone Environmentally friendly Oxidizing Agent
HF, HCl, HBr, or HI Acids that add H-X to alkenes
(or alkynes)
Markovnikov addition via carbocation, so watch out for rearrangements!
H2O with H2SO4 Adds H2O to alkenes to yield
alcohols (hydration)
Markovnikov addition via carbocation, so watch out for rearrangements!
Cl2 or Br2 Halogens that add X2 to
alkenes (or alkynes)
Use inert solvents; Follows the borderline SN2 mechanism, results in
anti addition
Br2/H2O or Cl2/H2O Adds 1 X and 1 OH to a C=C
(produces a product called a halohydrin)
Anti addition (inversion) occurs through the bromonium (or chloronium) ion, the water attacks 3°>2°>1° (borderline SN2)
1) Hg(O2CCH3)2,
H2O
2) NaBH4, NaOH
Adds H and OH to a C=C Markovnikov addition, with NO
rearrangements H2O, H2SO4, Hg2+(often
HgSO4 or HgO)
Adds H and OH to an alkyne--> results in the formation of a ketone
Markovnikov addition, an enol initially is formed, but spontaneously tautomerizes to the keto form as the product
1) BH3, THF
2) H2O2, NaOH
Adds an H and OH to alkenes or ‘internal’ alkynes
Anti-Markovnikov addition, with syn
(same side) addition; watch out for enol-keto tautomerization with the ‘internal’ alkynes
1) disiamylborane
2)
H2O2, NaOHAdds H and OH to a terminal alkyne --> results in the final formation of an aldehyde
Anti-Markovnikov addition, the enol
forms first, then tautomerizes the keto form (forms aldehyde)
Cu2+
CH2N2 --->
or or hv∆
Adds a CH2 (carbene) to a
C=C --> forms a cyclopropane
Adds with syn addition, which is important when product is chiral Ch2I2 with Zn(Cu) alloy Adds a CH2 (carbene) to a
C=C --> forms a cyclopropane
Simmons-Smith reaction; adds with syn addition
CHX3 with strong bases Adds a CX2 (carbene) to a
C=C --> forms a cyclopropane
Adds with syn addition; make sure to add CX2, NOT CH2
RCO3H or MCPBA Adds the 3rd (extra) oxygen to
a C=C --> forms an epoxide
Adds with syn addition, which is important when product is chiral 1) OsO4
KMnO4
---> or ---> 2)Na2SO3 H2O
NaOH
Adds 1 OH group to each carbon of a C=C --> forms diol
Addition occurs with syn (same side) addition
1) O3
---> 2) (CH3)2S
Breaks a C=C, adds a =O to each carbon, called ozonolysis
Understand the retrosynthetic technique to know what alkene underwent
ozonolysis (turn the two C=O back into a C=C)
H2
---> Pd, or Pt
Breaks a C=C, adds an H to each carbon (will convert alkynes to alkanes when > moles of H2 are used)
Under normal conditions, H2 does not
add to C=C in a phenyl (aromatic) ring. Addition is primarily syn
H2
--->
Lindlar Catalyst
Adds only one H to each carbon of a C=C (alkyne), converting it to an cis-alkene
Addition is syn, giving a cis-alkene. Without a Lindlar catalyst, the reaction cannot stop at the alkene
HNO3 + H2SO4
(Nitration)
Substitutes -NO2 on aromatic
rings
No limitations; heat reaction or use more vigorous conditions to get disubstituted product O || CH3CCl ---> pyridine
Protects amines (and alcohols) Remove group with KOH/H2O
Br2 or Cl2 + Lewis Acid
(AlX3, FeX3)
(Halogenation)
Substitutes -Br or -Cl on aromatic rings
Requires Lewis acid unless ring is strongly activated (e.g. phenol and aniline, in which case, beware of disubstitution)
H2SO4
(Sulfonation)
Substitutes -SO3H on aromatic
rings (mainly para if already substituted
Reaction is reversible, heat in the presence of H2SO4 and H2O remove the
R-Cl ---> AlCl3
Carbocation (usually formed by alkyl chloride - AlCl3 or alcohol losing
water when acid is added)
Friedel-Crafts Alkylation
Substitutes an (-R) on an aromatic ring
1. Product of alkylation is more
reactive than starting material, often leading to disubstitution.
2. Rings with moderately or
strongly deactivating groups will not
undergo alkylation
3. Watch out for carbocation
rearrangements O || R--C--Cl ---> AlCl3
Acyl cation (usually formed by acetyl chloride + AlCl3) Friedel-Crafts Acylation Substitutes a / O=C \R on an aromatic ring
1. Very sensitive to sterics, major product is always para
2.
Rings with moderately orstrongly deactivating groups will not
undergo alkylation
NaNO2/H+ Converts NH2 to N2, which can
be replaced by nucleophile
N2 is a good leaving group and can be
Nucleophile + aromatic halide (Nucleophilic Aromatic Substitution: Addition-Elimination)
Nucleophile replaces halide in a 2-step process; Nuc¯ attacks, and then halide leaves
The ring must have an electron
withdrawing group o- or p- to the halide. Leaving group ability:
F > Cl > Br > I Very strong base (e.g.
NaNH2) or base and high
heat (NaOH, ) ∆ (Nucleophilic Aromatic Substitution: Elimination-Addition)
Eliminates H-X on an aromatic ring, creating a reactive benzyne intermediate which then is attacked by anion
Results in 2 different products if the ring is asymmetric because both carbons of the intermediate alkyne will be attacked.
H2/metal catalyst or Metal
(Fe, Sn, SnCl2) + HCl
Converts NO2 --> NH2 Important synthetic step as a diazonium
Clemmensen: Zn(Hg) + HCl or
Wolf-Kishner: NH2NH2 +
KOH, or H∆ 2/metal
catalyst
Converts C=O --> CH2 H2/metal catalyst will work only if the
C=O is attached directly to the aromatic ring
1)KMnO4, NaOH, ∆
2) H3O+
Converts an R on an aromatic ring --> CO2H
Reaction will not work if the substituent C is quaternary (4°)
-[CN]
HCN ---> H2O
Adds a CN to the C and an H to the O of a C=O, forming a cyanohydrin
Only catalytic amounts of -CN are needed; follows the basic mechanism
Mg or Li Converts a R-X into a R-M;
which acts like a
R-X=Cl, Br, I; solvent must be aprotic, usually ether or THF is used
NH4Cl A weak acid (H+ donor) used to
protonate the Td of carbonyl
addition reactions
Avoids the E1 result for 3˚ alcohols
+ Ph3P--CR2
Ylide attacks C=O, resulting in its eventual conversion to C=C (P loves O!)
Witting reaction; BuLi is usually the base used to make the ylide from its
phosphonium salt precursor
NR2 N attacks C=O, resulting in its
final conversion to C=N
1° amines --> imines NH2OH --> oximes
2° amines --> enamines
H2/metal or NaBH3CN C=N reacts more easily than
C=O, allowing conversion of imines to amines
Either reagent can be used in the initial reaction mixture, so the imine is never isolated
LiAlH4 Reacts with all C=O
compounds from table 19.1
Has 4 H- available, converts C=O to CH 2
-OH (except for ketones)
NaBH4 Reacts only with ketones and
higher on table 19.1
Has 4 H- available, can use in presence of H2O, ROH, etc.
LiAlH(Ot-Bu)3 Converts acyl chlorides to
aldehydes at -78˚ C
Doesn’t over-reduce to R-OH Diisobutylaluminum
hydride (DIBAH)
Converts esters to aldehydes at -78˚ C
2 mol Grignard + acyl chloride, anhydride, or ester
Reacts twice (cannot stop at ketone) to yield alcohol.
Use NH4Cl as workup acid to avoid E1
elimination if 3˚ ROH
(R)2CuLi Adds only 1 R group to an acyl
chloride, yielding a ketone.
Same reagent that gave conjugate addition (Sec. 18.10)
Grignard + nitrile Grignard adds to the nitrile
once, and the resulting imine is hydrolyzed back to a ketone by H3O+.
Hydrolysis is exact reverse of imine formation (Fig. 18.3)
TsCl or MsCl Converts -OH into -OTs or
-OMs, which are much better leaving groups.
Reaction proceeds just like acyl chlorides, but attack is at S
X2 w/ acid a-halogenation of aldehydes or
ketones
reaction useful for adding only 1 halogen
x2 w/ base a-halogenation of aldehydes or
ketones
Excess (>3 mol) of X2 will convert methyl groups a to the carbonyl to carboxylates (haloform/iodoform reaction)
BuLi Strongest base pKa = 50 Also acts like a nucleophile, so must
avoid using when C=O present
LDA, NaNH2, NaH Very strong bases
pKa=35-38
Used to deprotonate H’s a to the C=O. LDA is used most often because it is totally non-nucleophilic (steric hindrance) NaOR
NaOH
Moderate bases pKa~16
Can be used to completely deprotonate 1,3-dicarbonyl compounds
Both reagents attack R-X as Nuc- in typical Sn2 reactions. The final step involves loss of CO2 gas via a 6-member transition state (make & break bonds around the ring). The enol which results
then tautomerizes to the more stable keto form
1,3-dithiane attacks R-X in typical SN2 reactions or C=O carbonyl reactions. The dithiane ring can be removed (regenerating the C=O by adding Hg2+ in H2O
Carboxylates are oxidized at the anode, resulting in a fragmentation reaction where CO2 is lost
Known as Kolbe electrolysis. Because a high concentration of Ro forms at the anode, the coupling reaction is
prevalent, resulting in a new R-R bond. Replaces H with a Br at the
location of the most stable radical.
Cl2 is too reactive (not selective enough) to be synthetically useful.
Known as NBS. Replaces H with a Br at the location of the most stable radical.
NBS is especially useful when
attempting to brominate allylic systems because it will not add (addition reaction) to the C=C
Replaces X with H
Autoxidation - adds an OOH group to the most stable radical position
Not often synthetically useful, but important in food spoilage and chemical decomposition
Anti-markovnikov addition of HBr to a C=C
HF, HCl, HI do NOT work well. Anti-markovnikov regio-chemistry is followed because a more stable radical is formed Each group adds to one side
of the C=C. The larger group (boxed) adds first, the smaller group adds second and goes to the carbon which would have the more stable radical.
Reduces benzene into 1,4-butadiene (not conjugated), or reduces the C=C of an a,B-unsaturated carbonyl, or reduces an alkyne into a trans-alkene
Known as Birch reduction. Also useful in alkylating a to the carbonyl in a,B-unsaturated carbonyl systems.
