Polymerization Conditions and techniques for conducting lab-scale polymerization reactions

Polymer Synthesis ROP Degradable polyesters/amides RAFT Wide range of monomers | Good for aqueous media
an opinionated guide... ROP of lactides and lactones
oganocatalysed alternative:
O
! Robust and well-established
RAFT agents
fragmenting/ stabilizing Best for these
Traditional RAFT
S OH
Class Notes RAFT agent monomer initiator
O
route to poly(ester)s initiating group group monomers S
O
Sn(Oct)2 O • versatile S
( )n
R’ Nu
+ Can control stereochemistry S S Z

··
Initiator
O R’
O(
O )n
OH
(meth)acrylates/ • high transfer const. R + + Int-X R
dry! with chiral catalyst R trithiocarbonates S Z
toluene
O
S S (meth)acrylamides • R-group structure
R’ OH alcohol
e.g.
R’ NH 2 primary amine (rare)
Caprolactone 110 ºC poly(caprolactone) Tolerant to presence of important

Before you start: Lab rules

PCL double bonds S • highly photo-labile
(example: alcohol-initiated)
xanthates acrylates/
R • low trasfer const. Typical systems for different initiators
S O acrylamides
O O O
• Typically operate via a “coordination-insertion” • broad dispersity

notes:
monomer initiator equiv. per
Cyclic ester- solvent initiator temperature time
O O O mechanism S • less hydrolytically
type class RAFT agent
based • Can suffer from back-biting termination reactions methacrylates/
monomers
O O O
R dithiobenzoates stable DMF AIBN methacrylate thermal 0.1- 0.2 70oC 4-6 h
Make sure you have on (at least) the following: O O
O
O
• Requires striclty anhydrous conditions to avoid initiaion
from water
S methacrylamides
• moderate trasfer const. DMF AIBN acrylate thermal 0.05 - 0.1 70oC 3-4 h
Lactide Glycolide Crown ether ester • Almost any cyclic ester structure is polymerizable
NCA-ROP S toluene AIBN methacrylate thermal 0.1- 0.2 70oC 8-12 h

Lab coat
vinyl esters/ • highly photo-labile
O R dithiocarbamates V-501/ acrylate/
S N vinyl amides • moderate dispersity H2O thermal 0.05 - 0.1 60oC 3-4 h
HN H
R O
Synthetic polypeptides; of bio- V-50 acrylamide
R’ Nu + O N
( N)
NH 2
H2O TPO acrylate photo 0.1 - 0.5 r.t. 0.5-1 h

··
R - n CO2
R’
H n logical interest
Initiator O O R
Enzymatically degradable
PET-RAFT H2O ascorbic acid/ acrylate/
Safety glasses
R’ NH 2 primary amine N-Carboxy α-amino acid poly(NCA) redox 0.5 - 1 r.t. 6-24 h
e.g.
R’ OH alcohol (rare) anhydride (NCA) (example: amine-initiated) tBu-OOH acrylamide

O O
S photo- hv PC+
S The best dispersity and chain-
H
Peptide • NCA monomers notoriously hard to handle - need to be + + end fidelity

notes:
O N Pn/R catalyst Pn/R•
inspired S
freshly-prepared and may require glove-box conditions S Z
-
S Z
O O
(PC) Compatible with Incompatible with
Methacrylates well-controlled
Gloves (latex or nitrile)
O HN HN
monomers • Several operating mechanisms can occur concurrently, M
O O complicating the reaction
• choice of blue, green, red, or near-infrared light (difficult for iniferter) O O
(Boc-protected) Lysine NCA (Benzyl-protected) Cystine NCA • Some amino acid functionalities require protection O R N
during polymer synthesis (e.g. acid, amine, thiol)
• lots of organic, inorganic, and porphyrin catalysts R OH
R OH
R R N
R R NH 2

Radical ROP (RROP) • oxygen-tolerance (depending on catalyst) carboxylic

acid
alcohol epoxide amide
R
3o-amine
1o-amine

R SH

+
O O O ( CH2 ) ( O ( CH2 ) )n Access to degradable polymers Photoiniferter-RAFT O O F thiol
Sensible waste disposal: R R R R R Cl R R
via radical polymerization Excellent for acrylates, acrylamides, and vinyl
hv
O (CH2) (CH2) R S
O
S R Br F F
O O
S esters
R R R H R N
H
alkyl flouro- thioether
Radical Ketene acetal ring-opening propagating poly(ester) Can be combined with RAFT Pn/R Pn/R• + ketone aldehyde
halide carbon 2o-amine
product S Z No additional reagents required - very simple
No chemicals/solvents down the sink
radical
to provide control •S Z
M set up
• Typically only used in combination with (e.g.) a (meth)-
R
May cause problems... R

notes:
Cyclic acetal- O Ph S acrylate monomer to provide “degradable linkages” photoiniferter xanthate + acrylate UV or purple
based
monomers O Ph
O N O S
S • Severe difficulties with reactivty ratios when used as light source trithiocarbonate + acrylate blue (or UV) OH
R S S R R H

co-monomer trithiocarbonate + methacrylate green or blue OH disulfide alkyne OH

Heterocyclic monomers capable of RROP • Cycle acetals difficult to handle as readily hydrolysed choice guide: dithiobenzoate + methacrylate green or blue catechol phenol

ATRP Robust & established | Lots of ATRP variations ROMP Powerful | Grafting-through brushes
Basic ATRP Key equilibria in ATRP
Cu(0)-mediated ATRP Photo-mediated ATRP Monomers Grubbs’ catalyst
ATRP Cu(II)
monomer catalyst
initiator & ki >> kp Metalic copper (i.e. copper in the zero-oxidation state, Cu(0)) Photo-mediated ATRP (photo-ATRP) has developed so rapidly in the past norbornene
Cu(I) can be used very effectively for polymerization few years there are now a multitude of different approaches!
R Br + + Cu R ( )nBr R N N
N N
ratio of deactivator rate of initiation much P
normally cleaned in acid just prior 1) Using photo-redox catalysts to reduce Cu(II) to Cu(I)

Photo-ATRP
to activator higher than propagation O oxanorbornene Cl
Example Cu(0)-ATRP reaction: to use to remove oxide coating Cl Ru

strategies
2) (related) Using the Cu(II)/L complex as a kind of photo-catalyst Cl
Ru
Ph
Cl Ph N Ru
Cl

Example ATRP reaction: Steps in detail: Cu-wire R

N
O 3) Replacing the copper entirely with a photo-redox catalyst power- P P Cl Ph
N 1) Combine monomer, initiator, ligand O DMSO oxanorbornene di- Br N
anisole O
+ + + N ( )nBr ful enough to directly (and reversibly) reduce the alkyl halide
O
( )nBr and solvent in flask Br Cu(II)Br2 O
carboxylic anhydride
Br + + Cu(I)Br + N O
O O O
r.t. 4) (related) As for 3) but using an organic photo-catalyst
O O O
80oC 2) Degas via 3 x freeze-pump-thaw 1.5 - 4 h
O O
O O
Br
N N
8-20 h
O O
3) Under an inert gas blanket, add alkyl halide acrylate “deactivator” 5) (not covered here) Using a photo-initiator (i.e. radical source) to 1st-gen
N R 2nd-gen 3rd-gen
alkyl halide methacrylate copper copper catalyst (solid) initiator monomer 0.05 equiv. ligand polyacrylate
reduce Cu(II) (as in ICAR-ATRP) -- less common these days
initiator monomer catalyst ligand polymethacrylate 4) Degas further 2 x freeze-pump-thaw 1 equiv. 100 equiv. e.g. Me6TREN product
1 equiv. 100 equiv. 1 equiv. 1 equiv. product 0.18 equiv. Olefin metathesis
5) Place in heating bath to start reaction
Example Photo-ATRP reaction (#2 above):
pros cons
for this direct Cu(II)/L complex irradiation
typically need light of λ < 400 nm -- i.e. UV
LnMt + LnMt LnMt ( )n
ARGET-ATRP eATRP - e- N hv
R LnMt
R
LnMt
R
R R

kp O
DMSO

recently - see ‘Key Papers’

some improvements made
Add a reducing agent to reduce Cu(II) (deactivator) anodic current Excellent control (end-group Strongly solvent dependent
O
( )nBr
+ + +
pros cons
Br Cu(II)Br2 N O
back to Cu(I) (activator) ka M fidelity, dispersity) over acrylates (basic version works best in
O O O
r.t.

Media:
Reducing
agents:
Pn Br + Cu(I)Br / Ln
kd
Cu(II)Br2 / Ln + Pn ●
Simple, fast, room temperature
DMSO)
alkyl halide acrylate copper
N 1.5 - 4 h
O O
Metal-free photo-
reaction Relatively poor control over initiator monomer catalyst ligand polyacrylate
aqueous { sodium ascorbate
ascorbic acid
cathodic current
Able to do in situ chain
methacrylate-type monomers 1 equiv. 100 equiv. 0.02 equiv. e.g. Me6TREN product
Robust, powerful, and tolerant
toward various functionalities
Usually requires expensive
ruthenium catalyst
ROMP
+ e- 0.12 equiv.
organic Sn(EH)2 extension -- i.e. easy multiblock/ Reaction/catalyst tends to “die” Removes need for metal
So powerful that it can easily catalyst
star polymer synthesis if running for too long -- hard to Stoichoimetric amount of cata-
Cu(II)Br2 Cu(I)Br mechano-ATRP mechano-active resuscitate! Example Photo-ATRP reaction (#3 and #4): polymerize through macro-
lyst (i.e. one per polymer chain)
OMe
catalyst monomers (i.e. grafting-through) Uses photo-redox
note: Ligand not shown Acrylamides possible when
For in situ chain extensions, O catalyst to oxidise
BaTiO3* BaTiO3 (particles) using aqueous variant
typically only very short blocks Br photo- hv O Access to conjugated polymer More stringgent reaction
vinyl ether (which
Can also be achieved by: kp
work well (DPn ≤ 20)
O
+ + catalyst O ( )nBr backbones conditions than RAFT or ATRP
acts as initiator)
Can polymerize hydrophobic O O
r.t.
BF 4
• radicals/initiators (”ICAR-ATRP”) (PC)
M
ka (e.g. tert-butyl acrylate) as well Precipitating from DMSO is a
O O
Highly reactive with typically Usually restricted to cyclic Blue LED O
+ + as hydrophilic (e.g. 2-hydroxy-
• electrochemical (“eATRP”) alkyl halide (meth)acrylate <0.1 mol%
Cu(II)Br2 / Ln Pn ●
Pn Br Cu(I)Br / Ln
kd real pain! For hydrophilic, best to fast reaction kinetics strained-ring monomers
ethyl acrylate) monomers initiator monomer poly(meth)acrylate MeO OMe
• ultrasound (”mechano-ATRP”) dialyse then freeze-dry 1 equiv. 100 equiv. product
Example Cu(0)-ATRP aqueous reaction:
Example ARGET-ATRP reaction: Note: adding salt (NaCl) might help! Iron-catalysed ATRP this complex “disproportionates” into Organic photocatalysts Inorganic ones “Grafting-through” polymerization:
Cu(II)Br2/Me6TREN and Cu0 particles
Ascorbic Although Cu is used most exten-
acid O N
sively, Fe catalysts also work. O O
O N 0.2 equiv. HO O ( )nBr H2O N
Br + O O + Cu(II)Br2 + OH
These are generally much slower;
however a recent example of
HO O
Br
+ + Cu(I)Br + N HO O ( )nBr N N
ROMP ROMP
(

HO O N O O
(

N O O ice bath
OH water ligand-free photo-ATRP using FeBr3 OH OH
O O O
RuII
IrIII
N r.t. appears promising! N 5 - 30 min N
O N N N N
6h O OH
)

FeBr3 ( )nBr
)

alkyl halide methacrylate copper R’

alkyl halide acrylate catalyst ligand
OH S
initiator monomer catalyst ligand polymethacrylate R’ Br + polyacrylate 3,7-di(4-biphenyl)-1-naph-
O O
hv O O initiator monomer 0.5 equiv. Me6TREN 10-Phenylphenothiazine
1 equiv. 100 equiv. 0.1 equiv. 0.2 equiv. product R product (PTH) thalene-10-phenoxazine fac-Ir(ppy)3 Ru(bpy)3 macromonomer “bottlebrush” polymer “bottlebrush” block copolymer
(450 nm) R 1 equiv. 100 equiv. 0.5 equiv.

Cationic RAFT Truly “living” Key papers a selection...

• Excellent control over less activated monomers same catalyst as for photo-ROMP Organocatalysed ROP: PET-RAFT: Cu(0)-mediated ATRP: Metal-free photo-ROMP:
Photo-catalysed:
OMe
• Can also use BrØnsted acid or electrochemical initiation Organic Catalysis for Ring-Opening Polymerization (2012) Synthesis of Discrete Oligomers by Sequential PET-RAFT Single-Unit Monomer Universal Conditions for the Controlled Polymerization of Acrylates, Methacrylates, Metal-Free Ring-Opening Metathesis Polymerization (2015)
hv M NCA-ROP: Insertion (2016) and Styrene via Cu(0)-RDRP (2017) Surface photo-ATRP:
Lewis acid mediated: S (450 nm) S
Ring-Opening Polymerization of N-Carboxyanhydrides Initiated by a Hydroxyl Photoiniferter-RAFT: Organo-photo-ATRP: Simultaneous Preparation ofMultiple Polymer Brushes under Ambient Conditions
M LA + + Group (2017) Ultra-High Molecular Weights via Aqueous Reversible-Deactivation Radical Organocatalyzed Atom Transfer Radical Polymerization Driven by Visible Light (2016) using Microliter Volumes (2018)
OR S S iBuO S Z
BF 4
iBuO S Z Polymerization (2017)
+ + Radical ROP: ROMP grafting-through: Fe-catalysed photo-ATRP:
●
LA O
Vinyl ether iBuO S Z
iBuO S Z MeO OMe
Radical Copolymerization of Vinyl Ethers and Cyclic Ketene Acetals as Cationic photo-RAFT: Graft-through Synthesis and Assembly of Janus Bottlebrush Polymers from Photoinduced Iron-Catalyzed Atom Transfer Radical Polymerization with ppm
monomers a Versatile Platform to Design Functional Polyesters (2017) Cationic Polymerization of Vinyl Ethers Controlled by Visible Light (2016) A-Branch-B Diblock Macromonomers (2016) Levels of Iron Catalyst under Blue Light Irradiation (2017)