Aromatic and Carbonyl chemistry

Question 1

What are 4 oxidation levels?

Answer 1

0 - just C—C/H bonds.

1 - Per carbon: 3 C—C/H bonds, 1 C—X bond (or a double bond).

2 - Per carbon: 2 C—C/H bonds, 2 bonds with X (either 2 singular with 2 X or double with 1 X)

3 - Per carbon: 1 C—C/H bonds, 3 bonds with X (either 3 singular with 3 X; or 1 double with 1 X and 1 single with 1 X)

4 - Per carbon: no C—C/H bonds, 4 bonds with X (either 2 double bonds with X; 1 double bond with 1 X and 2 single with 2 X; 4 single bonds with X).

Question 2

Can aldehydes undergo reduction?

Answer 2

YES, aldehydes can be reduced to primary alcohols with LiAlH4 or NaBH4.

Question 3

Can aldehydes undergo oxidation?

Answer 3

YES, aldehydes can be oxidized to carboxylic acids with chrome oxide (or manganese oxide) ions and strong acids.

Question 4

Can ketones undergo reduction?

Answer 4

YES, ketones can be reduced to secondary alcohols with LiAlH4 or NaBH4.

Question 5

Can ketones undergo oxidation?

Answer 5

NO, otherwise it will require cleavage of the initial molecule.

Question 6

Can primary alcohols undergo oxidation?

Answer 6

YES, they can be oxidised straight away to carboxylic acids (just through the intermediate aldehydes step) with chrome oxide (or manganese oxide) ions and strong acids.

Question 7

Can secondary alcohols undergo oxidation?

Answer 7

YES, they can be oxidised to ketones with chrome oxide (or manganese oxide) ions and strong acids.

Question 8

Can tertiary alcohols undergo oxidation?

Answer 8

NO, otherwise it will require cleavage of the initial molecule.

Question 9

Can carboxylic acids undergo reduction?

Answer 9

YES, they can be reduced straight away to primary alcohols (just through the intermediate aldehydes step) with LiAlH4 or NaBH4.

Question 10

What is the orbital structure of carbonyl group?

Answer 10

• C===O
• Dipolar (Oxygen has partial negative charge and Carbon has partial positive charge).
• Trigonal planar.
• There is a pi-bond (2 p-orbitals perpendicular to the plane).
• sp2 hybridisation (both C and O) for a sigma-bond.
• Oxygen has 2 lone pairs of electrons (on plane).

Question 11

What are the most characteristic reactions for carbonyl compounds?

Answer 11

Nucleophilic addition - nucleophiles attack partially positive carbonyl carbon (more common for aldehydes and ketones).

Nucleophilic substitution of X (more common for carboxylic acids and their derivatives).

Question 12

Why acid catalysis works for nucleophilic addition for carbonyl compounds?

Answer 12

Proton attaches to lone pair of electrons on carbonyl Oxygen, making it positively charged.

Two resonance forms appear: one with double bond and positive charge on O; another with hydroxyl group and positive charge on carbonyl carbon (carbocation).

More resonance forms - more stable and hence energetically favourable transition state - reaction is favoured.

Carbocation attracts nucleophiles even stronger.

Question 13

Why base catalysis works for nucleophilic addition for carbonyl compounds?

Answer 13

One way: OH- is actually a direct nucleophilic attack on carbonyl compound.

Another way: OH- removes H+ from the nucleophile, making it more negatively charged (creating an attacking lone pair).

Question 14

How nucleophilic addition is catalysed?

Answer 14

Through acid and base catalysis.

Question 15

What is a hemiacetal/hemiketal and how it is formed?

Answer 15

Hemiacetal/hemiketal is an aldehyde/ketone which underwent nucleophilic addition by alcohol. They are intermediate products.

1) alcohol attacks partially positive carbonyl carbon with hydroxyl oxygen lone pair.

2) pi-bond in C===O is broken, and carbonyl oxygen becomes negatively charged.

3) the proton which dissociated from alcohol attaches to negative charge on the former carbonyl O.

Question 16

What is acetal/ketal and how it is formed?

Answer 16

Acetal/ketal is hemiacetal/hemiketal which underwent substitution of its OH group, and it was replaced with the second OR. They are complete products of alcoholic nucleophilic addition.

Question 17

What are Schiff bases (imines) and why they are important?

Answer 17

Schiff bases (imines) are the special types of products of nucleophilic addition, which use ammonia derivatives as nucleophiles, and end up having C===NR instead of 4 single bonds.

Schiff bases (imines) formation is an important process in active sites of many enzymes.

Question 18

How are Schiff bases (imines) formed?

Answer 18

Formation of hemiaminal:
1) primary amine attacks carbonyl carbon with its lone pair of electrons on N (N becomes positively charged).

2) C===O pi-bond is destroyed and O becomes negatively charged.

3) One hydrogen detaches from amine to restore neutral charge on N.

4) The same hydrogen than attaches itself to negatively charged oxygen.

Formation of imine:
5) Acid catalysis: OH is protonated and O becomes positively charged.

6) Former carbonyl O detaches itself from the rest of the molecule to restore neutral charge on O.

7) N donates its lone pair again to reform double bond with former carbonyl C, and N becomes positively charged (imunium ion).

8) Another hydrogen detaches from amine to restore neutral charge on N. It regenerates acid.

Question 19

What is keto-enol tautomerism?

Answer 19

Ability of some aldehydes/ketones to turn into C===C forms by transferring H from the carbons that are the nearest to C===O (alpha-carbons) to carbonyl oxygen or bases.

This process can make alpha-carbons negatively charged, turning them into nucleophiles.

Question 20

What is aldol condensation?

Answer 20

Two aldehydes react with each other to form a bigger branched aldehyde with C===C (one bond away from carbonyl group: between alpha and beta C) and elimination of water.

However, there should be hydrogens on alpha-carbon.

Base and NaHSO4 are used as catalysts.

Question 21

What is the mechanism for aldol condensation?

Answer 21

1) Base deprotonates alpha-carbon on one aldehyde, making carboanion.

2) On another aldehyde, pi-bond on carbonyl is destroyed, making carbonyl carbocation and negatively charged oxygen.

3) Carbocation and carboanion join and make a new covalent bond.

4) Base donates proton back to negatively charged oxygen, making OH group.

5) This OH group from beta-carbon and H from alpha-carbon are removed (eliminated) with NaHSO4, resulting in alpha,beta unsaturated aldehyde.

Question 22

What are the main classes of carbonyl compounds and their nomenclature?

Answer 22

Aldehydes - “-al”

Ketones - “-one”

Carboxylic acids - “-oic acid”

Esters - “-yl” … “-ate”

Acid halides - “-oyl chloride”

Amides - “-amide”

Acetic anhydride - 2 carboxylic acids fused.

Question 23

What are similarities between aldehydes/ketones and carboxylic acids/their derivatives?

Answer 23

Both groups:

• dipole C===O
• few resonance forms
• lone pairs of electrons present, especially on Oxygen
• react with nucleophiles
• oxidation level is >1

Question 24

What are the differences between aldehydes/ketones vs carboxylic acids/their derivatives?

Answer 24

Aldehydes/ketones:

• 2 resonance forms (normal carbonyl, carbocation/negatively charged oxygen)
• Lone pairs on Oxygen only
• alkyl is a bad leaving group
• oxidation level of 2
• Undergo nucleophilic addition

Carboxylic acids/their derivatives:

• 3 resonance forms (normal carbonyl, carbocation/negatively charged oxygen, C===X)
• Lone pairs on Oxygen and X
• X is a good leaving group
• oxidation level of 3
• undergo nucleophilic substitution

Question 25

What is stability series of carboxylic acid derivatives?

Answer 25

A flow chart which shows which carboxylic acid derivatives are more reactive than others according to the goodness of their leaving groups. Acid halide is most reactive (halogens are the best leaving groups), carboxylic acid is least reactive (OH- is the worst leaving group). The order is 1) acid halide 2) acid anhydride 3) ester 4) amide 5) carboxylic acid

Question 26

How stability series of carboxylic acid derivatives are used?

Answer 26

Rule: carboxylic acid derivatives lower in series cannot be converted to carboxylic acid derivatives higher in series. For example, amides cannot be converted into esters, but esters can be converted into amides. This rule is used to predict a sequence of reactions to synthesise a certain substance. Acid chlorides and acid anhydrides are normally used to get to another derivatives. IMPORTANT EXCEPTION: carboxylic acid can be converted into acid chloride with SOCl2 or POCl2 (dehydrating agents).

Question 27

What is Claisen condensation?

Answer 27

Similar to aldol condensation, but 2 esters are involved. They are combined with nucleophilic substitution (OR is a leaving group), unlike nucleophilic addition in aldols. Product is beta-keto-ester.

Question 28

What are biologically relevant carboxylic acid derivatives?

Answer 28

- Acyl phosphates (very positive C, coordination with Mg2+). They are taken from ATP and phosphorylation helps glutamate to be converted into glutamine overturning stability series. - Thioesters (with coenzyme A). Co-A acts as a leaving group when thioester is attacked by SH from an enzyme. - Fatty acids and triglycides

Question 29

What is stability series for biologically relevant carboxylic acid derivatives?

Answer 29

Acyl phosphate is the most reactive, carboxylate is the least reactive. 1) Acyl phosphate 2) Thioester 3) Ester 4) Amide 5) Carboxylate Same rule applies.

Question 30

Why does not benzene react as a normal alkene (resists electrophilic addition)?

Answer 30

It is aromatic - it has delocalised p-electrons. Delocalised means electrons are evenly spread on the ring, which makes it very chemically stable, much unlike alkenes. Undergoing electrophilic addition would unbalance this stability.

Question 31

What are the 3 problems with Kekulé's structure of benzene?

Answer 31

1) The enthalpy change of hypothetical hydrogen saturation of three C===C in benzene is -360 kJ/mol, but it is only -208 kJ/mol for real benzene. 2) Double bonds (134 pm) are shorter than single bonds (154 pm) in normal alkenes, meaning benzene bonds would alter in length. However, in real benzene, all bonds are equal, and their length is an intermediate (139 pm). 3) Benzene does not react with bromine water, as expected from normal alkenes.

Question 32

How many resonance forms does benzene have?

Answer 32

Two.

Question 33

What compounds are considered aromatic?

Answer 33

Compounds which follow Huckel's rule: 4n + 2 = number of pi-electrons (n stands for integer number)

Question 34

What reaction do aromatic compounds undergo, and what are the 5 most common types of this reaction?

Answer 34

Electrophilic substitution: electrophile replaces H atom. Most common types: - halogenation (Cl or Br) - nitration - sulfonation - Freidel-Crafts alkylation - Freidel-Crafts acylation

Question 35

What are the 3 steps of electrophilic substitution?

Answer 35

1) A pair of pi-electrons attacks a superelectrophile and forms a covalent bond with it. 2) It creates a positively charged "hole" in a delocalised system at the place where electrons are bound to an electrophile. Other pi-electrons try to cover up the "hole" creating "holes" in other parts of the ring (shuffling bonds), resulting in 3 intermidiate resonance forms. 3) H+ under electrophile is removed, so its former covalent pair can regenerate aromaticity. Positive charge is conserved through the reaction.

Question 36

What is resonance and how does it contribute to stability?

Answer 36

It is when one molecule (resonance hybrid) can be depicted with 2 or more correct structural formulas, called canonical forms. The more resonance (canonical) forms, the greater the stability of the molecule.

Question 37

What is mesomeric effect?

Answer 37

Ability of substituents to donate electrons (M+) to or withdraw electrons from (M-) the aromatic ring. M+ (more stable) is caused by more resonance forms and charge stabilisation (for example, CH3). M- is caused by less resonance forms and charge destabilisation (for example, NO2)

Question 38

What is needed for the halogenation of benzene?

Answer 38

1) FeBr3 (Lewis acid catalyst) is needed to polarise Br---Br bond (in reagent) and make Br+ superelectrophile. Analogically for AlCl3 and Cl---Cl. 2) Br-/Cl- in FeBr3/AlCl3 accept ejected H from benzene ring. So products are substituted benzene and HBr/HCl; FeBr3/AlCl3 are regenerated.

Question 39

What is needed for the nitration of benzene?

Answer 39

1) Sulphuric acid (Lewis acid) and nitric acid (Lewis base) are needed to generate nitronium ion (superelectrophile). During that, nitric acid accepts a proton from sulphuric acid and releases H2O. 2) H2O accepts ejected proton from benzene and sulphuric acid is reformed.

Question 40

What is needed for the sulfonation of benzene?

Answer 40

1) Sulphuric acid (Lewis acid) and sulphur trioxide (Lewis base) are needed to generate protonated sulphur trioxide superelectrophile. 2) Sulphuric acid accepts ejected proton from benzene to reform itself.

Question 41

What is needed for Friedel-Crafts alkylation/acylation of benzene?

Answer 41

1) AlCl3/FeBr3 (Lewis acid) polarises chloroalkane/bromoalkane X---C bond by forming a coordination complex (in primary haloalkanes) or a carbocation superelectrophile (secondary or tertiary). 2) Cl-/Br- accepts ejected H from benzene to make HCl/HBr and AlCl3/FeBr3 is reformed. Analogously with acylation, but acyl halide is used and acylium ion superelectrophile is formed. Also, at the end of Friedel-Crafts acylation, AlCl3/FeBr3 reacts with carbonyl O, so with 3 H2O the product is back to acylbenzene and Al(OH)3/Fe(OH)3.

Question 42

Which of the electrophilic substitution reactions is reversible?

Answer 42

Sulfonation.

Question 43

Which of the electrophilic substitution reactions can do multiple benzene substitutions at once, and also rearrange coordination complexes/carbocations?

Answer 43

Friedel-Crafts alkylation (polyalkylation). Does not happen in Friedel-Crafts acylation (no polyacylation).

Question 44

What is the relationship between mesomeric effect, inductive effect and reactivity of substituted benzenes?

Answer 44

Activating substituent (chemical is more reactive than benzene): - more negative inductive effect (destabilization of the ring) - more positive mesomeric effect (donating electrons to the ring) - +M > -I - Examples: NH2, OH, OR, OCOR Deactivating substituent (chemical is less reactive than benzene): - any inductive effect (stability of the ring is not detrimental) - more negative mesomeric effect (withdrawing electrons from the ring) - -I > +M - Examples: halogens, CHO, SO3H, NO2

Question 45

How do substituents influence where the next substitution will take place?

Answer 45

Activating substituents are 2,4-directing activators (ortho and para). Deactivating substituents are 3-directing deactivators (meta). Halogens are exceptions: they are 2,4-directing deactivators.

Question 46

Why 2,4 position substitution (ortho and para) is more preferable for activating benzene substituents?

Answer 46

In ortho and para positions, the first substituent is able to donate electrons to the ring, creating an additional resonance form, hence increasing stability (NH2). In meta position, the first substituent is not able to make an extra resonance form, decreasing stability (NH2). Alternatively, there are no extra forms, just ortho and para forms are more stable than forms in meta substitution (CH3). The more balanced the structure, the more balanced the electron share.

Question 47

Why 3 (meta) substitution is more preferable for deactivating benzene substituents?

Answer 47

In ortho and para positions, withdrawing electrons from the ring makes the least stable resonance forms. The more balanced the structure, the less balanced the electron share (NO2). 3-position (meta) gives the most stable resonance structures.

Question 48

Where are aromatic compounds in biochemistry?

Answer 48

- ubiquinone (coenzyme Q) - NADH and FADH - Vitamin B2 (riboflavin) - purines and pyrimidines in nucleotides

Question 49

How does aromaticity help NADH, FADH and ubiquinone to perform their function?

Answer 49

Aromaticity helps them to stabilise charges (oxidized and reduced forms), and even free radicals.

Question 50

What is Grignard reaction?

Answer 50

A type of nucleophilic addition (in carbonyl compounds) to add new C-C bonds straight away to carbonyl carbon. Grignard reagent: alkane-MgBr or Br is replaced with another halogen. Products: compound-OH-added alkane