1. Study on the Effects of 18-Crown-6 in Solid Phase Peptide Synthesis

2. Introduction
Fmoc solid phase peptide synthesis produces long peptide chains attached to the same resin that may tangle
Tangle limits peptide length and causes a loss of yield
Use of Crown Ethers may stabilize intermolecular forces and act as a spacer to prevent tangle

3. Motivation
With the help of crown ethers, it may be easier to synthesize more complicated or otherwise impossible peptides.
Use of crown ethers may prevent tangling and increase yield.
Crown ethers may reduce the need for expensive protection groups to reduce nucleophilicity of R groups.

4. Intermolecular Tangle
Caused by interactions among polyamide backbone chain.
Is the limiting factor that prevents the synthesis of many useful peptides.
May be able to be controlled by forcing peptides to interact with another molecule instead of with sibling peptide chains.

5. Properties of 18-Crown-6
Electron density is directed towards the center of the ring.
Capable of hydrogen bonding.
Able to ‘thread’ a growing peptide chain. 2-4
Breaks down in the acidic conditions present during the final cleavage step.

6. Electrostatic Potential map of 18-Crown-6 shows reactive sites in the center of the ring

7. 18-Crown-6 as a Spacer
18-Crown-6 is ‘threaded’ on through intermolecular forces.
May reduce interactions with other peptide chains.

8. Crown Ether Locking
If a crown ether is threaded behind a large amino acid, it may become trapped if a second large amino acid is added after it.
Trapped ethers can still prevent peptide tangling

10. Non-Threaded H-Bonding
18-Crown-6 may still hydrogen bond even though it is not threaded.

11. Crown Ethers at Work in Fmoc Chemistry
Threaded crown ethers spread each of the chains apart
Non-threaded ethers hydrogen bond with R groups, stabilize charge, and reduce the need for protecting groups.

13. Conclusions
Incorporation of crown ethers may be an affordable way to increase yields and create more exotic peptides.
Crown ethers can easily be added to Fmoc protocol

14. References Merrifield, R.B. J. Am. Chem. Soc. 1963, 85, 2149.
Gong, C.; Ji, Q,; Subramaniam, C.; Gibson, H.W. Macromolecules. 1998, 31, 1814.
Gong, C.; Gibson, H.W. Macromolecules 1997, 30, 8524.
Gong, C.; Glass, T.E.; Gibson, H.W. Macromolecules. 1998, 31, 308.