Organic part 1 Flashcards
retrosynthesis arrow
double arrow = “can be made from”
curly arrow represents
the movement of a pair of e- from HOMO of NU- to LUMO of electrophile
main considerations molecular interactions
HOMO-LUMO interactions
Electrostatic interactions
also:
hardness/softness - FMO or electrostatics driven
orbital coefficients
symmetry
all molecules with __ or ___ can act as nucleophiles
a free pair of e-
or at least one pi-bond
relative nucleophilicity
-ve charge > lone pair > pi-bond > sigma-bond
example of sigma bond Nu-
(BH4)-
donates a hydride to e-phile
an electrophile must have…
full or partial positive charge
OR an atom which doesn’t have a full octet of e-
relative electrophilicity order
empty orbital (eg. p-orbital) > pi* orbital > sigma* orbital
two mechanistic steps of nucelophilic addition
to C=O
- Nucleophilic addition to the C=O (attack)
- protonation of the resulting anion
explain why and how the Nu- attacks the C=O
at the C rather than O due to the large dipole, e-rich Nu attracted to ∂+ C
orbitals of C=O:
both sp2 hydbridised. O l.p. in 2 HAOs, remaining p orbitals perpendicular to the plane.
C greater contribution to pi*antibonding, hence has largest coefficient in the LUMO, Nu attacks here at 107˚ to plane
define alkyl, aryl, vinyl, alkynyl
alkyl = alkane chain
aryl = aromatic ring attached
vinyl = C=C attached
alkynyl = C triple bond C attached
what is an organometallic reagent?
any compound with a C bonded to a metal
what makes Li and Mg based organometallic reagents good sources of carbanions?
the electronegativity of Li (1.0) and Mg (1.2) vs C (2.5) means that the metal is ∂+ and the R- group is left with a ∂-
what is the process of making a Grignard reagent called?
Mg insertion
how is a Grignard reagent made?
reacting alkyl/aryl/vinyl halide with Mg turnings, in ether
Mg insertion happens at the C-X bond
what is the process of making an organolithium compound called?
Lithium halide exchange
write “Li-Hal exchange” on the arrow
what reagents are required to produce an organolithium compound?
alkyl/aryl/vinyl halide
TWO equivalents of Li
in ether
what are the products in making an organolithium compound?
one equivalent of the organolithium
one equivalent of the lithium halide salt
how are alkynyl organometallic reagents made?
deprotonate alkynes with simple alkyl/aryl/vinyl organometallics
H and Li or MgHal “swap” essentially
common way to deprotonate an alkyne
use a strong Nitrogen base, commonly sodium amide Na+ -NH2
(NH4 formed as side product)
what happens to organometallics in water / protic solvents?
organometallic carbanion is immediately protonated, destroyed
three types of nucleophiles that aldehydes and ketones react with`
Hydride (NaBH4)
organometallic reagents
water and alcohols
explain why Nu- attack by the hydride ion itself does not happen
so small with such high charge density that it only ever reacts as a base
because the filled 1s orbital is the ideal size to react with the H contribution of the sigma* orbital of H-X bond and not the LUMO of the C=O
HOMO of NaBH4
B-H sigma bond
reaction mech NaBH4 attack ald/ket
attack: e- from B-H bond attack C of C=O, charge to O, BH3 lewis acid formed
protonation: -ve charge on O reacts with H of H-X solvent (eg. MeOH), forming an alcohol
what happens to the BH3 generated after the Nu attack of NaBH4 + ald/ket?
electron deficient and sp2 hybridised, empty p orbital hence a lewis acid
reacts quickly with the oxyanion that has been generated or a molecule of solvent to product tetravalent boron anion, another H- source
can theoretically repeat to use up all 4 H’s but not necessary
how do ald/ket react with organometallic reagents?
TWO steps: 1. organometallic, then 2. add H2O (bc organometallic very reactive w/ water)
e- from C-Metal bond attacks C=O, bond forms, O gains -ve charge
protonation from H-OH water to form alcohol
what are hydrates and how are they formed?
geminal diol - two -OHs attached to same C
formed by reacting ald/ket with WATER
what are acetals / hemiacetals?
acetals: two -OR groups attached to one C
hemiacetals: one -OR, one -OH attached to one C
how are acetals and hemiacetals formed from ald/ket?
by reaction with alcohols
identify to HOMO and LUMO in the reaction of water with ald/ket
HOMO: lone pair O sp3
LUMO: C=O pi*
reaction mech water with ald/ket
lp of O in H2O attacks C=O, bond formed (O attached has +ve charge) and O gains -ve charge
Another H2O molecule removes an H from -OH2 group to make -OH
Other O- is protonated w another H2O molecule to form HYDRATE
significant concentrations of hydrates are usually only formed from ___
aldehydes
why are hyrates better obtained from aldehydes than ketones?
bond angle changes from 120 to 109.5˚, so bigger R groups means greater steric clash in the product.
when might the formation of a hydrate from an aldehyde/ketone be favourable?
if there is a strained ring in the ald/ket, then forming the hydrate results in a release of ring strain with decreased bond angle.
LUMO and HOMO reaction alcohol with ald/ket
HOMO: lone pair in O sp3
LUMO: C=O pi*
how do acid catalysts work to increase the rate of hydrate / hemiacetal formation ?
by making the carbonyl group more electrophilic, by protonation of the O (gains H+)
how do base catalysts work to increase the rate of hydrate / hemiacetal formation?
by making the nucleophile more nucleophilic, by deprotonation (of water or alcohol) so that the O has a negative charge
how to push acetal formation to completion
every step is reversible, so must use XS alcohol and/or remove water from the reaction mixture as it forms (eg. by distillation)
why can acetal formation only be catalysed by acid?
because an -OH group must be made into a good leaving group, cannot happen under basic conditions
mech for acetal formation from hemiacetal
-OH group protonated –> good leaving group, C=+OR formed (effectively same as protonated C=O)
Another ROH attacks, repeat acid catalysed mech
substituions at a trigonal planar C=O group go through ___
a tetrahedral intermediate
return to trigonal planar by loss of leaving group
the best leaving groups are…
the ones that can most easily stabilise negative charge, ie. the most stable anion
how does the acidity of the conjugate acid relate to the stability of the anion?
the MORE acidic, the more stable the anion
eg. HCl strong, Cl- very stable
reaction of Grignard reagent and ketone produces… and why
a tertiary alcohol (OH generated from the C=O)
but none of the alkyl chains make good leaving groups
eqn pH
-log[H3O+]
acidity constant expression
Ka = [H3O+][A-] / [HA]
pKa expression
pKa = -log[Ka]
why are strong acids able to fully dissociate but weak acids only partially?
because of the stability of their conjugate bases
eg. Cl- not a strong enough base to deprotonate H3O+ to reverse the equilibrium, whereas the acetate ion is easily protonated by H3O+ (hence a stronger base than Cl-)
the stronger the acid, the ___ the conjugate base
weaker
how does pKa correspond to acid strength?
LOWER pKa = stronger acid!
eg. HCl has a pKa of -7
how does pKa correspond to leaving group ability?
the LOWER the pKa, the better the leaving group
(because stronger acid = more stable anion = better leaving group)
give the pKa of three strong acids
HI: -10
HCl: -7
H2SO4: -3
pKa of ethanoic acid
weak acid, around 4.8
pKa of H2S
weak acid, 7.0
conjugate base HS-
pKa of NH4+
weak acid, 9.2
phenol pKa
C6H5OH pKa = 10
what is considered the limit for reasonable leaving groups?
ethanol, with a pKa of 15.9
CH3CH2O- isn’t a very good leaving group
ethyne pKa
terminal H leaves
24
benzene pKa
43
methane pKa
48
three factors affecting anion stability
electronegative elements
delocalisation of -ve charge
strength of A-H bond
explain how electronegative atoms impact anion stability
increase e-neg of atom upon which a -ve charge sits, INCREASE stability
hence F- > OH- > NH2- > CH3-
how does delocalisation of negative charge impact anion stability?
the more resonance forms, the greater the stability
generally, increasing # O’s in conj base increases delocalisation due to increased number of available pi-orbitals
explain how the strength of the A-H bond affects anion stability
the weaker the A-H bond, the stronger the acid (more readily donates H+) hence the better the leaving group
eg. HI > HBr > HCl > HF
(larger atomic radii = longer, weaker bonds)
could not predict from e-neg alone
pKa of oxygen acids
sulfonic acids RSO2OH = 0
anion has 3 resonance forms, charge on O
carboxylic acids, RCO2H = 5
2 resonance forms, charge on O
ArOH = 10
charge delocalised on ring, charges on C, one structure w charge on O
ROH = 15
alkoxide no resonance forms, charge localised on O
define carbon acid
proton removed from C instead of O
how does hybridisation have an effect on pKa?
s-orbitals are closer to the nucleus than p-orbitals, more tightly held, hence more s-character = lower energy = more stable anion
sp > sp2 > sp3
general reaction mech of nucleophilic substitution at C=O
Nu- attacks at C and forms bond, O gains -ve charge
tetrahedral intermediate formed
leaving group leaves, O- reforms C=O
three major factors determining whether nucleophilic substitution will occur
strength of incoming Nu
reactivity of the C=O (ie. strength of ∂+ on C)
leaving group ability
(use these to determine if carboxylic derivatives will convert between each other)
how does pKa relate to Nu- strength ?
the HIGHER the pKa, the better the nucleophile
bc Nu readily forms new bonds w H and C
ie. good Nu = bad leaving group
three good Nucleophiles
R- (RH pKa = 50)
NH2- (NH3 pKa = 33)
RO- (ROH pKa = 16)
what two factors impact the dipole on C=O?
the inductive effect and the conjugative effect
what is the inductive effect and how does it impact the dipole on C=O?
relates to withdrawal of e-dens through SIGMA framework due to relative e-negativity of adjacent groups
more e-neg adj groups = greater dipole
O (3.5)
Cl (3.0)
N (3.0)
what is the conjugative effect and how does it impact the dipole on C=O?
involves delocalisation of lone pair from attached group into C=O pi* system
eg. amide
lp on N interact w C=O pi* MO, lowers energy
reduces +ve on carbonyl C
O, N, and Cl order in strength of lone pair donation
Cl < O < N
Cl worst donor, bc donates from 3rd shell, whereas O and N better matches w C as they are in the same O
N less e-neg than O, more willing to give lone pair
carboxylic acid derivatives (not incl ald/ket) order of reactivity and respective leaving groups
Acid chloride (-Cl)
Anhydride (RCOO-)
Ester (RO-)
Amide (RRN-)
Carboxylate anion
corresponds w C=O shift on IR!
convert acid chloride to ester
add alcohol, attacks C=O
Base deprotonates H+ from attached Nu, forming tetrahedral intermediate
Cl- good leaving group, C=O reforms
convert ester to amide
add NH3, attacks C=O
Base deprotonates H from +NH3, leaving NH2 attached to tetrahedral intermediate
-OMe okay leaving group, C=O reforms
