Exam 2

Activators

Electron donors and generally direct a second electrophilic attack to the ortho and para positions. Also make the reaction occur faster and more readily.

Deactivators

Electron acceptors, which generally direct electrophiles to the meta positions. Slows down electrophilic aromatic substitution on the benzene ring.

Electron Donor (activator) examples

-CH3, other alkyl groups

Electron Acceptor (deactivator) examples

-CF3, -NR2, -OR, -X (halogens), -COR, -C≡N:. -NO2 (one N=O bond and another N-O bond), -SO2OH

O = -NR2, -OR, -F, -Cl, -Br, -I

NO2 can be -COR, -C≡N:, -NO2, SO2OH

Rates of Electrophilic Attack on Derivatives of Benzene

The more electron rich the arene (benzene derivative) the faster the reaction. The more electron poor the arene the slower the reaction.

Fast reactions: -NH(C6H5), -OH, -CH3

Slower Reactions: -H, -Cl, CO2CHCH3

Really Slow reactions: -CF3, -NO2

Gives ortho and para substitution. Virtually no meta substitution is observed (as a result of the meta resonance forms not having a tertiary carbocation). Ortho and Para not formed equally due to steric effects. Thus is the substituent is larger the major product will shift toward para.

Meta directing because there is a destabilized resonance form in both the para and meta attacks. This results from the positive charge being on the carbon that is close to the electron withdrawing group (the aldehyde).

This also occurs with phenol because -NH2 and -OH are both strongly activating so the reaction proceeds very rapidly.

This and anisole (methoxybenzene) are less strongly activated so monosubstitution occurs.

Same logic for aniline. They both have a strongly contributing all-octet form (shown in red).

Ortho and Para have a strongly destabilized cation and meta has a less destabilized cation. Meta avoids placing the positive charge next to the electron withdrawing carboxy group.

While they are deactivating, they direct ortho and para substitution due to an all octet form.

Ortho and Para director strengths

(most activated) -NH2 > -NHR > -NR2 > -NHCOR > -OH > -OR (least activated) All of these have lone pair electrons on the atom connected to the benzene carbon.

Weak activators: Alkyl > phenyl

Weak deactivators: halogens (all approx equal)

Meta Director strengths

(least deactivated) -COOH > - COOR > -COR > -CF3 > -C≡N > -SO2OH > -NO2 > NR2 (most deactivated and least reactive)

Disubstituted Benzene Rules

1. The most powerful activator controls the position of attack.

2. The directing power of substituents can be ranked into three groups: NR2, OR > X, R > meta directors (higher ranking groups override the lower ranking groups)

3. When the products are predicted on the basis of guidelines 1 and 2 you can usually discount ortho attack to bulky groups or between two substituents.

4. These guidelines are also applicable to more highly substituted benzenes.

Interconversion of Nitro (meta director) with Amino (ortho, para director)

-NO2 ----(Zn(Hg), HCl or H2, Ni or Fe, HCl)----> -NH2

-NH2 ----(CF3COOOH - one O is double bonded to the C)----> -NO2

This is a useful strategy if you need a meta substituted aniline or an ortho/para substituted nitrobenzene.

Interconversion of Acyl (meta director) with Alkyl (ortho, para director)

-COR ----(H2, Pd, CH3CH2OH or Zn(Hg), HCl, Δ)----> -CH2-R

-CH2-R -----(CrO3, H2SO4, H2O)----> -COR

This can also be used to synthesize alkylbenzenes without the complication of alkyl group rearrangement and overalkylation.

Friedel-Crafts Electrophiles and strongly deactivated benzene rings

-NO2 will strongly deactivated a benzene ring so if you nitrate the ring first and then try to react it with CH3COCl, AlCl3 (Friedel-Crafts), no reaction will occur because friedel-craft electrophiles don't attack strongly deactivated benzene rings. If you do fiedel-craft first and then nitration after, however, the reaction will give you the desired product.

Using Reversible sulfonation to synthesize ortho-disubstituted benzenes.

If you nitrate a benzene with a bulky substituent you will get mostly para product, but what if you want ortho product? SO3 is a bulky electrophile so it will go almost entirely para when you react ---(SO3, conc. H2SO4). Then you nitrate the benzene ---(HNO, H2SO4)---> and with the para position blocked it will be forced to go ortho. Then you desulfonate ----(H+, H2O, Δ)---> and you have the desired product.

Preventing multi substitution.

NH2 and OH groups are so highly activating that they are hard to stop at monosubstitution. If you slightly deactivate the group first you can prevent this. For example for an aniline (-NH2), ---(CH3COCl---> will turn the -NH2 into -HNCOCH3. Then you can sulfonate ---(SO3, conc. H2SO4)---> to block the para position, nitrate ---(HNO3)---> and then deprotect ---(1. H+, H2O, Δ; 2. -OH, H2O)---> to get the desired product (an ortho -NH2 and -NO2 also called o-Nitroaniline).

Naphthalene Electrophilic Substitution

Activated. Attack at C1 allows two of the resonance forms of the intermediate to keep an intact benzene rings rather than 1 intact benzene ring seen by attack at other carbons. For this reason electrophilic substitution will occur at C1.

Electrophilic attack on substituted Naphthalenes

An activating group will direct the incoming electrophile to the same ring (para will be major contributor, ortho will be a minor contributor). A deactivating group will direct it away from the ring it is connected to (preferably to C5 and C8).

Regioselectivity of larger Polycyclic Aromatic Hydrocarbons

Based on the most stable or least destabalized resonance structures.

Naming Aldehydes

Treated as a derivative of alkane with the ending e replaced by -al to form an alkanal.

Ex. ClCH2CH2CH2COH = 4-Chlorobutanal

When the CHO group is attached to a ring the compound is called a carbaldehyde and the carbon connected to the CHO group becomes carbon 1.
Ex. CHO on a cyclohexane = Cyclohexanecarbaldehyde. CHO on a benzene = Benzencarbaldehyde (= Benzaldehyde).

Naming Ketones

Named as alkanones. Ketones can be part of a ring unlike aldehydes and are named as cycloalkanones.

Ex. 4-Chloro-6-methyl-3-heptanone

2,2-Dimethylcyclopentanone (ketone group is at carbon 1)

1-Phenylethanone (COCH3 group in a benzene)

Aldehydes and Ketones with other functional groups

7-Hydroxy-7-methyl-4-octen-2-one

HC≡CCOH = Propynal

5-Bromo-3-ethynylcycloheptanone

4-Formylcyclohexanecarboxylic acid (formyl = CHO substituent,acetyl = CH3CO)

CH3COCH2COH = 3-Oxobutanal (ketone named as an oxo when there isalso an aldehyde present)

Selective AlcoholOxidation

CH3CHOHC≡C(CH2)3CH3---(CrO3, H2SO4, acetone)---> CH3COC≡C(CH2)3CH3

Reagents: PCC, CH2Cl2, Na+-OCOCH3. Water causes overoxidation of primary alcohols (it will have two OH groups and treatment with PCC will turn it into a carboxylic acid).

Manganese Dioxide

Only attacks allylic OH groups (adjacent to a C=C bond) and turns them into =O groups (ketone).

Hydration of C≡C bonds (markovnikov hydration of alkynes)

Yields enols which tautomerize to ketones.

Ex. RC≡CR ---(HOH, H+, Hg2+)---> [RHO-C=CH2] -----> RCOCH3

Anti-Markovnikov Hydration of Alkynes

Using hydroboration-oxidation with HB-(cyclohexane)3. The OH will attach to the terminal carbon and after it tautomerizes it becomes an aldehyde.

Carbonyl Group Ionic Additions

-CO- + X-Y ---> -YCOX- (product is attached to the chain with an -OX attachment and a -Y attachment).

NaBH4 and LiAlH4

Aldehyde ---(1. LiAlH4, (CH3CH2)2O; 2. H+, H2O)---> primary alcohol. Neither reagent reduces carbon carbon double bonds though.

LiAlH4 works better for ketones.

Nucleophilic addition-protonation (basic conditions)

Attack by the nucleophile breaks the C=O bond when it attaches and the bond becomes a C-O- bond (alkoxide ion). Then ---(HOH)---> turns it into a C-OH bond.

Electrophilic protonation-addition (acidic conditions)

The C=O bond gets protonated to C=OH+ (carbonyl group) and then the nucleophile attacks it ---(:NuH)---> attaches to the carbon breaking the C=OH+ bond to C-OH and in the final step the nucleophile is deprotonated from NuH to Nu.

Addition of water to a ketone or aldehyde creates a geminal diol, which is a reversible reaction.

This can be done with either an aldehyde or ketone.

Hemiacetals can be formed by bases, but acetals must be formed by acids due to the required steps after the hemiacetal is formed (requires protonation of OH group).

Reaction of a ketone with HOCH2CH2OH, H+ creates a cyclic acetal that protects the carbon from being attacked by nucleophiles. The process can then be reversed after the reaction --(H+, H2O)---> and thus the molecule will be deprotected.

Thioacetal Hydrolysis

---(H2O, HgCl2, CaCO3, CH3CN)---> will turn a cyclic thioacetal into a ketone.

Cyclic Thioacetal Formation

---(HSCH2CH2SH, ZnCl2, (CH3CH2)2O)---> will form a cyclic thioacetal where a ketone C=O bond used to be.

Formation of a hemianimal and then an imine. This is called a condensation reaction because water is eliminated.

Method of deoxygenation

Carried out with a strong acid and ---(HOCH2CH3)2O)---> at high temperatures. This helps in alkylbenzene synthesis by reducing Friedel-Crafts acylation products.

Use a phosphorous ylide to attack an aldehyde or ketone. This creates a new carbon carbon double bond. Allows for more selectivity in the formation of a carbon carbon double bond as opposed to attempting to accomplish it through elimination. Gives mostly cis product. for non conjugated ylides and trans if they are conjugated.

First step in the Wittig reaction. The second step in the diagram is ylide formation.

The second step in the Wittig Reaction

Forms a C=C bond where the C=O bond was (expelling the O) and where the (C6H5)P=C bond is.

Creates a silver layer that adheres to glass.

Explains the acidity of aldehydes and ketones.

Preparation of Enolate Ions

Use LDA to deprotonate.

The thermodynamically more stable keto form generally predominates.

Keto-Enol Equilibria

Substituents can shift resulting in a mixture of products. As a result of these rapid interconversions if you treat it with D2O every alpha hydrogen will be switched with a D. Also optically active products will become racemic and trans isomers will predominate as they are more stable.

Acid Catalyzed alpha Halogenation of Ketones

Step 1. Enolization (ketone turns into an alkenol).

Step 2. Halogen Attack: the halogen breaks the double bond and attaches to the less substituted carbon (so the + is on the more stable carbocation).

Step 3. Deprotonation: The H falls off of the C=OH bond getting rid of the + charge.

Halogenation slows down enolization so this only occurs once.

Further halogenation doesn't occur because it slows down enolization (protonation is disfavored (the halogen is electron withdrawing making the O less basic than an unsubstituted ketone).

See the first example. Proceeds through an enolate ion (carbon has an alpha carbon removed, which gives it a negative charge that can react with the other carbon). Proceed through an Sn2 mechanism so it's really only feasible with primary haloalkanes (otherwise E2 eliminations converts the haloalkanes to alkenes). A second alkylation is also possible if another alpha H is lost.

Polyalkylation Products

Reaction of 2-methylcyclohexane with iodomethane by alkylation results in two monoalkylated products (two different alpha carbons) and two more polyalkylation products (including one where every alpha H has been replaced by CH3).

The dehydrated product that results after heating is called an alpha,beta-unsaturated aldehyde. The reaction is base catalyzed.

Step 1: Enolate generation

Step 2: Nucleophilic attack

Step 3: Protonation

Step 4: Aldol Dehydration (occurs at high temperatures)

The last one is an example of a ketone. Ketones are slightly more stable and thus have less of a driving force for aldol reactions.

Crossed Aldol Condensation

When you have a mixture of aldehydes/ketones (but mostly aldehydes) it results in a mixture of products. Both aldehydes can act as an enolate and both aldehydes can have their carbonyl carbon attacked simultaneously.

In order to avoid this you can use an aldehyde with no enolizable hydrogens (for example 2,2-dimethyl-propanal).

Occurs more rapidly than other aldol condensations.

Formic Acid

IUPAC: Methanoic acid. HCOOH

Acetic Acid

IUPAC: Ethanoic Acid, CH3COOH

Naming Carboxylic Acids

Replace the ending -e with -oic acid. The carboxy carbon is numbered 1 always. Dicarboxylic acids are called dioic acids. Cyclic carboxylic acids are called cycloalkane-carboxylic acids (ex. 1-Bromo-2-chloro-cyclopentane-carboxylic acid). Aromatic counterparts are called benzoic acids.

5-Oxo-4-propylhexanoic acid

COOH at carbon 1, =O at carbon 5 (oxo - ketone), and propyl at carbon 4.

6-heptenoic acid

c=c bond at carbon 6, COOH at C1

Ethanedioic acid

HOOCCOOH

Butanedioic acid

HOOCCH2CH2COOH

Explains high boiling point - hydrogen bonds

There is also a third resonance structure with no double bond and a + charge on the C. This resonance explains the additional deshieldling of the H.

Carboxylic Acid - Acidity

Carboxylic acids dissociate readily into H+ and a carboxylate ion. Electron withdrawing substituents increase the acidity of carboxylic acids (halogens for example).

Similar to resonance of the enolate ion.

Occurs on the carboxy not the hydroxy because a protonated carboxy is stabilized by resonance (the other resonance form has a C=OH+ bond on the other OH.

Formic Acid Synthesis

(an example of carbonation)

NaOH + CO ----> HCOO-+Na ---(H+, H2O)---> HCOOH

Acetic Acid by Oxidation of Ethene

CH2=CH2 ---(O2, H2O, catalytic PdCl2 and CuCl2)---> CH3CHO ---(O2, catalytic Co3+)---> CH3COOH

Acetic Acid by Oxidation of Butane

CH3CH2CH2CH2 ---(O2, catalytic Co3+)---> CH3COOH

Acetic Acid by Carbonylation of Methanol

CH3OH ---(CO, catalytic Rh3+, I2)---> CH3COOH

Carboxylic Acids by Oxidation

Primary alcohols oxidize to aldehydes, which in turn oxidize to carboxylic acids (use aqueous Cr(VI) aka CrO3, other reagents include KMnO4 and nitric acid - HNO3.)

RCH2OH ---(oxidation)---> RCOH ---(oxidation)---> RCOOH

Carbonation of Organometallics

R-MgX + CO2 ---(THF)---> R-COO-+MgX ---(H+, HOH)---> RCOOH

RLi + CO2 ---(THF)---> RCOO-+Li ---(H+, HOH)---> RCOOH

Caboxylic acids from Haloalkanes through nitriles

RX ---(CN-)---> RC≡N ---(1. -OH, 2. H+, H2O)---> RCOOH

This method is preferable to grignard carbonation when the substrate contains other groups that react with organometallic reagents (such as hydroxy, carbonyl, and nitro functionalities)

Undesireable grignard reactions

Grignard reagents will react with hydroxy, carbonyl, and nitro functionalities so these groups need to be protected if grignard synthesis is going to be used.

General Mechanism for Addition-Elimination

X- (a nucleophile) attacks an A=B bond turning it into a A-B- bond and then the leaving group Y, leaves so the A=B bond is regenerated. Y-AH=B ---> X-AH=B

Step 1 produces a tetrahedral intermediate.

Here Y is the leaving group. The catalytic proton is also regenerated.

Base Catalyzed Addition-Elimination`

Step 1: Deprotonation of NuH to Nu- by -B

Step 2: Addition-Elimination: -Nu attacks the C and the C=O bond becomes a C-O- bond (in the tetrahedral intermediate). Then the leaving group leaves while the C=O bond is regenerated.

Step 3: Regeneration of catalyst: -L (leaving group) + H-B ---> LH + -B (or -L can be a base in step 1)

This process helps by converting the poor leaving group (OH) into a good leaving group.

CH3CH2CH2COOH ---(SOCl2)----> CH3CH2CH2COCl

3x cycylohexanecarboxylic acid ---(PBr3)---> 3x cyclohexane with a Br-C=O substituent

Step 1. Addition

Step 2. Elimination

Butanoic Anhydride Formation

CH3CH2CH2COOH + ClCOCH2CH2CH2 ---(Heat, 8h)---> CH3CH2CH2OCOCOCH2CH2CH3

Acid catalyzed ester hydrolysis uses H2SO4, HOH, acetone, and heat.

Results in the formation of a lactone

Amines react with carboxylic acids as bases and as nucleophiles.

Results from the reaction of a carboxylic acid with NH3

Proceeds by way of a tetrahedral intermediate. NH3 attacks C as a nucleophile and C=O bond becomes a C-O- bond. Then the OH gets protonated and leaves, regenerating the C=O bond.

N,N-Dimethylbutanamide

Forms by reacting a dicarbocylic acid (in this case butanedioic acid) with NH3 to form a carboxylic salt and then heating it.

Form from amino acids. +H3NCH2CH2CH2COO----> H2NCH2CH2CH2COOH ---(heat, -H2O)---> a lactam (the cyclopentane one)

Usually the first step is done in THF

Step 1: Acyl bromide formation

Step 2: Enolization

Step 3: Bromination

Step 4: Exchange (one of the products reenters step 2)

Fatty Acids

Derived from the coupling of acetic acid. Formed from acetic acid units in the following steps:

Step 1: Thiol ester formation

Step 2: Carboxylation

Step 3: Acetyl and Malonyl group transfers

Step 4: Coupling

(Requires protein intermediates)

Carboxylic Acid Derivatives reactivity in nucleophilic addition-elimination with water (turning a derivative into a carboxylic acid with water)

[least reactive lowest electronegativity, worst acid] RONR'2 (amide) < RCOOR' (ester) < RCOOCR (anhydride) < RCOX (acyl halide) - [most reactive, best acid, highest electoegativity] . All these derivatives are stabilized by resonance. Decreasing electronegativity of L increases its contribution to the resonance form and thus makes it more reactive.

Most acidic on the left, least acidic on the right

Acyl Chloride Hydrolysis

CH3CH2COCl + H2O ---(OH2 attaches to the carbonyl C)---> CH3CH2C-(O-ClOH2+) ---(-Cl-)----> ---(-H+)----> CH3CH2COOH

Ester Synthesis from Carboxylic Acids through Acyl Chlorides

RCOOH ---(SOCl2)---> RCOCl ---(R'OH, base)---> RCOOR'

Usually done with N(CH2CH3)3 as a solvent

Organometallic reagents convert acyl chlorides into ketones

RLi and RMgX attack the carbonyl group of acyl chlorides to give the corresponding ketone.

Anhydride + H2O --> carboxylic acid

Nucleophilic Ring Opening of Cyclic Anhydrides

Butanedioic anhydride (pentagon) ---(CH3OH, 100 degrees C)----> HOOCCH2CH2COOCH3

Naming Esters

Names as alkyl alkanoates. Cyclic esters (lactones) are named systematically as oxa-2-cycloalkanones.

Methyl Acetate

2,3-dichloro-3-methylbutyl acetate

Ethyl Propanoate

Valerolactone. IUPAC: 5-methyloxa-2-cyclopentanone

Can be acid or base catalyzed. This allows conversion of one ester into another without proceeding through the free acid.

Conversion of a Lactone into an Open-Chain ester

Butyrolactone + 3-Bromopropanol --(H+)--> 3-Bromopropyl 4-hydroxybutanoate. The lactone opens up, adds to the OH and the C=O bond stays next to the O and the O in the lactone ring ends up on the end and becomes OH.

Uncatalyzed Conversion of an Ester into an Amide

Ester O is replaced with NH when an ester is added to R-NH2 (with heat).

Alkylation of an Ester Enolate

CH3COOCH2CH3 (Ester) --(LDA, THF)--> Ethyl acetate enolate ion (-O-Li+ and CH2=C bond) --(CH2=CHCH2-Br, HMPA)--> CH2=CHCH2CH2COOCH2CH3

Naming Alkanamides

Remove -e ending -amide. In cylic systems replace -carboxylic acid with -carboxamide. Substituents on the nitrogen are indicated by the prefix N- or N,N-.

2-bromo-N-methylpentanamide

N-Methylacetamide.

HCONH2 (Name This)

Formamide

Cyclopentane is aza-2-cyclopentanone and cyclohexane is aza-2-cyclohexanone.

The NH2 can then deprotonate the OH to O-

Naming alkanenitriles

Replace the -ic acid of carboxylic acid ending with -nitrile. The CN substituent is called cyano. Cyanocycloalkanes are called cycloalkanecarbonitriles.

Butanedinitrile

Cyclohexanecarbonitrile

Ethanenitrile

Benzonitrile

3-Methylbutanenitrile

Mechanism of the Acid-Catalyzed Hydrolysis of Nitriles

R-C≡N --(H+)--> [R-C≡NH+ <--> R-C+=NH] --(H2O)--> RCNHOH2+ --(-H+)--> RCNHOH ---(H+)---> [RCOHNH2+ <---> RCNH2=OH+] ---(-H+)---> RC=ONH2 --(H+)--> --(H2O)--> RCOOH + +NH4

Mechanism of the Base-Catalyzed Hydrolysis of Nitriles

R-C≡N --(-OH)--> RC=N-,OH --(HOH)--> RC=NH,OH + -OH --(-HOH)---> [RC=NH,O- <---> RCN-H,=O] ---(HOH)---> RC=O,NH2 + -OH ---> ---(H+)---> RCOOH + +NH4

Exam 2

Organic Chemistry 23101 with Kelly at Boston College

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