The use of an in-house hydrogen generator has myriad benefits over bottled hydrogen for hydrogenation.

The hydrogenation reaction, which is frequently used by chemists involved with the synthesis of compounds of pharmacological interest, involves the addition of hydrogen to an organic compound. While a number of specialized reagents have been developed for this purpose, the use of hydrogen gas with a metal catalyst (e.g. Pt) is a popular approach that has been employed for many years. In many laboratories, the hydrogen gas for the reaction is supplied by a pressurized bottle.

This paper describes the use of an in-house generator that is based on the electrolysis of water to supply the gas to the reaction. This approach is considerably safer, more convenient, and less expensive than the use of bottled gas. In addition, the use of in-house gas generation minimizes the possibility that the gas supply will stop due to an empty tank, which could have significant economic consequences, and it provides gas of extremely high purity.

Conventional hydrogen generation

In-house generation of hydrogen gas is based on the electrolysis of water. There are two general approaches for the electrolysis of water, which involve using either a metallic electrode or an ionomeric proton exchange membrane.

The traditional method of generating hydrogen via the electrolysis of water involves a metal anode (e.g. Pd) and a metal cathode. Since water does not conduct an electric current very effectively, a strong, water soluble electrolyte such as 20 % NaOH is added to the water.

To provide high purity hydrogen, a cathode in the form of a bundle of palladium tubes can be employed. Since only hydrogen and its isotopes are capable of passing through the cathode (oxygen and other impurities collect at the anode), hydrogen gas with purity in excess of 99.99999% can be obtained.

A typical system, such as the Parker Balston Model H2PD-300 Hydrogen Generator from Parker Hannifin Corp., Haverhill, Mass., generates hydrogen with a purity of 99.99999+ %, an oxygen content of <0.01 ppm, and a moisture content of 0.01 ppm at a maximum flow rate of 300 cc/min with a maximum pressure of 60 psig. Once the hydrogen is generated, it can be directly ported to the reaction vessel.

Some systems that generate hydrogen via the electrolysis of water via a metal electrode use a dessicant as the final drying agent instead of palladium tubes as the final purifier. The palladium tube cathode provides a very considerable improvement in purity which may be very important when the hydrogen is used for hydrogenation with a homogeneous catalyst and the reaction is blanketed with a nitrogen atmosphere because oxygen will destroy the catalyst.

Another method of in-house hydrogen generation is with a proton exchange membrane (PEM), which is designed to conduct protons while being impermeable to gases such as hydrogen and oxygen. PEMs are commonly used in fuel cells to create an electric current (and form water) from hydrogen gas and oxygen gas. When an appropriate potential is applied to a PEM in the presence of water, the reverse process will occur and the water will be dissociated to form oxygen and hydrogen. A significant benefit of this approach for the generation of hydrogen is that pure water can be employed and it is not necessary to use a 20% solution of sodium hydroxide (which is quite caustic) to promote the electrolysis.

A hydrogen generator based on PEM technology, such as the Parker Model H2PEM-510 Hydrogen Gas Generator, is capable of generating 99.9995% hydrogen at flow rates as high as 510 mL/min at pressures up to 100 psi.

Better than bottled

In-house generation of hydrogen is considerably safer than employing bottled gas as in-house generation allows for the generation of the required volume of gas on demand at a low pressure. In contrast, when bottled gas is used, the bottle may contain a considerable amount of hydrogen gas. If a leak were to occur, the gas in the tank would be released into the laboratory and would displace the air leading to the potential of asphyxiation and/or explosion. Since in-house hydrogen generators typically have a maximum output of 500 mL/min at a pressure of 100 psig, the volume of gas that could escape in the laboratory due to a leak in the system is very small.

An additional safety concern with the use of bottled gas is the requirement to transport the bottles from the storage location. If the individual moving the bottle loses control of it during transport and the valve is damaged, the tank can become a guided missile.

The in-house hydrogen generators described above include a variety of safety features to minimize the possibility of hazardous situations. As an example, if an overpressure or a pressure loss of the system is observed, hydrogen production will be immediately terminated and an error message will be generated. In addition, the error message can trigger an alarm and/or send a signal to an external controller.

Ready when you are

When an in-house hydrogen generator is employed, the gas is readily available on a continuous basis. The operator simply needs to add water on a periodic basis (full flow operation on a 24 hour/7 day basis requires approximately 4 L of water a week), and the water tank can be automatically refilled if desired when the tank is about half empty to ensure continuous operation.

The conductivity of the water used for PEM-based systems is continuously monitored (ionic materials in the water could foul the electrode and the system will shut down if the conductivity reaches a preset level). If a PEM-based system is employed, the user replaces the deionizer and filter every six months. On a periodic basis, the dessicant and the deionizer (on the PEM system) should be replaced. These activities depend on the level of use of the system, but are typically in the order of twice a year.

Michael DiMarco, research scientist at Ariad Pharmaceuticals, Cambridge Mass., is a typical user of a Parker in-house hydrogen generator. “Hydrogen gas for hydrogenation is always available on an on-demand basis,” states DiMarco. “Generation of the gas is convenient, and the system is extremely easy to operate. It requires a minimum amount of maintenance and has had no downtime in over five years of operation”.

In contrast, when a hydrogen bottle is employed, the operator must make certain that it contains a sufficient amount of gas for the desired operation. In many facilities, replacement bottles are frequently stored in a remote (outdoor) location for safety reasons and specially qualified personnel may be required to perform tank replacement. When bottled gas is employed, it is necessary to maintain a supply of spare bottles and order/return bottles on a periodic basis.

When a bottle is used to deliver the hydrogen, the connection between the source of the gas and the reactor must be broken when the bottle is replaced. This can lead to the introduction of contaminants such as moisture, oxygen, and any other materials which may be present in the laboratory atmosphere into the system. This may have a deleterious effect on the reactants, products, or catalyst, especially when homogeneous catalysts are employed as these are quite moisture sensitive. In contrast, when an in-house hydrogen generator is employed, a direct connection is made between the generator and the reactor, which need not be broken, thereby dramatically reducing the possibility of contamination.

Economic and time factors

The overall cost of operation of an in-house hydrogen generator is considerably lower than the use of bottled hydrogen. The only running costs for an in-house generator is for electricity and water. As an example, the power consumption for the 500 mL/min system is 235 W, so if the generator is used for 40 hr cycle on a 52 week basis, approximately 5000 kWh would be used (at 10¢/kWh, the running cost would be $500).

In addition, the cost of maintenance and replacement of the deionizer and dessicant is perhaps $500/yr when bottled gas is employed. While the payback period of the hydrogen generator clearly depends on the amount of gas that is consumed and the cost of the tank gas, the hydrogen generator pays for itself in a year in many facilities. When bottles are used to supply the gas, the time cost of ordering the gas and bottle demurrage should be included; these costs are not present with an in-house hydrogen generator.

An additional concern is the large time and economic cost if the hydrogen tank were to become empty during the hydrogenation reaction. In this situation, the hydrogenation reaction would stop, leading to less than the optimum amount of the desired hydrogenation product. If the compound being hydrogenated and/or the catalyst are not stable (e.g. a homogeneous catalyst was being used), it is likely they will decompose. This could have significant economic implications in the pharmaceutical laboratory as the precursors may be very valuable (e.g. the hydrogenation is but one step in a multi-step process), and homogeneous catalysts are quite expensive.

The catalytic hydrogenation of unsaturated compounds with molecular hydrogen can be readily performed with hydrogen gas that is generated in-house. In-house generation is considerably safer, more convenient, and less expensive that the use of bottled hydrogen for the pharmaceutical synthesis laboratory that is synthesizing compounds on the milligram to gram scale. Hydrogen generators are available using either metallic electrodes or a PEM, with the latter approach providing the ability to generate hydrogen without using a caustic electrolyte. These generate a continuous flow of hydrogen and are permanently connected to the hydrogenation system, so that the possibility of introducing impurities into the reaction system is minimized.

—Peter Froehlich, Peak Media, Franklin, Mass