Final answer:
Sodium ions (Na+) have the most difficulty diffusing through the lipid bilayer due to their polar and charged nature, as biological membranes are permeable primarily to small, nonpolar, or hydrophobic molecules like oxygen and carbon dioxide.
Step-by-step explanation:
The substance that would have the most trouble crossing a biological membrane by diffusing through the lipid bilayer would be the sodium ion (Na+). This is because biological membranes are selective in permeability, primarily allowing small, nonpolar, or hydrophobic molecules to pass through easily via simple diffusion. Molecules such as carbon dioxide (CO2) and oxygen (O2) can readily diffuse through the membrane because of their nonpolar nature and small size. However, sodium ions are polar and charged, which prevents them from passing through the hydrophobic interior of the phospholipid bilayer without assistance from transport proteins.