CHEM210 - EXAM#4 - Lecture #26: Carbanions as Carbon Nucleophiles: Synthesis and Stability
In the product (Li+Br- or R-Mg+ Br-) the Br remains
"negative"—it doesn't change its oxidation level.
In the vinyl carbanion - the stabilization of the lone pair (lowering its energy) can be achieved only by:
(i) by minimizing the repulsions between the three electron domains (lone pair, double C=C bond, and C-H bond) and (ii) increasing the s character in the orbital holding that pair
Carbon Oxidation State - Carboxylic Acid
+2
Carbon Oxidation State - Carbon Dioxide
+4
If the carbon atom is using one extra electron, the carbon will have an oxidation state of
-1
Carbon Oxidation State - Alcohol
-2
Carbon Oxidation State - Alkane
-4
Carbon can range in oxidation state from
-4 to +4
Carbon Oxidation State - Aldehyde
0
The lone-pair orbitals in acetylide anions have more s character than those in alkyl anions - therefore,
1-propyne can be deprotonated by the ethyl anion (CH3CH2-)
Second way to Prepare Carbanions:
Lithium Reagent
Carbanion Stability - Resonance Stabilization requires
MO overlap; rehybridization to sp2 to achieve better overlap
Larger Angle between the carbon hybrid orbitals forming the C-H bonds:
MORE ACIDIC
Carbanion Effects: Resonance = Greater S Character =
MORE stabilizing MORE stabilizing
Empty -
MOST P
Filled -
MOST S
Lithium Reagent: __________ lithium most common
N-butyl
If you are moving a negative charge,
NEED something else to move
Carbanions are now going to be
NUCLEOPHILES
Reactions of Alkyl Halides - Grignard Reagents - R-X → via Mg →
R-Mg-X
Resonance Vs. Hybridization ??
RESONANCE - suffers poor hybridization to gain resonance stability
epoxides are very good candidates for
SN2
R (partial negative charge)
STRONG negative charge - nucleophile Nu:
Whenever we run a reaction that involves a decrease in oxidation state, we say that
a REDUCTION has occurred
An epoxide is
a cyclic ether with a three-atom ring
Carbanion Stability - Hyperconjugation - It is in this logic that underlies the observation that
a primary carbanion is less destabilized than a secondary carbanion, which in turn is less destabilized than a tertiary carbanion
Preparing Alcohols via Reduction - the second step
a proton source is used to generate the alcohol
Carbanion Stability - Resonance - Like radical and carbocation intermediates, there is an
absolute geometric requirement for MO overlap in order to participate in resonance
Must have the means to generate these nucleophilic carbanions in concentrations high enough to achieve
acceptable rates of substitution reactions, as we have described for alkoxides or other negatively-charged nucleophiles
The ethyl anion can deprotonate 1-propyne, which means that
acetylide anion is more stabilized than ethyl anion, or, equivalently, that acetylide is a weaker base than ethyl anion.
Solvent Effects - carbanion will pull off
acidic hydrogens on OH and NH bonds
Reactions of Alkyl Halides - Grignard Reagents can also be made from
alkenyl (vinylic) and aryl (aromatic) halides
To make carbanions, react an
alkyl halide with magnesium to form a Grignard Reagent
"superbases"
alkyl lithiums
The simple proton transfer presupposes that
alkyl lithiums are available, even if not by a deprotonation reaction
The organic residue can be
alkyl, alkenyl, or aryl
Carbanion Stabilization Summary - Stabilization via Hybridization (increased S character) - Most Stabilized:
alkynyl H--(triple bond)--(-) 50% s character pKa 24
n-BuLi can be used to generate
alkynyl carbanion in essentially 100% yield
When working through reaction mechanism problems,
always draw what did not change first
Whenever we run a reaction that increases the oxidation state, we say that
an OXIDATION has occurred
When a Grignard reagent attacks a ketone or aldehyde, it forms
an alcohol, with a nexly installed R group
The formation of a Grignard reagent or an organolithium reagent is
an oxidation/reduction process.
Carbanion-type reagents are completely incompatible with
aqueous environments, alcohols, thiols, acids, N-H amines, etc.
Preparing Alcohols via Grignard Reactions - Both H- and R- can
attack a ketone or aldehyde to give an alcohol
Epoxides - In SN2 conditions, a nucleophile will
attack the LESS sterically hindered carbon
Carbanion Stability - Resonance - lone pair P orbital aligned with pi*(C=C) antibond =
best overlap for resonance
the s character may be determined from the angles
between the carbon hybrid orbitals forming the C-H bonds
Reactions of Alkyl Halides - Grignard Reagents - the electron rich character of the carbon
bonded to magnesium
Carbanion Stability - Resonance - For carbanions, the key MO interaction is between the
carbanion lone pair (nucleophile) and the empty pi* orbital (LUMO) of the alkene
Use of a reducing metal (typically Mg or Li) and a C-halide is a reliable method to form
carbanions as their MgX or Li salts
electrophile substrate =
carbon
Oxidation - two new bonds formed between
carbon and a more electronegative element
Reactions of Alkyl Halides - Grignard Reagents - Because hydrocarbons are such weak acids, with pKa's in the range 44 to 60,
carbon anions are very strong bases
In a Grignard reagent, there is a
carbon atom that is directly connected to a magnesium atom
need carbon nucleophiles and allow them to react with
carbon electrophiles
Carbanions are now going to be nucleophiles - form _________________________ bonds instead of just replacing the functional group
carbon-carbon bonds
To prepare carbon-carbon bonds, must generate ___________ ____________ ______________, called _________________
carbon-centered nucleophiles carbanions
This method of carbanion generation via halocarbon reduction is more general and versatile than hydrocarbon deprotonation, and it accounts for the
confidence that we have in the availability of superbases like n-BuLi
The substrate R, on the other hand, starts out as R(δ+) as a consequence of the ___________________________ but ends up as
electronegativity of Br R(δ-) in the R-Li or R-MgBr product. So, R is reduced.
Epoxides are _______________
electrophiles (carbon bonded to an electronegative atom)
We will also assume that any carbanion synthesis/reaction will occur in a solvent (typically an ________ solvent) that is both compatible and beneficial for the chemistry, and so we will not explicitly denote solvent
ether
Allyl system will be ___________
faster
a methyl carbanions has favored ___________ geometry
favored
Reactions of Alkyl Halides - Grignard Reagents - Organo_____________ rarely react with magnesium
fluorides
To calculate oxidation state, treat all bonds as IONIC:
give both electrons to the more electronegative bond for each of the C-H bonds, carbon is very slightly more electronegative than hydrogen, so carbon will get both electrons in each case for the C-C bond, neither atom is more electronegative then the other, so we must place one electron on each carbon atom
metallic magnesium
grignard
RMgX
grignard reagent
CANNOT have acid groups in the presence of
grignard reagents
Goal of the Reaction:
growing carbon chains
The second common method of carbanion generation is via
halocarbon reduction
If we have a synthesis problem where the carbon skeleton is getting larger, then we know we will
have to creat a C-C bond
Carbon acids can be deprotonated to give carbanions, but typically with difficulty as they
have very HIGH pKa values (not a strong acid)
Hydrocarbons define the
high end of the pKa scale
Carbanion Stability - Hybridization - sp
holds electron density closer to nucleus = stabilizing uses all of it's s character
typical base
hydroxide, OH- pKa = 16
Carbanion Stabilization Summary - least stabilized carbanions
hyperconjugation destabilization (carbanions with nothing else happening for them) least stabilized = tertiary most stabilized = primary, methyl
Carbanion Stability - Hyperconjugation - compare
hyperconjugation is mildly stabilizing for radicals and quite stabilizing for carbocations
The oxidation sate of the carbon atom in an alcohol will be dependent on the
identities of the atoms that are attached to the carbon atom
HP does not always work, BUT
if you deprotonate an SP-hybridized C-H bond = FAST, but cannot do SP2
Grignard reagents are formed by inserting a magnesium
in between a C-X bond (where X is a halogen)
The elements Boron and Aluminum
in the same column of the periodic table has three valence electrons - therefore, can comfortably form three bonds
STRONG bases and nucleophile =
incompatible with anything with a bond (O-H, N-H, S-H) cannot make or break in the presence of these
Carbanion Stabilization Summary - Stabilization via hybridization
increased S character Cyclopropyl (pKa 45) Secondary Vinyl (pKa 44) Primary Vinyl (pKa 44)
Reduction
increases electron density on carbon by FORMING this: C-H or BREAKING one of these: C-O, C-N, C-X
Ethers are
inert and are often used as solvents for Grignard reactions.
To calculate the oxidation state of an atom, treat all bonds as _________, regardless of whether they are or not
ionic
In the specific case of an alkynyl lithium, the bond is essentailly
ionic and so we represent it as the "+ -" form
alkynyl anion has a(n) ________ bond
ionic bond (almost like a salt)
A negative charge on a carbon atom
is NOT stable
Preparing Alcohols via Reduction - the first step, the reducing agent (LAH)
is simply functioning as a source of H-
Whenever we have a synthesis problem we must always ask two questions:
is there a change in the carbon skeleton, and is there a change in the functional group
Therefore, we can make alcohols by reducing
ketones or aldehydes
Nu: will attack the
less sterically hindered carbon OR the one that is one away from a double bond - in an ALLYLIC position
Carbanions and SN2 - previously with SN2, we were reacting a nucleophile with a carbon chain and the nucleophiles had
lone pairs and/or negative charges
Reactions of Alkyl Halides - Grignard Reagents - Alkyl halides, RX, react with ______________ metal in ether or tetrahydrofuran (THF) to yield:
magnesium alkylmagnesium halides, RMgX (called Grignard Reagents)
Reactions of Alkyl Halides - Grignard Reagents - A grignard reagent is formally the
magnesium salt, R3C(-+)MgX, of a carbon acid, R3C-H, and thus is a carbon anion or carbanion
chains and rings →
making carbon - carbon bonds
Carbanion Stability - Resonance - Carbanions can rehybridize in order to
maximize the orbital overlap between the carbanionic carbon and the alkene LUMO
n-BuLi includes
metal counterion
These carbanions are NOT compatible with
molecules containing acidic protons (alcohols, amines, thiols, acids) or electrophiles (C=X bonds, C-LG bonds)
Carbanion Stability - Hybridization - The more S character in the hybrid orbital holding the carbanion, the
more stabilized
example of alkyl carbanions
n-butyl lithium (n-BuLi)
The Br in the substrate starts out slightly negative (R(δ+)-Br(δ-)) due to its
natural electronegativity
"R" partial _________ charge
negative
Carbon atoms of any formal hybridization can bear a
negative charge
Making Carbanions - carbanions are
not stable on their own
Carbanions and SN2 - previously with SN2, we were reacting a
nucleophile with a carbon chain
Carbanion Stability - the hydrocarbon pKa values should be taken as
order-of-magnitude representations, and the relative stabilities of those species without explicit hydrocarbon pKa values are based solely on estimations based upon structural features
metallic lithium
organolithium
Reactions of Alkyl Halides - Grignard Reagents - examples of __________________ compounds because they contain a carbon-metal bond
organometallic
n-BuLi is NOT effective at deprotonating
other sp3-hybridized C-H bonds, or even the more acidic sp2 C-H bonds - - it is just too kinetically slow
In the vinyl carbanion, the orbital holding the lone pair cannot
overlap with the π system and gain resonance stabilization
converting a primary alcohol into an aldehyde or a carboxylic acid:
oxidation
converting a secondary alcohol into a ketone
oxidation
The chlorination reaction of methane to yield chloromethane is a(n) ______________ because
oxidation a C-H bond is broken and a C-Cl bond is formed
losing electrons
oxidized
In the process of supplying the electrons, the metal become
oxidized (Mg° → Mg2+, Li° → Li+)
Carbanion Stability - Hybridization - differences in carbanion electron pair stability is obvious in the ________ of the ____________ ___________
pKas corresponding hydrocarbons
Carbanion Stability - Hybridization - Since carbanions are electron rich,
placing the excess carbanionic electron density in a hybrid orbital with higher S character is favorable
Nucleophilicity is dependent on
polarizability (size of the atom)
A C-MgBr bond is so strongly
polarized towards carbon, it's almost ionic
Reactions of Alkyl Halides - Grignard Reagents - the carbon-magnesium bond is
polarized, making the carbon atom of Grignard reagents both nucleophilic and basic
"M" partial ________ charge
positive
All solution-phase carbanions must be accompanied by a
positively charged counterion
carbanions persist in solution as
potent nucleophiles
More stabilized sp-hybridized carbanions can be
prepared by direct deprotonation
Carbanion Stability - Hyperconjugation - most stabilized
primary
Carbanion Stability - Hyperconjugation - An interaction between a carbanion adjacent to a lone-pair containing heteroatom is
quite destabilizing - even more so than the sigmaC-H interaction as the heteroatom lone pair is significantly HIGHER in energy (and therefore closer to the carbanion orbital energy level) than the sigmaC-H energy level
The structural features that influence carbanion stability can be categorized in exactly the same manner as
radical stability and carbocation stability
different metals can be used to affect
rate and stability R(partial negative charge)--------M(partial positive charge)
Alcohols, amines, and carboxylic acids are acidic enough to
react with Grignard reagents through a proton transfer (acid-base chemistry).
gain electrons
reduced
The C-X bond is __________ by the electrons, yielding:
reduced the carbanion "R-" and the halide X-
The metal supplies the electrons, so it is the
reductant
converting a ketone of aldehyde into an alcohol
reduction
The conversion of an alkyl chloride to an alkane via a Grignard reagent followed by protonation is a(n) _______________ because
reduction a C-Cl bond is broken and a C-H bond is formed
The ranking of the hydrocarbon pKas will be determined by the
relative stability of their conjugate bases (carbanions).
Second way to Prepare Carbanions - Lithium Reagent:
replace a hydrogen with lithium once again, the bond is nearly ionic = think carbanion
Carbanion Stability - Resonance - effect is completely analogous to
resonance stabilization of both radicals and carbocations
Structural features that influence carbanion stability in order of decreasing important for stabilization:
resonance ~~ hybridization, and then hyperconjugation
The H-C-H bond angles in cyclopropane and ethylene are 115° and 118°, respectively. Cyclopropane and ethylene have very similar pKas - in both carbanions, the main stabilizing factor is the
s character in the hybrids holding the lone pair.
The larger that angle, the higher the _______________ of the orbital holding the lone pair, the more _______________ _______________ that pair is by interaction with the carbon nucleus, and the more
s-content electrostatically stabilized acidic the hydrocarbon (i.e., it has a lower pKa value).
due to the role of a metal counterion in determining the carbanion's stability (and ease of synthesis) - we might expect
significant solvent effects when studying carbanion reactions
The product of reducing a C=O bond is
simply an alcohol
H-
small - NOT a great nucleophile excellent base
Carbanion Stability - Hybridization - carbanion electron pairs order of stability:
sp > sp2 > sp3 > p
Vinyl Carbanion Lone Pair Stabilization - that minimum of energy can be reached if the carbon is
sp2 hybridized; nominal 120° angles between domains and 33% s character in the lone-pair hybrid
The H-C-H bond angles in cyclopropane and ethylene are 115° and 118°, respectively. Cyclopropane and ethylene have very similar pKas - for both species, the carbons utilize approximately
sp2 hybrids for their C-H bonds
Less stabilized carbanions
sp3, sp2
Carbanion Stability - Resonance - Resonance interactions (and their MOs) stabilize carbanions by
spreading out the charge density of the carbanion lone pair over a larger area of the molecule
Carbanion Stabilization Summary - Moderately Stabilized:
stabilization via hybridization (increased S character) resonance stabilization
Hyperconjugation is __________ for carbocations, but ______________ for carbanions - why?
stabilizing destabilizing - because it's adding negative charge to an already negative atom
Tip for Epoxide Reactions:
start with drawing the part of the molecule that does NOT change counting carbons can also help eliminate choices
Carbanion Stability - Hyperconjugation - least stabilized
tertiary
Carbanion Stabilization Summary - Resonance Stabilization (least stabilized to most stabilized)
tertiary allyl secondary allyl primary allyl (pKa 42), secondary or tertiary benzyl (R = H or CH3, pKa 42) primary benzyl (pKa 41)
With H-
the carbon skeleton does NOT change at all
With R-
the carbon skeleton gets larger - we are forming a C-C bond
Main difference between using H- and R- to attack a ketone or aldehyde:
the effect on the carbon skeleton
Carbanion Stability - Hybridization - HIGHER S Character is favorable as
the excess density can better be stabilized by the now more proximate nucleus
Once a magnesium atom is inserted between a C-X bond,
the newly formed C-Mg bond is somewhat ionic in character (because carbon is so much more electronegative than magnesium)
We have for the first time explicitly acknowledged
the presence of a metal counterion (Li+) for the carbanion
Vinyl Carbanion Lone Pair Stabilization - That arrangement contrasts with
the sp-hybridized vinyl cation, which only has two electron domains and no s character is "wasted" on the empty orbital (it is pure p in this case)
Boron and Aluminum are each capable of forming a fourth bond in order to obtain an octet, but
then each element will bear of formal charge of -1
Carbanion Stability - Hyperconjugation - The hyperconjugative MO mixing between the (filled) carbanion orbital and the (filled) sigmaC-H bond results in a 2-orbital/4-electron configuration:
there is more destabilization than stabilization!
less stabilized carbanions cannot readily be prepared by simple deprotonation -
there is no base strong enough (kinetically slow also)
Bond is almost ionic =
think carbanion
reaction that converts an alcohol into an aldehyde or carboxylic acid
this reaction would constitute an increase in oxidation state
Treat as ionic -
treat all electrons as being completely unshared (all ionic bonds)
Carbanion: carbon with
two electrons
Alkyl halide - treat with metal (focusing on Mg and Li) →
undergoes oxidation-reduction reaction
Want to prepare carbanions in a way that they persist in solution and engage in substitution reactions as potent nucleophiles
unlike fleeting carbon radicals or carbocations
we can alkylate a terminal alkyne, or we can
use a Grignard reagent to attack a ketone or aldehyde
hydrocarbon deprotonation by typical bases is quite ineffective at generating a
useful amount of carbanion, 1 + 2 → 3
Even for the most acid hydrocarbon species, hydroxide would only provide
vanishingly small quantities of the carbanion
the type of bond between the carbanion and a metal counterion will
vary along a covalent/ionic continuum as per the metal and the carbanion
Carbanion Stability - Hyperconjugation - Hyperconjugative (and related) interactions between a carbanion and an adjacent sigma electron pair play a very ___________ _______ in carbanion stability compared to the role that these types of interactions play in either radical or carbocation stability
very different
Grignard reagents are incredibly important because
we are not only converting a C=O bond into an alcohol, but we are also introducing an R group into the compound
Combination of the organic halide with either metallic magnesium or metallic lithium in an inert ether solvent, often with the aid of an "activator" to scour the metal surface,
will lead to a facile oxidation-reduction reaction
Carbanion Stability - Hyperconjugation - If one hyperconjugative interaction is bad, it stands to reason that two or three such interactions
would be worse (more destabilizing)
Solvent Effects - If you have a Grignard,
you CANNOT have a PROTIC solvent
LEAST Stabilized
100% P, 0% S
Carbanion Stability - Hyperconjugation - Stability of Alkyl Halides
1° > 2° > 3° since hyperconjugation is destabilizing, less hyperconjugative opportunities = most stabilized
Reactions of Alkyl Halides - Grignard Reagents - R-X "R"
1° alkyl 2° alkyl 3° alkyl alkenyl aryl
Carbanion Stability - Hyperconjugation - results in
2 orbital/4 electron mixing
Terminal Alkynes have pKas in the range of
20-30 depending on the nature of the "R" group
The H-C-H bond angles in cyclopropane and ethylene are 115° and 118°, respectively. Cyclopropane and ethylene have very similar pKas. What is the main reason for that similarity?
Both carbanions have similar s character in their lone-pair orbitals.
Comparing Electronegativity Values for C and Mg:
C is much more electronegative than Mg - therefore, carbon pulls more strongly on the electron density and will develop a negative charge
This is a _______ _______ _____________ reaction
C-C bond forming
The H-C-H bond angles in cyclopropane and ethylene are 115° and 118°, respectively. Cyclopropane and ethylene have very similar pKas - in both carbanions, the main stabilizing factor is the s character in the hybrids holding the lone pair - in ethylene that hybridization is the result of the __________ bond, whereas in cyclopropane it results from ___________ the _________ _________
C=C bond minimizing the angle strain For both species, the carbons utilize approximately sp2 hybrids for their C-H bonds.
Grignard reagents also attack other compounds possessing a
C=O bond (such as esters) to produce alcohols
R (partial negative charge) ~~
Carbanion, "R-" = VERY STRONG nucleophile (HIGH energy HOMO) and also very strong base
Reactions of Alkyl Halides - Grignard Reagents - R-X "X"
Cl Br I
Insert Mg into a C-X bond where X is
Cl, Br, or I R--Mg--X
Reactions of Alkyl Halides - Grignard Reagents - The Halogen can be:
Cl, Br, or I although chlorides are LESS reactive than bromides and iodides
All carbanion-type reagents described so far are
EXTREMELY sensitive to water and other acidic-proton-containing materials AND SO they are COMPLETELY INCOMPATIBLE with aqueous environments, alcohols, thiols, acids, N-H amines, etc.
Reactions of Alkyl Halides - Grignard Reagents - Mg
Ether or THF
R-MgX
Grignard Reagent where R is an alkyl group
R(partial negative charge)----MgX(partial positive charge)
Grignard Reagent (carbanion - covalent bond)
The most commonly used versions of these reduction reactions deliver either
Grignard reagents or organolithiums
Hyperconjugation was mildly stabilizing with radicals and more strongly stabilizing with carbocations, but the
electron surplus of a carbanion ensures that such interactions will be STRONGLY DESTABILIZING
Neither oxidation or reduction:
One new C-H bond and one new C-Br bond formed
Carbanion Stability - Hyperconjugation - destabilizing rationale can be appreciated by examining the corresponding MO interactions:
The hyperconjugative MO mixing between the (filled) carbanion orbital and the (filled) sigmaC-H bond results in a 2-orbital/4-electron configuration
double bond between X-metal =
VERY polarizable
Grignard and lithium reagents are formed readily from the
corresponding halide with I > Br > Cl defining the facility of formation
R(partial negative charge)---Li(partial positive charge) + LiX
covalent bond STRONGEST Nu: (R-Li)
Oxidation
decreases electron density on carbon by: FORMING one of these: C-O, C-N, C-X or BREAKING this: C-H
Terminal Alkynes are readily
deprotonated by alkyl carbanions
Carbanions synthesis by REDUCTION...NOT
deprotonation
common method of carbanion preparation is by
deprotonation
we can use alkyl carbanion, if available by some means, as the "superbase" in a
deprotonation of a more acidic hydrocarbon at least for one important class of hydrocarbons - the terminal alkynes
Carbanion Stability - Hyperconjugation of a carbanion with an adjacent sigma bond (or lone pair)
destabilizing
Solvation of a metal counterion plays a crucial role in
determining the carbanion's stability (and ease of synthesis)
We will assume that the precise nature of the metal counterion (say Li+ vs. Na+ vs. MgBr+, etc.) will not have a
dominant effect on either carbanion synthesis, stability, or reactivity so we may just illustrate carbanions with a generic metal M, as in R-M
alkyl -
double bond
Carbanion Stability - Hyperconjugation - these stabilities do NOT take into accound
either solvent effects or metal counterion effects - both of these variable can have a BIG impact on carbanion stability and facility of carbanion synthesis
