1,1-Diethoxyethane (DEE) is an important chemical with versatile applications. Here, we report the efficient synthesis of DEE via two-sequential reactions of ethanol including the selective dehydrogenation of ethanol to acetaldehyde and the subsequent acetalization of acetaldehyde with ethanol to DEE. The ethanol dehydrogenation was examined on Cu catalysts supported on SiO2, Al2O3, ZrO2 and TiO2 supports with similar Cu dispersions, and Cu/SiO2 was more selective to acetaldehyde with 99.0% selectivity at 493 K, due to the inert surface of SiO2, compared to the other three oxide supports with stronger acidity and basicity facilitating the side reactions of acetaldehyde. For the equilibrium-limited acetalization reaction, comparison of representative solid acids (e.g. SO42-/ZrO2, Amberlyst 15, H-Y zeolite and AlCl3/SiO2) showed that while they offered nearly 100% DEE selectivities, the Bronsted acid sites were more active than the Lewis acid sites. This was confirmed by the higher activities (normalized per acid site) for the H-Y zeolites with higher factions of the Bronsted acid sites obtained by calcination at lower temperatures in the range 773-1073 K. Combination of the ethanol dehydrogenation on Cu/SiO2 at 493 K and the acetalization reaction on H-Y (calcined at 773 K) at 293 K in the two-sequential flow microreactors led to the steady conversion of ethanol to DEE in a yield of as high as 35.0%. This yield could be further improved, for example, to 70.5%, the highest yield from ethanol reported to date, after removal of water in the acetalization reactor by 3A zeolite. Such two-sequential reactor configuration also applied to the efficient synthesis of other important acetals, and as an example, dimethoxymethane was synthesized directly from methanol in a yield of 84.1% on iron molybdate and H-ZSM-5 catalysts. (C) 2014 Elsevier B.V. All rights reserved.