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The first Professor of Chemistry and Natural Sciences was Father Massea. He began instruction in chemistry in 1856, five years after the founding of Santa Clara College. While Santa Clara College shares with the present University of Pacific the honor of being the first college-level institutions in California, Santa Clara's Chemistry Department is clearly the oldest presently surviving, and probably the original, Chemistry Department in California. It has seen the acceptance of Avogadro's hypothesis, the rise of the periodic table, and the expansion of the number of elements from 45 to over one hundred.

Within a year, in 1857, the College had bought for ten thousand dollars in Paris "a complete philosophical and chemical apparatus" with various instruments, mineral specimens, and scientific treatises. Another great asset was Father Bruengo, who authorized and supervised the building of the first science building. It was completed in 1864, and had three stories: classrooms on the first floor, chemistry laboratories on the second floor, and physics laboratories on the third floor. Above this rose a large spire, which was intended to call attention to Santa Clara College.

In early diary records, the Chemistry Department was characterized by "a genuine family spirit." Under Father Massea, the science curriculum emphasized chemistry, mineralogy, agriculture, and domestic economy. From 1860 to 1905, Father Anthony Chichi was in charge of the Chemistry Department in a period of growth and much success. His enthusiasm and interest in research inspired his students. His field trips were one of the very few ways a student could leave the campus. He was interested in wine-making, mineral content of the waters at various health spas, and in mining. About twenty years after the gold rush, the chemistry labs at Santa Clara were deeply involved in assaying. Indeed, it was quite natural for this to happen since in the those days Santa Clara's chemistry laboratories were by far the most modern and well equipped in California. In 1878, advanced chemistry students studied much analytical chemistry, with subjects like Practical Assaying, Minerology, and Geology. One of Cichi's students, Peterson by name, advised miners to go deeper, in accord with Cichi's dictum that whatever was on top must have come from below. Peterson's advice led to gold worth twenty million dollars.

The Chemistry Department was not alone in its success after the Civil War. Father Neri not only taught analytical chemistry but, in his main field of physics, contributed to the general strength of the natural sciences. Father Neri, for example, introduced carbon arc lights to San Francisco in 1876 for the Centennial celebration. One of Father Neri's students at St. Ignatius College in San Francisco was John J. Montgomery, who is famous as the aviation pioneer who introduced controlled flight with the curved wing on his gliders. There is a monument to Montgomery on the campus. As a professor of physics at Santa Clara, Montgomery was able to use the excellent conditions for gliding at the east side of the Santa Clara Valley.

Another physicist, Father Richard Bell, greatly influenced Santa Clara's Chemistry Department after Chichi's retirement in 1906. Father Bell was involved in experiments in radio, and his accomplishments were greatly admired by many, including Marconi. Bell's great success in research on radio were, however, not chemical. Although Bell was in charge of both physics and chemistry and, of course, the Bruengo Science Building, it was clear that chemistry was only his second love. In 1917, the chemistry department was moved to a wooden building, a renovated student chapel beside the Mission Church. There, Fathers Galtes and McGarrigle, both with considerable previous teaching experience in chemistry, continued the tradition of excellent chemistry training. One of the more famous of McGarrigle's students was Koch, who took his B.S. from Santa Clara in 1920, did graduate work at Harvard, and was directly involved in discovering several oil fields in Canada. Father Galtes is presently remembered for his extraordinarily extensive collection of marble (limestone) and in the name of the Galtes Chemical Society, the undergraduate chemistry club for student affiliates of the American Chemical Society.

The Alumni Science Hall, built in 1924 and still used by part of the College Sciences after several extensive renovations, was first used by physics (first floor), biology (second floor), and chemistry (third floor). About this time, lay professors began to replace the Jesuit fathers. Surely the crucial event in those years was the arrival of Dr. Joseph Deck in September, 1936. He found the equipment and facilities of the Chemistry Department in great disarray on the third floor of the Alumni Science Hall. With almost superhuman service and dedication, Deck labored. By 1972, at age 65, he had forged the Department into one of the strongest at Santa Clara. From 1936 to 1955 or so, it was typical for instructors to stay at Santa Clara for about five years. Heavy teaching loads, meager salaries, little apparatus, and few students, especially during World War II, were only part of the handicap. In those days, students were required to take many courses in theology, philosophy, and humanities; the extra burden of science courses was a deterrent to large enrollments in chemistry.

In 1955, two events changed the attitude then current at Santa Clara that research marred the effectiveness of undergraduate education. In 1955, Dr. Sheehan, who eventually succeeded Dr. Deck as chemistry's chairman in 1972, arrived from Shell Development Company to begin teaching physical chemistry and general chemistry. And, more important, Father King, who had been Dean of the College of Sciences since 1950, called for research in all the sciences. Perhaps this was in response to the 1954 arrival of Dr. Drahmann, who became Dean of the College of Sciences since 1969, and to the arrival of other professors dedicated to research as well as teaching. In any case, Dean King's 1955 call for research, inspired by an attempt to meet criteria of the American Chemical Society, was a turning point. The desired ACS accreditation came in 1959.

From 1936 to 1970, University enrollment rose from about 400 to 3000 full-time undergraduate students. During World War II, total enrollment was briefly as low as 75. The rising enrollment, of course, strained the three laboratories, balance room and stockroom atop the Alumni Science Hall. And so again, as in the early 1920's, the chemistry department had make-shift facilities. In the 1950's, however, only about one-third of the department was in temporary buildings, which had been used elsewhere for psychiatric rehabilitation of servicemen from World War II. Their defective heating and cooling made volumetric analysis impossible, and it was a two-story climb to the stock room.

The Edward J. Daly Science Center, completed in 1966, had most amply remedied any deficiencies in facilities for chemistry and physics, provided enrollments stayed steady. The Vincent O'Donnell Chemistry Building (Daly Science 100) provided ten thousand square feet of very efficiently used space. This is supplemented by a shop, a medium-sized laboratory, and other facilities in other parts of the Daly Science Center. In the O'Donnell Chemistry Building were four large laboratories for teaching and five small laboratories for professors. It also contained two stockrooms, six offices and several storage areas and instrument rooms.

Daly Science 100 was modernized in 1994 and is highlighted on the facilities page.

In 2008, the department officially offered biochemistry as a major, whereas in prior years, it was offered as an emphasis.  In 2009, the department changed its name to department of chemistry and biochemistry.