Carbonyl Addition Reactions: Part I

1
Carbonyl Addition Reactions Part I
Chem 313Spring Semester 2009
2
The Carbonyl Group
Background

• McMurry Aldehydes and Ketones Chapter 19
• - Nomenclature
• - Mechanism of nucleophilic addition reactions
• Section 19.4 -19.9 especially
• relative reactivity of aldehydes and ketones
• addition of negatively charged and neutral
  nucleophiles
• addition of Grignard reagents
• nucleophilic addition-elimination reactions of
  amines
• Section 19.12
• Enantioselective Synthesis p. 720-721
• 2. McMurry Carboxylic Acids and Derivatives
  Chapter 20, 21
• - Nomenclature
• - Preparation by carboxylation of Grignard
  reagents p. 748
• - Reactions of nitriles p. 751
• - Reaction of acid chlorides, esters with
  organometallic reagents p. 786, 795

3
Addition of Nucleophiles
Topic Sequence
1. Addition of 'simple' nucleophiles
- the reaction provides the 'simple' addition
product
2. Addition of 'complex' or 'functionalized'
nucleophiles
- the reaction proceeds via the addition product,
which reacts further depending upon the
functionality 'G' present in the nucleophile ?
alkenes, epoxides, ?,?-unsaturated ketones etc.
4
Addition of 'Simple' Nucleophiles
(McMurry Ch. 19) three types
a. Negatively charged (anionic) nucleophiles Nu
(usually in protic solvents)
b. Non-charged (neutral) nucleophile HNu
activation of carbonyl group by protonation
product is deprotonated by base B- (usually in
protic solvents)
Irreversible or reversible dependent upon nature
of nucleophile ? carboxylic acid derivatives
5
Addition of 'Simple' Nucleophiles (cont)
c. Carbon nucleophile M-Nu - associated with a
metal ion M activation of the carbonyl group by
M (a Lewis acid) must take place (usually in
aprotic solvents)!

• Reactions are usually
• kinetically complex involve aggregates of
  the organometallic nucleophile
• air- and moisture sensitive - the product is
  the metal alkoxide
• exothermic consider pKa differences between
  conjugate acid of organometallic nucleophile and
  alcohol corresponding to alkoxide product!

Focus on organometallic nucleophiles of Group I
(Li) and Group (II) (Mg, Zn) metals
6
Grignard Reagents
Organometallic compound - soluble in diethyl
ether with covalent polar Mg-C bond.
diethyl ether must be anhydrous! also best to
conduct reaction in an inert atmosphere, e.g.
nitrogen
Preparation i. Oxidative insertion Mg, ether
solvent organic halogen compound

• R 1, 2, 3 alkyl, aryl, vinyl, allyl in
  ether solvent.
• X F, Cl, Br, I - I most reactive, Cl, Br more
  economic, F requires
• special conditions).
• Vinyl - CH2CHX (X Cl, Br), use
  tetrahydrofuran (THF) as solvent

unstable in diethyl ether
7
Grignard Reagents Preparation (cont.)
ii. Metal-hydrogen exchange

• relies on basicity of Grignard reagent
• - pKa CH4 ? 55 pKa HC?CH ? 27 exothermic
  proton transfer!
• - only works well for terminal acetylenes, other
  hydrocarbons
• with pKa ? 27-30.

Problems with preparations for multifunctional
organic halogen compounds watch for competing
reactions
?
for pKa check http//www.chem.wisc.edu/areas/reic
h/pkatable/
8
Grignard Reagents Preparation (cont.)
If incipient Grignard site cannot be connected
'electronically' with a second halogen di-Grignard
reagent may be stable
However
Contrast
inductive effect of 5 Cl atoms!!
9
Grignard Reagents-Structure
RMgX R-Mg bond is polar covalent Mg coordinates
with donor ligands ('Lewis bases') such as ether

• Mg within regular tetrahedron
• Octet structure completed by overlap with
  fully-occupied sp3 orbitals on O ('lone pairs')In
  dilute solutions (lt0.1M), RMgX.(OEt2)2 exists as
  monomeric species can be isolated by careful
  cooling!
• At higher concentrations, complex series of
  equilibria involving aggregates, and the
  generation of dialkylmagnesium species by the
  Schlenk equilibrium

2RMgX ? R2Mg MgX2

• Removal of ether drives equilibrium to right to
  form R2Mg.MgX2

10
Organolithium Reagents
Organometallic compound - soluble in hydrocarbon
and ether solvents with covalent polar Li-C bond

• hexane must be anhydrous!
• reaction must be conducted in an inert
  atmosphere (usually N2 or Ar)

Preparation i. Oxidative metallation Li,
hydrocarbon solvent organic halogen compound
(except for CH3Li, when ether solvent must be
used) in inert atmosphere

• R 1, 2, 3 alkyl, aryl, vinyl, allyl.
• X F, Cl, Br, I - I most reactive, Cl, Br more
  economic, F requires
• special conditions).

CH3Li, n- and sec-C4H9Li, tert-C4H9Li, C6H5Li
prepared commercially this way on ton scale!
Except for CH3Li (ether), alkyllithiums are
stored in hydrocarbon solvents pentane
(tert-C4H9Li), hexane or cyclohexane (n- and
sec-C4H9Li)
11
Organolithium Reagents-Preparation (cont.)
ii. Metal-hydrogen exchange - in inert atmosphere!

• Reaction is general - works well for terminal
  acetylenes, other hydrocarbons
• with pKa ?40, depending upon alkyllithium used.

pKa ? 31
pKa C4H10 ?51
pKa ? 29
deep red triphenylmethide anion
pKa ? 16
cyclopentadienide anion

• Some Li-H exchange processes may be immeasurably
  slow kinetic barrier to proton transfer e.g.
  benzene C6H6! (pKa ? 37!)

12
Organolithium Reagents-Preparation (cont.)
iii. Metal-halogen exchange - in inert atmosphere
pKa C10H8 ? 37
pKa C4H10 ?51

• Reaction works when pKa of parent hydrocarbon of
  halogen compounds is less than that of conjugate
  acid of alkyllithium !

tert-butyllithium must be used in excess (gt2.1
equiv.) product tert-butyl bromide undergoes
facile elimination!
fast E2 elimination!
13
Organolithium Reagents -Structure
Very different to Grignard reagents tendency to
form aggregates in hydrocarbon and even ether
solutions!

• (MeLi)4
• Li4 tetrahedron with Me groups capping the faces.
  
• four localized four-centre Li3C bonds, one over
  each face of Li4 tetrahedron.
• 1 sp3 orbital on C overlaps 3 sp3 orbitals from 3
  Li in the capped face.
• each Li has vacant sp3 orbital pointing away from
  the Li4 tetrahedron - intermolecular bonding in
  solid (MeLi)4x aggregate.

(MeLi)4 'sovated' by diethyl ether disruption of
intermolecular bonding, but unit tetramer remains
intact donation by the filled sp3 orbital from
solvent into the vacant Li sp3 orbital at the
corners of the distorted cube.
n-C4H9Li hexamer in C6H12, tetramer in Et2O
t-C4H9Li tetramer in C6H14, monomer in THF
C6H5Li tetramer in Et2O
14
Organozinc Reagents
Less reactive than organolithium, Grignard
reagents
Preparation i. Oxidative metallation
difficult to carry out - use freshly precipitated
Zn metal (prepared by reduction of Zn2 by, Na, K
or Li naphthalenide)

• Organozinc compatible with functional groups
  on organic substrate!

Use Zn-Cu couple, and heat to decompose
intermediate ethylzinc iodide to produce
diethylzinc

• Organozinc reagents usually handled as the
  dialkylzinc reagents

15
Organozinc Reagents (cont.)
Preparation ii. Transmetallation with
organolithium, Grignard reagents in hexane or
ether solvent in inert atmosphere
R 1, 2, 3 alkyl, aryl, vinyl, allyl etc.

• Structure R2Zn linear, monomeric low melting
  and boiling points
• Et2Zn m.p. -28 C b.p. 118 C soluble in
  hexane, toluene, ether solvents
• Donor ligands form tetrahedral complexes e.g.
  N,N,N,N-tetramethylenediamine
• (TMEDA)

• R2Zn spontaneously flammable react vigorously
  with oxygen, water
• Lower dialkyl zinc compounds commercially
  available

16
Grignard and Organolithium Reagents - Reactions
Carbonyl Addition Reactions McMurry Ch. 19 Ch. 21

• Reactions in ether, THF or similar ether solvent.
• RLi more reactive than RMgX.
• reaction is 'quenched' with dilute aqueous acid
  to liberate 'neutral' product (e.g. NH4Cl/H2O).
• Reaction 7 immediate
• product of addition is imide, which is
  hydrolysed to ketone on treatment with H/H2O.
• Groups related to carbonyl also react (preferably
  with RLi).

17
Grignard and Organolithium Reagents Reactions
(cont.)
i. In general, reactions will proceed until all
leaving groups attached to a carbonyl group are
replaced, and sp2 centre is converted to sp3
e.g. addition to esters -
ii. In general, groups which are 'carbonyl-like',
will also undergo addition for unreactive
groups, organolithium reagents may be used
18
Grignard and Organolithium Reagents Reactions
(cont.)
iii. Nitriles - special case sp centre is
converted to sp2 centre, which is stable in the
reaction mixture
Useful reaction .. final ketone is itself
synthetically useful ? CHEM 111, 212 for
preparation of nitriles!!
19
Grignard and Organolithium Reagents Reactions
(cont.)
iv. RLi more nucleophilic than RMgX
Side reactions compete with nucleophilic addition
of Grignard reagents.!
20
Grignard and Organolithium Reagents Side
Reactions
- reduction of carbonyl compound

• Grignard reagent transfers 'H-' to carbonyl
  group
• Grignard reagent must contain ?-H atom

- formation of enolate from ketones

• Grignard reagent acts as base abstract acidic
  ?-H from ketone
• (pKa 22-28)
• Ketone must contain ?-H atom!
• Quenching of reaction mixture provides
  'unchanged' ketone!

21
Grignard and Organolithium Reagents Side
Reactions (cont.)
Reduction and enolate formation (cont.)

• Nucleophilic addition reaction is sensitive to
  steric effects!

22
Grignard Reactions Mechanism of Addition
i. Activation of carbonyl group by complexation
with RMgX or MgX2

• 'Ligand exchange'
• Activation by complexation is essential
  prerequisite for carbonyl addition!

ii. Addition actual pathway not known, but may
involve termolecular complex

• Formal transfer of "CH3-"!

• 'six-membered transition state' coordinating
  ether molecules omitted for clarity

23
Grignard Reactions Mechanism of Addition (cont.)
Consider also Schlenk equilibrium

• MgI2 Lewis acid which activates carbonyl by
  complexation.

'six-membered' transition state can be
represented in 'chair' form!

• coordinating ether molecules omitted for clarity
  may be quasi-'axial' or quasi-'equatorial' a
  'transition state model' (explains results, but
  we don't know precise structure of TS!)

24
Grignard Reactions Mechanism of Addition (cont.)
Side reactions
- reduction Grignard reagent possesses
?-hydrogen atom

• formal transfer of hydride H- from Grignard
  reagent to ketone 'reduction'

- enolate formation ketone possesses ?-hydrogen
atom

• formal transfer of proton - H - from ketone to
  Grignard reagent

25
Organolithium Reactions - Mechanism of Addition
Very complicated reacts through various
aggregates however, activation of carbonyl
group by complexation with (RLi)n

• breakup of aggregate as reaction takes place
• final lithium alkoxide may be tetrameric,
• or a higher aggregate

26
Reactions of Organozinc Reagents
Less reactive than organolithium and Grignard
reagents in addition reactions - Zn(II)
relatively poor Lewis acid for carbonyl
activation in carbonyl addition reactions - If
R2Zn is generated in situ from ZnBr2 and RMgBr or
RLi, MgBr2 or LiBr is present which activates
carbonyl group (Slide 14)!
Reformatsky Reaction

• Reaction proceeds via formation of zinc reagent -
  'ester enolate'

Actual structure is dimer (X-ray of reagent
recrystallized from THF)
27
Grignard, Organolithium Reactions Stereochemistry
Consider i. reaction with prochiral aldehyde or
ketone-
()
Addition to each enantiotopic face
R

• enantiomeric transition states equal in energy
  in an achiral environment
• products formed in equal amounts racemic
  mixture!

enantiomers
S
28
Grignard, Organolithium Reactions
Stereochemistry (cont.)
Consider ii. reaction with chiral aldehyde or
ketone faces are diastereotopic!
78
R
R

• diastereomeric transition states different
  energies
• products formed in unequal amounts!

R
diastereomers
R
S
12
R
R
R
R
S
2
98

• Pre-existing chiral (chirogenic) centre induces
  formation of new chiral centre with a 'preferred'
  absolute configuration (R or S) 'asymmetric
  induction'
• A reaction on a single starting compound which
  gives a mixture enriched in one diastereomer is a
  'diastereoselective reaction'

29
Grignard, Organolithium Reactions
Stereochemistry (cont.)
In general formation of major product
rationalized as follows
minor product 'anti-Cram product'
major product 'Cram product'
S 'small' M 'medium' L 'large' groups R
group attached to CO
Cram's rule of asymmetric induction trajectory
'A' is preferred!

• Large group adopts conformation
• perpendicular to CO group
• M group gauche to carbonyl
• S group gauche to R group
• Nu experiences greater steric and
• torsional strain with L or M groups in TS!

'B' and 'C' give 'anti-Cram' product
30
Grignard, Organolithium Reactions
Stereochemistry (cont.)
Cram's rule (cont.)
i. L, M, S groups may be alkyl, aryl, normally do
not contain heteroatom capable of forming a
complex ('chelating') with Li or Mg
'counterion' ii. trajectory of attack by NuM is
critical!

• The Bürgi-Dunitz trajectory!
• Established on basis of X-ray crystal structures
  of model molecules
• Molecular orbital considerations (Eliel and
  Wilen, p. 877-878)

109
Presence of chelating groups at ?-carbon atom
alters stereochemical outcome
'anti-Cram' product
If L group is C6H5CH2O-, then trajectory
corresponds to 'C'!
31
Grignard, Organolithium Reactions
Stereochemistry (cont.)
Chelating groups (cont.)
i. Chelation involves formation of 'metallocycle'
between carbonyl O and O (or other chelating
heteroatom) attached to C? (or C?) and metal (Li
or MgX) ii. Attack by NuM then takes place on
side opposite to larger non-chelating group.
major product 'anti-Cram product
'Chelation control'
32
Grignard, Organolithium Reactions
Stereochemistry (cont.)
Addition of RMgX, RLi to cyclic ketones i. 3-5
membered rings
991 overall yield 60

• Preferential addition 'anti' to alkyl group
  adjacent to carbonyl actual ratio depends on
  size of nucleophile
• for alkyl groups more distant from carbonyl in
  cyclopentanones, mixtures of diastereomers are
  obtained

ii. Six-membered rings
'equatorial addition'
'axial addition'

• Stereoelectronic preference for 'axial addition'
  to give equatorial alcohol
• As size of nucleophile increases, amount of
  'equatorial addition' to give axial alcohol
  increases

33
Grignard, Organolithium Reactions
Stereochemistry (cont.)
ii. 6 membered rings (cont.)
'equatorial addition'
'axial addition'
LiAlH4 (H-) gt90 - HC?CNa 88 12 CH3Li 35
65 CH3MgBr 47 53 CH3CH2MgBr 29
71 (CH3)3CMgBr - 100

• Difficult to rationalize!
• Reactions are irreversible therefore product
  stability plays no role!
• Bürgi-Dunitz trajectory and adjacent axial H
  atoms?

34
Grignard, Organolithium Reactions
Stereochemistry (cont.)
Reactions of Grignard reagents complexed to
chiral ether or amine ligands chiral ethers or
amines in principle may be used to form complexes
with Grignard or organolithium reagents
i. With prochiral carbonyl compound in chiral,
non-racemic solvent-

• With a chiral non-racemic solvent, the
  environment is now 'chiral'
• In a chiral environment, as the reactants
  approach respective transition
• states at each of the Si and Re faces, the
  transition state structures
• will be diastereotopic!

35
Grignard, Organolithium Reactions
Stereochemistry (cont.)
Prochiral ketone - addition to each enantiotopic
face in chiral solvent

• transition states are not enantiomeric - they are
  not mirror images
• unequal in energy the environment is 'chiral'
• products formed in unequal amounts
• a reaction which produces more of one enantiomer
  than the other is called 'enantioselective'
• efficiency enantiomer excess (ee).

enantiomers
RS 6238 ee 24
ee R-S/R S x 100 R -S
However, reactions involving chiral complexing
agents with Grignard reagents always give low
enantioselectivities! Why?
36
Grignard, Organolithium Reactions
Stereochemistry (cont.)
Reason for low enantioselectivities
Rapid exchange of solvent ligands to magnesium
via Schlenk equilibrium at least two different
organomagnesium reagents are present! (higher
aggregates?) - The diphenyl magnesium has
different steric requirements, and either phenyl
group can be transferred at either of the Si or
Re face! Other factors also important steric
environment about carbonyl group, reaction
temperature etc.
Note equilibration of diphenyl magnesium with
magnesium halide to produce B!
B is identical with A!
37
Grignard, Organolithium Reactions
Stereochemistry (cont.)
ii. With prochiral carbonyl compound and chiral
non-racemic ligand
Example of (-)-sparteine naturally occurring
alkaloid use as ligand in the non-chiral solvent
diethyl ether -
ee 22
The Grignard reagent is too reactive the
addition of the ligand-free reagent competes with
the addition of the ligand-complexed reagent to
the aldehyde!
38
Organozinc Reagents Stereochemistry

• Much better than alkyllithium, Grignard reagents
  for stereoselective reactions
• Less reactive
• Complexes with chiral ligands are stable no
  exchange!.

98 ee 99 S-enantiomer 1 R-enantiomer

• Reaction requires catalytic amount of ligand
  (just 2 mol!)
• -()-3-exo-N,N,-dimethylaminoisoborneol
  '()-DAIB'
• Proceeds via formation of zinc chelate with amino
  alcohol
• Use (-)-DAIB to obtain other enantiomer!

The monomeric complex is in equilibrium with
dimeric complex
39
Organozinc Reagents Stereochemistry (cont.)
A proposed model

• 4-Membered TS addition to Si face of aldehyde
• Reaction of dimethylzinc with aldehyde very slow
  or does not proceed
• in absence of ligand - so called 'ligand
  acceleration'

40
Organozinc Reagents Stereochemistry (cont.)
A remarkable reaction other examples

• Also works with (-)-DAIB to give other enantiomer
• Works with other chiral amino alcohols
• Organozinc reagents are the best for
  enantioselective nucleophilic addition
• with chiral ligands

41
Grignard and Organolithium Reactions -Problems
Work the following problems (examination format)
1. Indicate carefully how the following reactions
proceed. Where stereochemistry in the product is
important, please carefully indicate this in your
structure, and rationalize the stereochemical
outcome
a
The possible reactions are 1. nucleophilic
addition to the ketone carbonyl 2. nucleophilic
addition to the ester carbonyl 3. metal-hydrogen
exchange this reaction is important if the
substrate is relatively acidic! - pKa ? 27-30.
Ka 10-14.2 pKa 14.2
Stabilized anion!
42
Grignard and Organolithium Reactions Problems
(cont.)
1a. (cont.) with strongly basic CH3MgBr,
reaction is exclusively metal-hydrogen exchange!

Quenching of the reaction mixture (NH4Cl/H2O)
regenerates the starting compound (ethyl
acetoacetate). - By measuring amount of CH4
released, it was possible to determine number of
'active' (that is, acidic) hydrogen atoms so
called 'Zerewetinoff determination (spectroscopic
methods now used)
43
Grignard and Organolithium Reactions Problems
(cont.)
1b.

• Epoxide or oxirane
• behaves like carbonyl group 'shared over two
  carbon atoms' (although each is sp3 hybridized!)
• possesses bond angle (ring) strain
• is electrophilic at C (check Mc.Murry Ch. 18.
  Section 18.8!).
• O atom is strongly Lewis basic.
• decision needs to be made as to which carbon
  atom undergoes nucleophilic attack!

Reaction is SN2 reaction! inversion at carbon
atom undergoing substitution. - As for carbonyl
group, activation of epoxide oxygen is required.
However, it is not possible to draw 'cyclic'
6-membered TS model!
44
Grignard and Organolithium Reactions Problems
(cont.)
1c.

• Isothiocyanate
• sp carbon atom is electrophilic
• monoaddition only!

45
Grignard and Organolithium Reactions Problems
(cont.)
1d.
Clearly, Re face is less hindered than the Si
face. are diastereotopic only one product is
formed! Attack along Bürgi-Dunitz trajectory
impossible from Si face.
46
Grignard and Organolithium Reactions Problems
(cont.)
1e. Monensin 1 is a polyether antibiotic, a
natural product so-called for its antibiotic
properties and the presence of ether linkages.
It was prepared by total synthesis. The
synthesis relied on nucleophilic additions to
carbonyl compounds under the 'Cram' and
'chelation controlled' models. With reference to
the reactions below, use the models to predict
the major diastereoisomer formed in each case.
i
The OSi(CH3)3 group does not participate in
this particular case in chelation
ii
47
Grignard and Organolithium Reactions Problems
(cont.)
1e. (cont.)
i. The OSi(CH3)3 group does not participate in
this particular case in chelation the therefore
the Cram 'open chain' model may be used.
Therefore, reorientate starting aldehyde
according to the model in Newman projection.
Ensure that L group is orthogonal to carbonyl,
and that chirality is the same as in starting
compound
Next, draw attack by nucleophile along
Burgi-Dunitz trajectory
Finally, redraw product in zig-zag projection
48
Grignard and Organolithium Reactions Problems
(cont.)
1e. (cont.)
ii. The OSi(CH3)3 group does not participate in
this particular case in chelation however, the
other chain attached to C-? contains a strongly
chelating 'diether'. Therefore the 'chelation
model' is used. Therefore, reorientate starting
aldehyde according to the chelation model which
aligns the carbonyl group with the chelating
group
Next, the nucleophile attacks the chelated
carbonyl on the side opposite to the non-chelated
larger group
Take care to redraw the product with the correct
chirality!