Formic Acid

The story behind this acid is much more interesting than the acid itself.

The name "formic acid" comes from the Latin word for ants ("formica"). Basically, scientists noticed acidic vapors rising from anthills, so they decided to do what anyone would do - boil up a bucketload of ants and try to isolate the acid. They did, and called it formic acid.

It is useless.

Well it's not useless. It is widely used to preserve feed for livestock during cold winter months. But that was only discovered recently. The scientists who discovered formic acid certainly didn't know that.

If you ask me, they just wanted to boil ants.

Bacteria making you feel VILIFIED? Try SULFANILAMIDE!

Sulfanilamide - based drugs kill nasty bacteria by pretending to be p-aminobenzoic acid. The silly bacteria tries to use the sulfanilamide to make folic acid, but it can't, because it needs p-aminobenzoic acid! So the bacteria can't make any folic acid, and it dies, and we all enjoy a good laugh.

Anyway, you can make these sulfanilamides yourself. Just chlorosulfonate an acetanilide, and then add ammonia. The ammonia will attack the sulfur and knock out the chlorine. Now just hydrolyze the COCH3 off of the amino group and you've got pure 100% home-grown sulfa drug.

If acylating anilines is what you've tried, maybe you should use an acid chloride!

Hi there.

I know that acylating anilides can be a real pain. All you want to do is a simple Friedel-Crafts reaction, and it just doesn't work. It's that darn amino group. That thing attacks acids like a puppy dog chasing a squirrel. And you don't want to add your acyl group to the amino group, you want to add it to the aromatic ring! What's a fella to do?

Luckily, there is a solution. You can use the amino group's little habit to your advantage. Just feed it a little acid chloride, and it will gobble it right up. That will keep it occupied for a while, but won't change the amino's ortho-para directing powers. With the amino group tied up with the acid chloride, you can acylate the aniline to your liking, and when you're done, just throw in a little acid to hydrolyze the amide and clean up your original amino group.

It's a piece of cake, my friends.

CHAPTER 12: IFRARED SPECTROSCOPY AND MASS SPECTROSCOPY

- IR: The theory

o A vibrating molecule with n atoms has 3n-6 modes of vibration

o IR active molecules absorb energy from the rapidly reversing electric field found in an EM wave. This field stretches and compresses the molecule.

o Looser = lower tighter = higher

- IR: Reading the charts

o Conjugated double bonds are looser than normal ones (spread charge)

o Sp³ is looser than sp² (less s character)

o Hydrogen bonding gives broad peaks for OH, sharper ones for NH

o Primary NH (or amide) – 2 spikes, Secondary NH (or amide) – 1 spike

o Aldehydes give a pair at 2700 and 2800

o Carboxylic acid’s OH peak is shifted down to 3000

o Double bonds conjugate carbonyls, lowering them

o The N in an amide pulls electrons away from the C==O, lowering it

o C-N bonds are stiffer and more polar than C-C

- Mass Spec: The theory

o Only the positive ions are detected by the mass spectrometer

o Because HRMS can get the mass to a good number of decimal places, we can figure out exactly which atoms are in the molecule

- Mass Spec: The charts

o The isotopes of atoms come in predictable percentages, and they give rise to M+1 and M+2 peaks

o Molecular ions usually have even numbers and fragments have odd numbers. When nitrogen is involved, it’s the other way around.

o A methyl radical is weak, but ok. A methyl cation can’t be formed at all.

o A branch carbon atom is a good place to cleave since it leaves a secondary or tertiary carbocation

o Allylic-stabilized carions show strong absorption

o Alcohols lose water readily, so you almost never see their molecular ion. Instead you see the “M-18” peak.

CHAPTER 14: ETHERS, EPOXIDES AND SULFIDES

- Ethers

o Polarity of Ethers

§ What dissolves in ether

§ Boiling points of ethers

o Naming ethers

o Mass spectroscopy

§ α carbons

o Synthesis

§ Williamson

· Substrate must be primary, unhindered

· To get your alkoxide…

1. Add Na, K or NaH to an alcohol

2. Add a substrate

· If you’re getting your alkoxide from a phenol, just add NaOH, because the phenol is acidic enough to lose its proton and form the alkoxide. Then add substrate

§ Alkoxymercuration-Demercurization

· Start with an alkene

· Add Hg(OAc)₂ to make a mercuric ion

· Bust it open with the OR of your choice

· Clean up the HgOAc with NaBH₄

§ Bimolecular Dehydration (industrial)

· Fuse two primary alcohols with heat and acid

· Issues:

o Can’t be too hindered

o Equilibrium must favor products

o General conditions for reacting ethers

§ You need an acid to protonate the O, then you have an alcohol as a leaving group

§ You need a strong nucleophile to kick out the alcohol

o REACTION 1: Chopping up ethers with HBr

§ HBr protonates the ether

§ The Br- nucleophile kicks out the alcohol

§ The alcohol gets protonated

§ The Br- nucleophile kicks out water via S_N2

· Since a phenol can’t do S_N2, it will not get brominated. It will stay as an alcohol

o REACTION 2: Autoxidation

§ It’s very simple, people: Ether + oxygen = peroxides. Peroxides + flame = EXPLOSION

- Sulfides

o Synthesis

§ Make a thiolate ion by reacting a thiol (like an alcohol but with an S) with NaOH

§ Have that thiol attack a primary halide (or other good leaving group)

o Oxidizing them

§ You add hydrogen peroxide in acetic acid to oxidize a sulfide once. That makes a sulfoxide. Then you do it again and you get a sulfone.

§ Sulfides are good reducing agents, because it’s very easy to oxidize them.

o Having them do nucleophilic attacks

§ They can attack unhindered alkyl halides to produce sulfonium salts

§ Once you have this sulfonium salt, another nucleophile can attack it and knock out the sulfide as a leaving group

- Epoxides

o Synthesis

§ Using peroxyacids

· Alkene + peroxyacid = expoxide

· However, you can’t have lots of strong acid around, or else it will bust open the epoxide ring before you even get started

· So, you use a weakly acidic peroxyacid called MCPBA

· And you do it in CH₂Cl₂ to keep it aprotic

· The mechanism is concerted, so you retain stereochemistry about the double bond (cis/trans stuff)

§ Making a halohydrin attack itself

· Make a halohydrin

o Take an alkene and add halogen water (bromine water, chlorine water)

o The double bond attacks one of the chlorines and makes a halonium ion (+)

o The water attacks the +

o The water loses a H, leaving you with a halohydrin

· Add a base to the halohydrin

o The base rips the proton off the OH group

o The OH turns into an O-

o The O- knocks out the halogen via S_N2

o It’s good to use bulky bases so that they take the proton from the OH but don’t knock out the halogen via S_N2

o Busting epoxides open: Acids

§ Acid + water

· The acid protonates the O, the water attacks the vulnerable + charge on one of the carbons

§ Acid + alcohol

· Same concept, just OR instead of OH, so you get OR stuck on the former epoxide

§ HCl, HBr, HI

· The H protonates and the Cl- or Br- opens the ring.

· Then, the OH is protonated and bumped out via another Cl-, Br-, etc.

o Busting open epoxides: Bases

§ To go from ether to alcohol using a base is thermodynamically unfavorable and has a high activation energy. However, going from epoxide to alcohol has a lower activation energy and is thermodynamically favorable

§ The base attacks the carbon and pops out the O from the epoxide. The O then gets protonated by water

§ Again, you can use an alkoxide ion (CH₃O-) to put something on one of the carbons besides OH

§ You can use ammonia as your base

· Ammonia can pair up with three epoxides on the same N

o Where stuff attacks when you’re opening an epoxide ring

§ Acids: When there’s an acid around, the epoxide gets protonated and there’s a partial + on one of the carbons, which will be on the more highly substituted one. The acid goes for that one.

§ Bases: The base attacks the less hindered carbon. This includes Grignards.

CHAPTER 17: REACTIONS OF AROMATIC COMPOUNDS

- The Sigma complex

o When the double bonds from an aromatic ring donate their electrons to a strong electrophile, it forms a sigma complex because there is a new sigma bond between the aromatic ring and the electrophile

o The positive charge exists ortho and para to the site of the electrophile being added

o The sigma complex is not aromatic, but once the proton at the site of addition gets abstracted, the ring goes back to being aromatic because the electrophile donates a p orbital to the ring

- Sticking a halogen onto a benzene ring

o You start with Br-Br, but that isn’t a strong enough electrophile to pull electrons out of the double bonds in the benzene

o You mix the Br₂ with FeBr₃, which bonds with one of the electron pairs on one of the Br molecules. In this complex, the Br in between the other Br and the Fe has a partial positive charge. Then, the double bond can attack the leftmost Br, which then gives an electron pair to its partially positive neighbor, forming the sigma complex.

o Then, the FeBr­₄- acts as a base and rips out the hydrogen, leaving the final product.

o The transition state is rate-determining, and is endothermic (because it makes an aromatic nonaromatic)

o Overall, the substitution of Br into the benzene ring is exothermic, but you require the Lewis acid catalyst (FeBr₃, because it sucks in the electrons from the Br-Br)

o When using chlorine, you use AlCl­₃ as your catalyst

o When using iodine, you need HNO­₃, nitric acid. This oxidizes the iodine, which removes electrons from it and makes it electrophilic. It also produces NO₂ and water.

- Sticking an NO₂ group onto a benzene

o You mix benzene and nitric acid in sulfuric acid.

o The sulfuric acid protonates the OH group in the nitric acid. A protonated OH group is an OH₂ group, or water. So that leaves. You’re left with NO₂, which is nitronium.

o The middle of the nitronium is a positively charged N. The benzene double bond attacks this N and forms the sigma complex.

o The HSO₄- ion left over from the protonation acts as the base to abstract the H

- Sticking a sulfonyl group onto a benzene

o Add SO₃ to benzene in sulfuric acid.

o The SO­­₃ has resonance forms where the oxygens are – and the central S is +. This central S is a strong electrophile and gets attacked by the double bond in benzene.

o The HSO₄- ion abstracts the proton from the sigma site, and the sulfuric acid present protonates the O- in the SO₃ group, forming benzensulfonic acid.

§ Blast from the past: you can use this product with alcohols to stick an OTs or tosylate group where an OH group used to be… that OTs group is a good leaving group, etc.

- Taking a sulfonyl group off of a benzene

o You mix the sulfonated benzene with dilute acid and heat and water (steam)

o The acid protonates the ring and recreates the sigma complex. Then, the SO₃ can leave the benzene ring and react with the water to form normal sulfuric acid (the equilibrium favors the sulfuric acid, so the SO₃ gets used up).

- Putting D into a benzene ring

o If you react benzene with D₃O⁺, you form a sigma complex with one of the carbons α to the + carbon having one H and one D. Then, either the H or the D is abstracted to give the substituted benzene

o The final equilibrium shows the relative concentrations of H and D in the solution

- The categories of groups that you can stick on benzene and what they do

o Activating groups make substitutions go faster, deactivating groups make substitutions go slower

o Ortho-para directing groups result in substitutions ortho and para to them, meta directing groups result in substitutions meta to them

o Example: toluene

§ When you try nitrating a toluene, the NO₂ could come in at any carbon

§ When it sticks to the carbons ortho and para to the CH₃ of toluene, one of the resonance forms has a + charge on a tertiary carbon, making the overall transition state more stable

§ With meta, it’s still a little more stable than benzene because the CH₃ group is electron donating.

- Sticking different things on benzene promote different reactions

o Alkyl groups: inductive stabilization, they stabilize the transition state by donating electron density to the + charge area

o Methoxyl groups: the O back donates a pair of pi electrons into a double bond with the adjacent carbon, making the + charge more stable

§ When the substituent is added ortho or para to the methoxyl group, one of the positive charges from the resonance forms lands on the carbon next to the O. This positive charge then goes onto the O which back donates an electron pair to double bond with the C (very stable)

o Amino groups: the N does a job similar to O in the methoxy group, donating its available pi electrons

o Nitro group: strongly deactivating, slows down reaction, puts a positive charge on the N next to the carbon in the ring. This means that any attack at the ortho or para positions puts 2 + charges next to each other which is BAD. So the whole reaction is slower, of course, but of the products that you do get, you get more of the meta.

o You can apply this to other substituents with double bonded O’s (which such up electron density, leaving the atom next to the carbon with a partial positive charge) – such as carbonyls, sulfonic acid, esters, cyanos (nitrogen, but same idea), ammonia, etc.

o Halogens:

§ they withdraw electron density from the ring, which means they are deactivating, because you want the ring to have lots of electron density to draw in the electrophile

§ they also back donate electron density because of their lone pairs

§ so it’s harder for the substituents to attack, but when they do, they will be ortho-para so that the + charge can land next to the halogen in one or more of the resonance forms.

§ When that + charge gets there, it’s like a halonium ion (-X⁺-), and is more stable then without it (meta attack)

- When you have competing effects

o There are 3 classes of groups

§ Strong: the powerful ortho para directors

§ Medium: ortho para directors like alkyl and halogen

§ Weak: meta directors

o The group of the stronger class dominates. If they are within the same class, you get a mixture

o If you have more than one ring, pick one ring that is most activated and consider the activation of that ring only!

- Friedel-Crafts alkylation

o For tertiary halides:

§ Mix your tertiary halide with a lewis acid catalyst (sucks up electrons) such as aluminum trichloide. That takes the halide off of the alkyl group and leaves you with a carbocation

§ The aromatic ring attacks the carbocation

§ The AlCl₄^- is the base that abstracts the proton

o For primary halides

§ Mix the primary halide with the same lewis acid. This time, the carbocation does not break off, but there is a partial positive charge on the carbon α to the halogen.

§ The aromatic ring attacks this carbon, and the AlCl₄- breaks off and then acts as the base

§ This is basically S_N2

- How to prepare various carbocations for the F-C reaction

o Alkenes + HF = carbocation (remember the markovnikov orientation)

o Alcohols: the O donates a lone pair of electrons to the B in a BF₃, forming a BF₃OH leaving group and a carbocation, which gets attacked by the ring

o Later, the BF₃OH acts as the base and HF breaks off, leaving BF₂O, which is NOT what you started with (BF₃), so you need a full equivalent of starting material

- Problems with F-C

o If the aromatic ring has a deactivating group, the synthesis doesn’t work

o Carbocations rearrange

o Once you put an alkyl group onto benzene, the product becomes activating, even more activating than benzene. Therefore, it will react with your halogenated substrate faster than the benzene itself, and you will only get a small amount of mono-substituted produc.

o Solution? Add a ton of benzene. Or use another system.

- Friedel-Crafts acylation

o You start with an acyl halide, and mix it with a catalyst like AlCl₃

o The catalyst takes available electrons from the halogen atom and rips it off

o Now you are left with an acylium ion, which has a positive charge on the carbon in one of the resonance forms

o So the ring attacks that carbon and the Cl- acts as the base, forming HCl

o Afterwards, the O part of the carbonyl that is now attached to the aromatic ring draws in the AlCl₃ to form a complex, which can be hydrolyzed off with water

o The acylium ion is usually bulky, so it mostly adds in para

o The acylium ion is stable, so it doesn’t rearrange

o The product of an acylation has a carbonyl group, which makes for a deactivated product, hindering further reaction

- Turning acylation products into alkylation products using the Clemmenson reduction

o You start off with your normal F-C acylatoin

o You then use zinc in aqueous HCl to reduce the carbonyl back to an alkane

- How to make an aldehyde out of benzene (Gatterman-Koch)

o Carbon monoxide reacts with HCl to make HC==OCl, which is unstable. Along with AlCl₃ and CuCl, you get the HC==O ion, which gets attacked by benzene

CHAPTER 16: AROMATIC COMPOUNDS

- Cyclic MO’s

o Besides the bottom and top MO, the MO’s come in degenerate pairs

o Instead of a node at each antibonding interaction you have pairs of antibonding interactions that lie along a nodal plane. As you increase the energy of a MO, you add a nodal plane, not one antibonding interaction (as before)

- The benzene MO

o All the electrons are very comfortable, because they are in low lying, bonding orbitals

- The cyclobutadiene MO

o The last two electrons have to get isolated into two nonbonding orbitals. It’s like having a diradical. If you thought plain old radicals were unstable, this is WORSE.

- What’s the official definition of aromatic

o It needs to be cyclic, with conjugation, no sp3 hybridization, a continuous ring of p orbitals (planar), and spreading the electrons around the ring must lower the energy

o Sometimes, spreading the electrons around raises the energy, as in cyclobutadiene. That’s called antiaromatic

o Sometimes, you have a ring that you might think is aromatic, but it doesn’t meet the criteria. That’s called nonaromatic.

- Huckel’s Rule

o If a ring has a continuous p system, you can use this rule

o 4N + 2 = aromatic

o 4N = antiaromatic

- Aromatic ions

o You can apply Huckel’s rule to ions, and those that are aromatic will be very stable and unreactive.

- Nitrogen

o Pyridine has a lone pair of electrons; the reactions that involve these electrons do not affect the stability of the ring and you don’t count those electrons for Huckel’s rule

o Pyrrole has a nitrogen with lone pairs that interact with the ring. That makes it a weaker base, because taking a proton in means disrupting the stable ring structure

o Pyrimidine has two basic nitrogens (6 membered ring)

o Imidazole has one basic, one non-basic nitrogen (5 membered ring)

o Purine is a fusion of pyrimidine and imidazole

- Furan and Thiophene

o Are basically the same as pyrrole, but with a lone pair instead of the H sticking out

- Bigger aromatic chains

o These can react similarly to normal alkenes

- UV specs of aromatics

o There is a characteristic benzenoid band around 254