A new mechanism for glucose dehydration to HMF without the intermediate isomerization to fructose is discussed for surface models of anatase TiO₂ using periodic density functional theory calculations. Activation of the glucose at glucose's C3-OH position by titania starts the reaction resulting in adsorbed 3-deoxyglucosone. The mechanistic study reveals two possible pathways for the acyclic form of glucose. Comparison of different surface models shows that the presence of tetrahedral Ti⁴⁺ species on a defective TiO₂(101) anatase surface is essential for explaining the activity. Synergy between a strong Lewis acidic Ti site and a vicinal basic oxygen site of a TiOH group is essential to establish the direct conversion of glucose to HMF. IR spectroscopy of adsorbed chloroform in the presence of water confirms the presence of water tolerant Lewis acid sites in close proximity to basic sites. In conventional glucose dehydration, Lewis acid sites and proton donors act as catalytic sites for efficient sequential isomerization-dehydration to HMF, while direct dehydration to HMF requires the cooperation of Lewis acid-base pairs.