Exploring Ligands for Nanoparticle Surface Effects

Design and Synthesis of Ligands to Promote Exploration of
the Effects of Nanoparticle Surface Charge and Distribution
Prof. Erin E. Carlson
Contracted Synthesis Partner, ECOCHEM Research, Inc.
University of Minnesota
November 27, 2024
2
Examples of ligands utilized in previous CSN studies: Monomeric
ligands
Previous work has shown that NP surface charge has dramatic
affects on their toxicity. We are generating a standardized set of
ligands to enable thorough exploration of this issue.
3
Examples of ligands utilized in previous CSN studies: Polymeric
materials
Charge density is difficult to control with large polymer-based
coatings.
4
Critical design elements of the ligand library
Modular synthesis that enables
generation of ligands with diverse
attachment groups and display
groups
Hydrophobic region near the
particle to minimize ligand
hydrolysis
A similarly sized hydrophilic
component that increases water
solubility of the resulting NPs
Inclusion of only linear connection
points (e.g. no amide bonds) to
maximize ligand packing
Scalable synthesis that does not
include prohibitively expensive
reagents and reactants or
exceptionally low yielding
reactions
Example Ligand
5
Synthesis scheme is dependent on the Williamson synthesis, which is
well-known to be low yielding and difficult to reproduce.
Initial step in route requires monofunctionalization of the
polyethylene glycol which was also irreproducible and low yielding.
Iida, et. al 
Langmuir
, 
2015
, 
31
, 4054-4062
Initial synthesis based on previously reported route
6
REACTION TRIAL and YIELD
Trial #1  No Product  (0.0%)  NN-61-A
 
Trial #2  0.90 grams  (13.7%)  NN-62-A
Trial #3  1.55 grams  (23.6%)  NN-63-A
 
Trial #4  0.13 grams  (2.0%)  NN-68-A
Trial #5  1.57 grams  (23.9%)  NN-71-A
 
Trial #6  2.77 grams  (42.2%)  NN-75-A
Trial #7 & #8 Combined Average 4.12 grams (62.8%)  NN-98-A & NN-99-A
Optimization included: added potassium iodide, pre-drying PEG, higher
temperatures, reaction times of up to 10 days
Iida, et. al 
Langmuir
, 
2015
, 
31
, 4054-4062
Extensive optimization of the first step in the synthesis scheme
improved yield
7
Preparation of the tosylated intermediate proceeded normally in >80% yield
Critical alcohol reaction produced a complex mixture, even with a simple coupling
partner, with minimal (<5%) product
This result led to a re-evaluation and re-design of the synthesis scheme
Iida, et. al 
Langmuir
, 
2015
, 
31
, 4054-4062
Subsequent steps in the literature procedure gave no product
8
Reaction of bromide-containing starting materials with the
desymmetrized PEG dramatically increases yield and ease of synthesis
and purification
Preparation of the Boc intermediate over four trials gave generally
acceptable 0.5-1.0 gram scale yields of 61%, 73%, 59% and 40%,
respectively.
Synthesis redesign to increase yields, reproducibility and scalability
 
 
 
 
 
9
Removal of the Boc to produce the desired pendant amine with TFA appeared to
proceed by TLC, NMR and MS. However, product could not be purified by silica or
reversed phased chromatography. Additionally, it rapidly oxidizes.
Current efforts are focused on development of a PTSA salt crystallization method.
This approach may be significantly more complicated when the preparation of the
pendant thiol and silyl derivatives is attempted.
Synthesis redesign to increase yields, reproducibility and scalability
 
 
 
 
 
10
New route was devised to remove previously required desymmetrization step based
on the commercial availability of the monobutyl substituted tri-PEG. Butyl-PEG-alkene
compound has been produced in good yield.
The butyl-PEG-alkene molecule is currently being used for:
   - Optimization of the alkene to thiol conversion
- Functionalization of nanodiamond (Hamers)
Re-thinking initial target compounds and synthesis redesign to
increase yields, reproducibility and scalability
 
 
 
 
 
11
The multi-gram scale synthesis of the butyl-PEG-alkene demonstrated
the potential feasibility of gram scale preparation of the butyl-PEG-thiol
and butyl-PEG-silane as illustrated.
These compounds will be prepared for distribution as “fit-for-purpose”
models of the alkyl-PEG-alkyl-FG molecular design strategy.
PRIMARY GOAL:  Synthesize gram scale quantities of butyl model
compounds for consortium evaluation
 
 
 
 
 
Or AIBN
12
Model ligand evaluation goals
Evaluation of the butyl series of ligands by the consortium to
include:
  Nanoparticle loading optimization – minimal ligand quantity to
provide required coverage
  Nanoparticle loading characterization
 Ligand “fit-for-purpose”; does this ligand design have the
characteristics we want? Water suspension, stability, etc.
13
Future directions: Expanding the scope of ligands
Subsequent to the preparation and evaluation of the butyl series of
ligands, the next phase of the synthesis program will be to prepare
the pendant amine series of alkene, thiol and silane compounds.
Purification and stability studies underway
This work was supported by the 
National Science Foundation
 Center for Sustainable Nanotechnology,
funded as a 
Center for Chemical Innovation
 CHE-1503408 [Phase II]
Blog:
 
http://sustainable-nano.com
Acknowledgements
 
Dr. Robert E. Carlson, ECOCHEM Research, Inc.
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Design and Synthesis of Ligands for studying Nanoparticle Surface Charge and Distribution, including examples of monomeric and polymeric ligands. Critical design elements of the ligand library are discussed, emphasizing scalable synthesis and key features. Initial synthesis challenges are noted, with improvements achieved through extensive optimization.


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  1. Design and Synthesis of Ligands to Promote Exploration of the Effects of Nanoparticle Surface Charge and Distribution Prof. Erin E. Carlson Contracted Synthesis Partner, ECOCHEM Research, Inc. University of Minnesota November 27, 2024

  2. Examples of ligands utilized in previous CSN studies: Monomeric ligands N HS Br (16-mercaptohexadecyl)trimethylammonium bromide (MTAB) N HS Br cetyltrimethylammonium bromide (CTAB) C18 thiol (or any length chain) O O OH O Na O- HS O O Na Na O O 3-mercaptopropionic acid (MPA) trisodium citrate Cl HS NH3 3-aminopropane thiol hydrochloride (MPamine) Previous work has shown that NP surface charge has dramatic affects on their toxicity. We are generating a standardized set of ligands to enable thorough exploration of this issue. 2

  3. Cl NH3 n poly(allylamine hydrochloride) (PAH) O- Examples of ligands utilized in previous CSN studies: Polymeric materials O n poly(acrylic acid) (PAA) n Cl N Cl NH3 poly(diallyldimethylammonium chloride) (PDADMAC) n poly(allylamine hydrochloride) (PAH) n O- O n O S O O Na poly(acrylic acid) (PAA) poly(sodium 4-styrenesulfonate) (PSS) n N Cl Charge density is difficult to control with large polymer-based coatings. (PDADMAC) poly(diallyldimethylammonium chloride) n 3 O S O O Na poly(sodium 4-styrenesulfonate) (PSS)

  4. Critical design elements of the ligand library Modular synthesis that enables generation of ligands with diverse attachment groups and display groups Hydrophobic region near the particle to minimize ligand hydrolysis A similarly sized hydrophilic component that increases water solubility of the resulting NPs Inclusion of only linear connection points (e.g. no amide bonds) to maximize ligand packing Scalable synthesis that does not include prohibitively expensive reagents and reactants or exceptionally low yielding reactions Example Ligand 4

  5. Initial synthesis based on previously reported route Synthesis scheme is dependent on the Williamson synthesis, which is well-known to be low yielding and difficult to reproduce. Initial step in route requires monofunctionalization of the polyethylene glycol which was also irreproducible and low yielding. Iida, et. al Langmuir, 2015, 31, 4054-4062 5

  6. Extensive optimization of the first step in the synthesis scheme improved yield REACTION TRIAL and YIELD Trial #1 No Product (0.0%) NN-61-A Trial #3 1.55 grams (23.6%) NN-63-A Trial #5 1.57 grams (23.9%) NN-71-A Trial #7 & #8 Combined Average 4.12 grams (62.8%) NN-98-A & NN-99-A Trial #2 0.90 grams (13.7%) NN-62-A Trial #4 0.13 grams (2.0%) NN-68-A Trial #6 2.77 grams (42.2%) NN-75-A Optimization included: added potassium iodide, pre-drying PEG, higher temperatures, reaction times of up to 10 days Iida, et. al Langmuir, 2015, 31, 4054-4062 6

  7. Subsequent steps in the literature procedure gave no product Preparation of the tosylated intermediate proceeded normally in >80% yield Critical alcohol reaction produced a complex mixture, even with a simple coupling partner, with minimal (<5%) product This result led to a re-evaluation and re-design of the synthesis scheme Iida, et. al Langmuir, 2015, 31, 4054-4062 7

  8. Synthesis redesign to increase yields, reproducibility and scalability Reaction of bromide-containing starting materials with the desymmetrized PEG dramatically increases yield and ease of synthesis and purification Preparation of the Boc intermediate over four trials gave generally acceptable 0.5-1.0 gram scale yields of 61%, 73%, 59% and 40%, respectively. 8

  9. Synthesis redesign to increase yields, reproducibility and scalability Removal of the Boc to produce the desired pendant amine with TFA appeared to proceed by TLC, NMR and MS. However, product could not be purified by silica or reversed phased chromatography. Additionally, it rapidly oxidizes. Current efforts are focused on development of a PTSA salt crystallization method. This approach may be significantly more complicated when the preparation of the pendant thiol and silyl derivatives is attempted. 9

  10. Re-thinking initial target compounds and synthesis redesign to increase yields, reproducibility and scalability New route was devised to remove previously required desymmetrization step based on the commercial availability of the monobutyl substituted tri-PEG. Butyl-PEG-alkene compound has been produced in good yield. The butyl-PEG-alkene molecule is currently being used for: - Optimization of the alkene to thiol conversion - Functionalization of nanodiamond (Hamers) 10

  11. PRIMARY GOAL: Synthesize gram scale quantities of butyl model compounds for consortium evaluation Or AIBN The multi-gram scale synthesis of the butyl-PEG-alkene demonstrated the potential feasibility of gram scale preparation of the butyl-PEG-thiol and butyl-PEG-silane as illustrated. These compounds will be prepared for distribution as fit-for-purpose models of the alkyl-PEG-alkyl-FG molecular design strategy. 11

  12. Model ligand evaluation goals Evaluation of the butyl series of ligands by the consortium to include: Nanoparticle loading optimization minimal ligand quantity to provide required coverage Nanoparticle loading characterization Ligand fit-for-purpose ; does this ligand design have the characteristics we want? Water suspension, stability, etc. 12

  13. Future directions: Expanding the scope of ligands Purification and stability studies underway Subsequent to the preparation and evaluation of the butyl series of ligands, the next phase of the synthesis program will be to prepare the pendant amine series of alkene, thiol and silane compounds. 13

  14. Acknowledgements Dr. Robert E. Carlson, ECOCHEM Research, Inc. This work was supported by the National Science Foundation Center for Sustainable Nanotechnology, funded as a Center for Chemical Innovation CHE-1503408 [Phase II] Blog: http://sustainable-nano.com

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