1
Acid catalyzed reactions you should be able to write arrow-pushing mechanisms for.
O
H
H
O
O
S
O
O
O
H
O
O
S
H
H2SO4 / H2O
(-H2O)
H
O
S
H
OH
O
O
R
R
OTs
O
O
OH
O
OH
(-H2O)
(-H2O)
∆
R
OTs
OH
R
R
OH
R
HO
(-H2O)
OH
O
O
H
O
O
∆
HO
(both ways)
R
R
(-H2O)
∆
H3C
H2SO4
H2O
OH
H
O
OTs
H
H2SO4
H2O
O
OH
O
O
H3C
H2SO4
CH3OH
H2SO4
H2O
(THP)
O
H2SO4 / H2O
O
OH
H2SO4
H2O
O
OH
OH
OH
O
O
H2SO4
H2O
H
CH3
H
OH
OTs
O
H3C
H
OH
O
H
O
O
H2SO4
H2O
H
O
H2SO4
H2O
C
OH
(both ways)
H2N
OH
R
O
pH≈ 5
H
OTs
(-H2O)
O
R
N
imines
R
O
CH3
O
H2SO4 / H2O
OH
NH2
H2SO4
H2O
O
H
OTs
(-H2O)
O
H
OTs
O
N
O
CH3
R
H2SO4 / H2O
O
R H
ketones &
aldehydes
R = C or H
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N
pH≈ 5
H
OTs
(-H2O)
pyrrolidine
H2SO4 / H2O
N
R
enamines
2
Examples of acyl substitution reactions, you should be able to write arrow-pushing mechanisms for.
O
O
O
O
O
O
OH
Cl
N
O
O
O
O
N
H
O
O
SH
Cl
O
S
O
O
O
O
AlCl3
Rriedel-Crafts
reactions
OH
Cl
H
O
O
O
O
H
R
OH
O
N
Cl
H
H Li
R
N
H
Al
H
O
O
H
O
Li
R
Cl
(cuprates)
O
R 1.
O
H (DIBAH)
H (DIBAH)
H
2. WK
O
O
O
O
Cl
O
H
2. WK
H
very slow reaction
Al
Al
Cl
H
Na
H
O
O
1.
B
O
Cu
O
N
H
R
H
N
O
H
O
undesired
side rxn.
2 eqs.
O
1.
O
R
O
O
Li
OH
R
2. WK
R
(Grignard reagents too)
Cl
O
AlCl3
Rriedel-Crafts
reactions
O
R
O
O
O
1. H
2. WK
Na
R
O
R
O
OH
O
HO
OH
HO
O
O
N
O
1. H
2. WK
Na
O
HN
OH
Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc
3
Reaction Mechanism Worksheet Guidelines
1. Factors to consider when looking at reactants, reaction intermediates and product(s).
a. Are there any resonance effects?
b. Are there any inductive effects?
c. Are there any steric effects?
d. Are there any stereochemical considerations?
2. Where are the pairs of electrons that can be donated? (nucleophilic sites)
3. Which site(s) can accept a pair of electrons? (electrophilic sites)
4. Is the reaction in acid? (A Lewis or Bronsted acid = E+ = strong, the acidity drives the reaction)
a. Usually use a strong acid to supply protons, often the strong acid is the protonated solvent. (ROH2+),
(nonproton Lewis acids can also be species with an empty valency such as BH3, BF3, AlCl3, FeBr3, TiCl4, SbF5,
etc. which all complex very well with lone pairs.)
b. There are no strong electron pair donors in strong acid (bases or nucleophiles are weak). Often the weak
base or leaving group is the neutral solvent. (ROH)
5. Is the reaction in base? (The strong base/nucleophile drives the reaction.)
a. Usually use a weak acid to supply protons, usually the neutral solvent, (ROH), or other neutral molecule of
similar acidity.
b. Usually an anion (often the conjugate base of the solvent) acts as the strong nucleophile, strong base or good
leaving group (RO --)
6. Are free radicals or one electron transfers involved? Often a photon or neutral (or reduced) metallic compound
is part of the reaction. Oxygen or a peroxide can also serve as a free radical initiator.
In mechanism problems of our course include the following.
1. Show all lone pairs of electrons
2. Show all formal charge, when present
3. When resonance is a factor in the stability of an intermediate, draw at least one additional resonance
structure, including the “best” resonance structure.
4. Show all curved arrows to show the flow of electrons (full headed arrow = 2 electron movement)
5. Any free radical centers if present (half headed/fish hook arrow = 1 electron movement)
Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc
4
Mechanism for “Fischer” synthesis of ester - Has catalytic toluene sulfonic acid with removal of water to shift
equilibrium to right.
tosylsulfonic acid = TsO-H
H
OHTs
H
OTs
O
H
O
H
O
O
O
H
H
H
H
O
H
H
O
O
O
H
H
O
O
H
H
O
H
O
O
H
H
R
H
O
H
O
H
H
O
O
O
H
O
O
O
O
H
H
R
H
O
O
O
O
O
R
H
H
O
O
O
Mechanism for hydrolysis of ester in acid - Has catalytic sulfuric acid in large excess of water to shift equilibrium to
the right.
H2SO4 : aqueous sulfuric
acid (and lots of water)
O
ester
OSO3H
H
H
O
OSO3H
O
O
O
O
H
H
O
O
H
H
O
O
alcohol
H
O
H
H
O
H
H
O
H
H
O
H
O
H
O
O
O
O
O
H
O
H
O
H
H
O
H
O
O
H
O
H
O
H
O
H
O
H
H
O
carboxylic acid
Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc
H
H
5
Mechanism for hydrolysis of ester in base (also called saponification) – Aqueous sodium hydroxide (NaOH).
H
ester
O
O
H
O
H
O
O
O
O
O
O
2. workup
O
O
H
H
O
H
H
O
H
O
H
H
O
carboxylic acid
alcohol
O
Protecting Aldehydes and Ketones as acetals and ketals with ethylene glycol (…and deprotection)
Possible mechanism for synthesis of ketal - Catalytic toluene sulfonic acid with removal of water to shift equilibrium
to right.
O
ketone
H
H remove H2O
H
O
OTs
O
H
ethylene glycol
OHTs
H
H
H
OH
H
O
O
H
O
TsO
H
O
O
H
H
O
O
R
H
HO
O
O
O
hemiketal
HO
HO
OH
HO
H
O
O
O
O
O
R
H
Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc
O
ketal
6
Possible mechanism for hydrolysis of ketal or acetal = addition of water with catalytic amount of sulfuric acid.
H
O
H
OH
O
O
O
OH
OH
O
O
ketal
H
H
O
H2O
(water added)
H
OH
H2O
H
H
O
O
OH
O
O
OH
H
H
H
H
O
O
O
OH
H
O
H
O
H2O
O
ketone
OH
ethylene glycol
Imine Formation from Aldehyde or Ketone Reaction with Primary Amines R-NH2 derivatives (primary
amines and hydrazine)
1. Follow by reduction with sodium cyanoborohydride (NaH3BCN) to form 1o, 2o and 3o amines, or
Step 1 - making an imine
acid cat. = TsOH
(remove water)
H
O
H
N
H
O
H
N
primary amine
OTs
OTs
H
H
carbonyl group
OTs
O
N
H
H
H2O (remove)
H
H
O
H
O
H
N
N
N
imine
H
Step 2 - reducing an imine to an amine with sodium cyanoborohydride
Na
N
imine
H
H2BCN
H
B
H
CN
H
O
N
H
sodium cyanoborohydride
(reduces imines to amines)
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H
R
N
secondary amine
OTs
7
Possible Hydrolysis Mechanism of an imine (if not reduced to an amine) = addition of water with catalytic
amount of sulfuric acid.
H
H
N
H
H
OH2
N
N
N
O
imine
H
H2O
primary amine
H
H
O
O
O
H
H
H2O
H
N
H
N
H
N
H
H
O
carbonyl group
OH2
O
H
H
Possible Mechanism for reaction of hydrazine H2NNH2 with aldehydes and ketones in strong base leading to
reduction to a methylene group (CH2) = Wolff Kishner Reduction.
H
O
H
R
O
O
N
O
H
H
carbonyl group
O
NH2
N
primary amine
N
NH2
H
H
H
H
O
NH2
H
H
O
O
O
R
N
N
N
H
N
H
N
H
H
R
H
O
H
N
H
H
H
O
H
O
N
H
R
N
N
N
N
H
N
H
H
R
H
H
H
N
N
H
O
N
H
N
O
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R
R
8
Possible Enamine Mechanism – Secondary amine plus carbonyl compound with removal of water (we’ll always
use pyrrolidine).
acid cat. = TsOH
(remove water)
H
O
H
OTs
H
O
N
O
OR
H
H
N
N
carbonyl group
pyrrolidine
H
(remove water)
H
H
O
H
O
O
H
H
N
N
N
enamine
Possible Mechanism of Enamine with an Electrophile, (allyl bromide used in this example), Followed by
hydrolysis of imminium ion back to a carbonyl compound.
H2O
O
N
N
N
H
H
N
H
O
H
H
H
Br
enamine
O
H
H
NHR2
O
H
H
NHR2
N
O
N
H
alkylated
ketone
resonance
Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc
OH2
O
H
9
Wittig Reaction (pronounce “Vittig”)
1. Form Wittig salt with triphenylphosphine SN2 reaction on an RX compound.
2. Use a strong base to remove a proton from the carbon alpha to the phosphorous atom and
3. Add a carbonyl compound (aldehyde or ketone) which undergoes an addition / elimination reaction
to alkenes (we’ll assume usually Z stereochemistry).
Possible Mechanistic steps for preparation and reaction of a Wittig reagent.
1. Make the Wittig salt.
Ph
Ph
Ph
P
Ph
Br
SN2 reaction
Ph
P
Ph
RX compound
triphenylphosphine
Br
Wittig salt
2. Make the ylid.
Ph
Br
Ph
H
P
C
Ph
Li
Ph
Ph
H
CH2
CH3
Ph
acid/base
proton transfer
Ph
n-butyl lithium
Wittig salt
P
C
H
Ph
CH3
P
H
C
Ph
CH3
ylid and its resonance structure
3. React the ylid with a carbonyl compound.
O
Ph
Ph
P
C
H
H
H3C
dipolar ylid
CH3
Aldehydes and
ketones react.
Ph3P
O
C
H
Ph
Ph3P
C
C
H
H3C
H
H2C
CH3
intermediate
"betaine"
Ph
Ph
C
H
H2C
O
Ph
triphenylphosphine
oxide
CH3
intermediate
"oxaphosphatane"
H
P
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O
H
C
H3C
C
H2C
Usually the Z alkene
is the major product.
CH3
10
Nucleophilic hydride reactions: with organic electrophiles such as: aldehydes, ketones, esters, epoxides,
nitriles and RX compounds.
Common forms of nucleophilic hydride used in this course. (Remember NaH is always basic in our course.)
A
H
H
Li
Al
H
H
H
Na
B
H
H
H
H
Na
B
C
H
N
H
Sodium borohydride, NaBH4 (somewhat
reactive, reduces aldehydes, ketones,
epoxides, and RX compounds)
Lithium aluminium hydride, LiAlH4,
(LAH, very reactive, reduces many
functional groups in our course, including
aldehydes, ketones, esters, epoxides,
nitriles and RX compounds.)
H
Sodium cyanoborohydride, NaBH3CN
(used to reduce imines to amines in a
reaction similar to the reduction of
aldehydes by sodium borohydride).
Diisobutylaluminiumhydride,
DIBAH (or DIBAL), used to
diliver a single hydride to esters,
nitriles and acid chlorides which
become aldehydes after the workup
hydrolysis step. This hydride is
different from the others in that it is
neutral and only has a single
hydride nucleophile.
Hydride nucleophiles (e- pair donors) + organic electrophiles (e- pair acceptors), WK = work up = acidic
neutralization (electrophilic “hydrogen”).
a. formaldehyde (methanal) = reduced to methanol
H
H
Al
Li
H
H
H
2. workup
H
C
O
H
H
H
Li
C
O
H
H
NaBH4 works too.
H
OH2
C
O
H
H
b. general aldehydes = reduced to primary alcohols (like an ester or carboxylic acid with LAH)
H
H
Al
Li
H
H
H
2. workup
H
C
O
H
R
H
Li
C
O
H
R
NaBH4 works too.
H
OH2
C
O
H
R
primary alcohols
d. general ketones = reduced to secondary alcohols
H
H
B
Li
Li
R
2. workup
H
H
R
R
C
R
O
H
C
R
LiAlH4 works too.
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O
H
H
OH2
C
O
R
secondary alcohols
H
11
e. general esters = reduced to primary alcohols only with LAH (like the aldehyde or a carboxylic acid)
H
H
R
Li
Al
C
H
Li
R
O
H
C
R
R
O
C
H
O
C
O
O
H
H
O
R
H3Al
R
H
H
O
2. workup
R
H
OH2
R
Two equivalents of nucleophilic hydride add to the ester carbonyl carbon.
One equivalent of electrophilic hydrogen (acid) adds at the oxygen atom.
Only LAH will reduce esters at a practical rate under normal conditions.
H
C
primary alcohols
R
O
H
f. general carboxylic acid = reduced to primary alcohol (like the aldehyde or ester)
H
H
R
Li
Al
C
H
R
H
R
O
C
H
Al
H
C
O
H
H
O
O
H3Al
Li
O
H
O
Al
H
H
H
2. workup
R
H
C
O
H
H
H2O
H
R
C
Li
O
H
R
O
C
H
Al
H
H
R
Li
H
C
O
H3Al
H
O
H
H
primary alcohols
g. ethylene oxide (epoxides) = reduced to ethanol
H
Na
H
H
B
Na
O
O
H
O
OH2
H2C
H2C
H
2. workup
H
H
H
f. imines (made from primary amine and ketone or aldehyde) reduced to amines with sodium cyanoborohydride
Na
N
imine
H
H2BCN
H
B
H
CN
H
O
N
H
sodium cyanoborohydride
(reduces imines to amines)
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H
R
N
secondary amine
12
Na
H
N
H
H2BCN
B
H
N
CN
H
iminium ion
tertiary amine
sodium cyanoborohydride
(reduces imines to amines)
g. nitriles reduced to 1o amines with 1. LiAlH4, 2. workup.
R
R
C
R
nitrile
C
H
Li
N
C
H
Al
N
H
H
H
R
Li
N
Al
H
H
H
Al
C
N
H
H
X
H
H
Al
H
H
H
H
Al
X
H
H
2. workup
H
H
H
R
H
C
H
H
C
C
H
(neutralize)
primary amine
R
N
H
O
H
X
Al
X
C
N
H
H
X
Al
X
H
O
H
H
H
N
H
H
O
H
H
H
H
N
H
R
H
R
H
X
X
X
H
h. esters and nitriles = reduced to aldehydes with diisobutylaluminium hydride, DIBAL (text = DIBAH)
nitrile
R
C
N
N
H
Al
R
C
R
R
N
Al
H
H
H
H
R
O
N
Al
H
R
R
C
H
R
R
H
O
H
O
R
H
H
R
R
C
R
C
O
aldehyde
H
O
H
H
H
R
R
N
C
C
O
H
H
O
H
Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc
H
H
R
Al
H
R
O
H
H
H
Al
R
H
O
H
H
N
C
H
H
H
Al
O
N
H
R
R
C
H
H
O
Al
R
H
13
i. hydrolysis of nitriles in HCl/1 eq H2O to amides
j. hydrolysis of nitriles in H2SO4/excess H2O to carboxylic acids
k. hydrolysis of nitriles in NaOH/H2O to carboxylic acids
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14
Possible Mechanism for some of the cuprate reactions– Supply all necessary mechanistic details, including lone
pairs, formal charge and curved arrows to show electron movement.
a. Formation of dialkyl lithium cuprate
2 equivalents
organolithium reagent
Li
Cu
Li
Br
1 eq.
CuBr
Li
Cu
Cu
Br
Li
A transmetallation allows the more electronegative anion (Br) to pair up with the more
electropositive cation (Li), producing a better salt. The less electronegative anion (C)
then pairs up with the less electropositive cation (Cu) to produce a better covalent bond.
dialkyllithium
cuprate
b. Conjugate addition to α,β-unsaturated carbonyl
Li
O
Li
Cu
O
O
H
H O H
Cu
2. WK
c. Acyl substitution with an acid chloride
Li
O
Li
Cl
O
O
Cl
Cu
Li
Cu
Cl
The ketone is LESS reactive than the
acid chloride and does not react further
with a cuprate reagent. (It would react
further with an organolithium reagent.)
d. Coupling reaction with an RX compound
Li
Li
Br
Br
Cu
Cu
This reaction can be viewed as an SN2 reaction,
but free radicals are likely involved. Lithium and
magnesium reagents produce a lot of side
reactions that make this coupling poor for them.
2 "R" groups are coupled
together with both coming
from RX compounds.
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15
Possible Mechanism for Formation of Organometallics – Supply all necessary mechanistic details, including
lone pairs, formal charge and curved arrows to show electron movement.
Grignard (Mg) reagents
R
Mg
carbanion
nucleophile
Br
Mg
R
Mg
Br
R
Mg
Mg
Br
Mg
Mg
Mg
Mg
R
Br
R
Br
Li Li Li Li
Li
Mg
Li
R
Br
Li Li
Li
Br
carbanion
nucleophile
Lithium reagents
Li
Mg 2
R
Mg
R
Li
Li Li
Li
Li
Possible Mechanism for Reaction of Organometallics with typical Organic Electrophiles – Supply all
necessary mechanistic details, including lone pairs, formal charge and curved arrows to show electron movement.
H
H
R
(MgBr)
carbanion
nucleophile
R C O
C O
H
(MgBr)
C O
Br
R'
R'
C O
R C O
R"
ketones
+2
Mg
Br
R"
R
(MgBr)
Mg
O
+2
Mg
Br
epoxides
H
1o alcohol
H
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H
H
H O H
R C O
H O
R'
2o alcohol
H
2. Workup
H
R'
H O H
R C O
H O
R"
3o alcohol
H
H
2. Workup
H
R
O
H O H
H O
H
R C O
2. Workup
H
+2
R C O
O
R
Br
H O
H
R'
(MgBr)
Mg
H
H O H
methanal
R'
aldehydes
R
+2
H
H
R
2. Workup
H
it depends
H
H
16
O
R
C
(MgBr)
O
(MgBr)
Mg
R"
esters
R
Li
carbanion
nucleophile
H
carbanion
nucleophile
H
Li
R C O
R C O
C O
H
R C O
Li
R C O
H O
Li
H O H
H O
H
2. Workup
H
Li
H O H
H O
H
2. Workup
H
H
R'
aldehydes
H
Li
R'
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(MgBr)
R
H
R C O
H
R C O
H
H
1 alcohol
o
H
R C O
H
H
1o alcohol
H
H O H
R C O
H O
R'
2o alcohol
H
H
H
1o alcohol
2. Workup
H
methanal
R C O
H
H O H
H O
H
C O
R'
2. Workup
H
H
H
R
R
H O H
methanal
Li
carbanion
nucleophile
H
R C O
H
H
R
R'
2. Workup
H
H
C O
(MgBr)
R"
methanal
Li
R
R
H
H
R
C O
Br
H
C O
H
R'
Mg
Esters react twice with organomagnesium and lithium
reagents, since the initially formed intermediate
collapses back to a ketone, which is more reactive
than the initially attacked ester, and gets attacked a
second time.
H
O
H
O
O
R C
carboxylic acid
+2
R C O
O
H O H
H O
R'
C O
Br
O
R'
R
+2
R C
O
carbon dioxide
2. Workup
H
H
O
R"
17
R'
R
R'
C O
Li
R C O
R"
ketones
R"
O
R
Li
O
R
Li
H O H
R C O
H O
R"
3o alcohol
Li
H
H
O
R
H
H O H
H O
O
R C
O
carbon dioxide
O
O
R C
O
carboxylic acid
Li
Li O
C O
O
H
H
R'
R C O
O
H
H O H
R'
C O
Li
Li
H O
R'
it depends
2. Workup
H
O
C
Li
R
R'
2. Workup
H
epoxides
R
2. Workup
H
R
R"
R"
R"
esters
R
Esters react twice with organomagnesium and lithium
reagents, since the initially formed intermediate
collapses back to a ketone, which is more reactive
than the initially attacked ester, and gets attacked a
second time.
R'
Li
2. Workup
H
H
R'
H O H
R C O
R C O Li
H O
R
R
H
This is the one difference between Mg (Grignard) and Li reagents in our course. The lithium organometallics are a bit more
reactive and will add to even a carboxylate, which after workup hydrolyze to a ketone. This takes the addition of three protons.
R H
O
R'
C
O
second
equivalent
O
R
H
Li
R'
C
Li
O
R
carboxylic acid
H
Li
O
R'
C O Li
R
Li
H
H
H O H
O
R'
H O
R
H
O
R'
C
R
H
R'
C O
R
H
H O H
H
H O H
C O Li
H O
H
H O
H
R'
C O
R
Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc
R'
C O
R
H
H
H
H O H
O
R'
C O
R
H
18
Oxidation of alcohols with chromium reagents (PCC, Jones,there are others too…)
Overall Reactions
b. Jones reagent
a. PCC reagent
methyl alcohol
H3C OH
methyl alcohol
O
N
CrO3 /
H
C
H3C OH
OH
CrO3 /
primary alcohol
O
N
C
H
H
primary alcohol
O
N
CrO3 /
CrO3 /
OH
OH
O
N
OH
H
secondary alcohol
OH
CrO3 /
secondary alcohol
OH
O
N
tertiary alcohol
OH
CrO3 /
O
N
tertiary alcohol
CrO3 /
N
OH
No Reaction
CrO3 /
N
No Reaction
Possible Oxidation Mechanism – all viewed as CrO3 (either without water present or with water present). Supply
all necessary mechanistic details, including lone pairs, formal charge and curved arrows to show electron
movement.
a.
PCC - without water present – no carbonyl hydrate forms
H
O
R C
H
H
primary
alcohol
O
Cr O
O
Cr = +6
CrO 3 /
N
PCC conditions
(no water)
N
H
O
R C
H
N H
O
Cr O
O
O
H
R C
H
O
Cr O
O
H
N
O
N H
Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc
R C
H
aldehyde
O
Cr O
O
Cr = +4
19
H
O
R C
O
Cr O
O
H
R'
secondary
alcohol
N
CrO3 /
H
N
O
PCC conditions
(no water)
R C
R'
Cr = +6
O
Cr O
N H
O
O
R C
H
R'
O
Cr O
O
H
N
O
Cr O
O
N H
R C
R'
ketone
O
Cr = +4
PCC with water – Possible Hydration Mechanism, followed by oxidation of the carbonyl hydrate (Jones
reaction).
H
H O
O
H
O
R C
H
aldehyde
from first
Cr oxidation
O
R C
H
R C
H
O
H
O
R C
O
carboxylic
acid
Cr
O O
Cr = +4
R C
H
R C
O
O
H
O
H
O
O
H
R C
H
H O
O
Cr
O
H
H O
H O
H
H
That’s all I could do for now. Try some keto/enol mechanisms in acid and in base.
Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc
H
O
Cr O
O
Cr = +6
carbonyl
hydrate
H
H
H O
H
H O
H
H
H
H
O
H O
H O
H
H
O
H
H
O
Cr
O O