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