Which substance would have normally have the least difficulty crossing a cell membrane?

 There is a small difference between the difficulty of substances to cross a cell membrane since the diffusion of substances through cell membranes always occurs going down by gradients of concentration. It does not require an energy expenditure (ATP).Plasma membranes have selective permeability. Different molecules move in different regions and at different speeds. A concentration gradient directs the three types of passive transport: simple diffusion, facilitated diffusion and osmosis.