Ring chemistry Flashcards
What cyclic ring can you never make?
cyclic amine
What causes ring strain?
non-ideal molecular geometries
What causes torsional strain?
repulsion between electrons and substituents on adjacent atoms
What causes bond length strain?
bond stretching or compression
What ring is predicted to be most stable based on angles?
5-membered ring
What causes more influential strain, bond angle or bond length strain?
Bond angle deformation is less costly than changes in bond length
Conformation
the different shapes of molecules that result from the deformation of bonds (no bonds are broken or made to make conformational isomers)
Configuration
the connectivity of atoms within stereoisomers
Is the chair or boat conformation more strained and why?
Boat conformation is more strained as the C-H bonds are eclipsed whereas in the chair conformation they are staggered so there’s almost no strain
What ring size constitutes a small, normal, medium, large ring?
3-4: small
5-7: normal
8-11: medium
12+: large
Why are medium rings less stable than cyclohexane?
due to bond angle strain, torsional strain and transannular clashing due to the more atoms present
If rings are large enough what characteristic can they adopt?
the space in the middle of macrocycles (its cavity) becomes accessible to guests
What does low temperature 1H NMR measure?
measure the relative concentrations of the conformers spectroscopically
other spectroscopic techniques such as IR can also be used
A values
the free-energy differences between two chair conformations
(the larger the value, the more likely it will lie equitorial)
What group always sits equatorially?
tBu will always sit equatorially because it is so bulky - it is a conformational lock
Where does a carbonyl sit in a ring?
between axial and equatorial position
General guidelines for predicting lowest energy conformations
- the conformation with fewer axial substituents is lower in energy
- if there are equal numbers of axial and equatorial in the two conformations, refer to the A values
What position does polar (H-bond accepting) solvents favour?
diequatorial conformer
What position does apolar solvents favour?
diaxial conformer
What position does high dielectric solvents favour?
diequatorial conformer
What position does low dielectric solvents favour?
diaxial conformer
Spiro compounds
contain two rings linked through a single atom (spiroatom)
Decalins
molecules containing two fused cyclohexane rings
What are stereoelectronic effects?
they are the chemical consequences (structure, reactivity and properties) of the relative arrangements of orbitals in space
What is a stereoelectronic effect in E2 eliminations?
the proton and the leaving group must be anti-periplanar (preferred) or syn-periplanar for there to be good orbital overlap
What is a stereoelectronic effect in nucleophilic addition to a carbonyl?
the trajectory of nucleophilic attack at a carbonyl - 107º
Baldwin’s rules
- All endo-tet are disfavoured
- All exo-tet are favoured
- All exo-trig are favoured
- All endo-dig are favoured
- (3,4,5) endo-trig are disfavoured, (6,7) endo-trig are favoured
- (3,4) exo-dig are disfavoured, (5,6,7) exo-dig are favoured
When is Baldwin’s rules usually disobeyed?
reactions involving second row atoms (e.g. sulfur) often do not follow the rules due to larger variations in their bond lengths and the presence of accessible d orbitals
Energetics of different size ring formation
Making a LARGE ring:
- high entropic cost due to having to organise many atoms to get reaction
- enthalpically okay
Making a SMALL ring:
- entropically okay (less atoms to organise)
- enthalpically costly due to the product formed having very high ring strain
What sort of reactions are thermodynamically controlled and which are kinetically controlled?
- irreversible reactions are kinetically-controlled
- reversible reactions are thermodynamically controlled
General trend for ring closure of saturated rings
Fastest: Slowest:
5 > 6 > 3 > 7 > 4 > 8-11
2 most common ring-closing reactions
1) Ionic reactions
2) Pericyclic reactions
What sort of reactions do small ring synthesis favour?
irreversible, kinetically-controlled reactions
What is a [2+1] cycloaddition?
addition of singlet carbenes to olefins to form cyclopropanes
What reaction is the addition of triplet carbenes?
a radical reaction
What is a [2+2] cycloaddition?
Cyclisation of two olefins to form cyclobutanes
- photochemical excitation is necessary to achieve correct orbital symmetry
What are thermal [2+2] cyclisations?
only occur for substrates with two double bonds at the same carbon atom (e.g. ketenes and isocyanates)
What are lactams?
cyclic amides
What do ketenes and isocyanates react with to form β-lactams?
Ketenes (CCO) react with imines (CN)
Isocyanates (OCN) react with alkenes (CC)
What molecule does a β-lactam ring form a key structural feature of?
the penicillin class of antibiotics
How does a β-lactam in penicillin work as an antibiotic?
During bacterial cell wall synthesis, an enzyme catalyses peptide bond formation between a Gly and a D-Ala residue. The β-lactam ‘imitates’ the D-Ala and forms a covalent bond to the active site, irreversible inhibiting the enzyme.
Two examples of ring contractions?
- Favorskii
- Wolff
What sort of reaction do normal ring formations occur under?
they are generally favourable so can occur under kinetic or thermodynamic control
Nazarov cyclisations
used to form cyclopentanones from divinyl ketones
What is the most important way to form a 6-membered ring?
through Diels-Alder cycloaddition
[4+2] cycloaddition
Reduction of aromatics
- Birch reduction
- Catalytic hydrogenation using Pd/ C and H 2 under harsh conditions
What are the four strategies to make larger rings?
- high dilution
- templation
- ring expansion (including fragmentations)
- phase separation
What impacts the rate of intermolecular reaction?
The rate of intermolecular reaction is concentration dependent, whereas the rate of the intramolecular reaction is not - thus, lower concentration minimises intermolecular reaction
What is required for a cyclisation with a low effective molarity?
high dilution conditions in order to favour the cyclic product
Pros and cons for high dilution method of forming large rings
Pro: widely applicable - no specific structural features are required
Cons:
- very large quantities of solvents are required, which can be costly and limits the scalability of reactions
- to counteract slow reaction rates, high temperatures and/ or long reaction times are required - not ideal and the reactive functional groups must be robust in order to survive the conditions
Olefin Metathesis
allows the exchange of substituents between different olefins - a transalkylidenation
Conditions for ring-closing olefin metathesis
the reaction conditions are mild, the reactive functional groups are robust and the catalysts are efficient - this reaction performs well at high dilution
Suitable catalysts for ring-closing olefin metathesis
carbene complexes of Ru, W, Mo and other transition metals
Do ring-closing olefin metathesis result in a mixture of diastereoisomers?
yes - often a mixture of E and Z diastereoisomers is formed - the E isomer is usually more stable for large rings so its frequently the major product
What type of dimerisation is the acyloin reaction?
a radical-radical dimerisation
What happens in the acyloin reaction?
an ester is reduced using sodium metal, resulting in a 1,2-diketone after dimerisation and then eventually a ɑ-hydroxyl-ketone after further reduction
What reaction is best for making medium and large carbocyclic rings?
the acyloin reaction
What is the McMurry reaction?
a radical-radical dimerisation of ketones, promoted by titanium (0), which is formed in situ
What do chemical templates do?
they influence the geometry of a substrate, usually through noncovalent bonding interactions such as:
- hydrogen bonding
- coordination to a metal centre
- donor- acceptor interactions
What aids the formation of crown ether macrocycles?
it’s templated by alkali metal cations
(the O lone pairs interact with the positively charged cation, causing the intermediate species to ‘wrap around’ the metal and bringing the end groups close together in space)
Are SN2 reactions faster when nucleophile attacks axially or equatorially?
attack at axial leaving groups are faster - the approach of the nucleophile along the direction of the C-X σ* orbital is less hindered for axial substituents
What is the preference for epoxide opening?
attack at a position that results directly in chair formation rather than a twist boat, regardless if it ends up a chair in the end
Reduction of cyclohexanones: which reducing agents undergo equatorial attack vs axial attack?
bulky reducing agents undergo equatorial attack whereas small reducing agents attack in an axial manner
Why do large nucleophiles not attack axially?
the axial attack of large nucleophiles would suffer from unfavourable steric interactions with other axial groups as the nucleophile approaches the face of the ring
What is the Thorpe-Ingold Effect?
adding substituents makes the cyclisation reactions go faster
Thorpe-Ingold Effect: enthalpy
Bond angle compression
- in the formation of small rings, starting from a smaller bond angle is advantageous because then there is less of a change necessary to form the small ring and therefore less strain is introduced
Thorpe-Ingold Effect: entropy
the substituents reduce the number of conformers that are accessible to the acyclic precursor which means that it suffers less of an entropic penalty to form the transition state
Geminal relationship
a cation stabilising group attached to the same C atom as a leaving group stabilises the cationic intermediate of an SN1 reaction
Vicinal relationship
a functional group at the carbon next to the reaction centre (neighbouring group)
What is a fragmentation reaction?
involves the cleavage of a C-C bond, causing tje molecule to break open
Common characteristic of spirocyclic systems
often chiral
Synthesis of Nornornanes: alkyne as the dienophile
the product contains 2 double bonds
How are carbocations stabilised?
by the electrons in neighbouring σ orbitals
Why does the bridgehead position not allow for carbocations?
Would need for the σ orbitals to overlap with the vacant p orbital thus the carbocation must adopt a trigonal planar geometry. However the rigid structure of the bridgehead position would result in a massively distortion to form the planar carbocation
What chemistry can happen at bridgehead positions?
- no Sn1 or Sn2
- elimination reactions don’t tend to happen
they are generally very unreactive positions and chemistry only occurs if it involves an anionic or radical species at the bridgehead, rather than a cation or double bond
The Cope Rearrangement
a pericyclic [3+3]- sigmatropic rearrangement in which electrons in p orbitals shuffle around a 6-membered ring transition state
Bredt’s rule
it’s ‘impossible’ for there to be planar bridgehead carbons therefore double bonds can almost never be formed to bridgehead carbons in bicyclic systems
