What is the maximum flow rate/throughput of the FlowSyn?
Each of the pumping channels on FlowSyn can deliver up to 10 ml/min as standard.

However, Uniqsis also offer the FlowSyn Maxi. This instrument is fitted with higher capacity pumps that are able to deliver up to 50 ml/min on each channel.

There are some other changes too to make the instrument more suitable for higher flow flow/throughput use and scale up applications.

Is a simple 'T'-piece mixer adequate to ensure good control of mixing and reproducible results?
Controlled mixing is a key requirement for robust, reproducible chemistry.

That said, in practise a simple 'T'-piece mixer will often give good results - particularly where the chemistry is not mixing dependent and suffers from relatively slow kinetics.

However, for rapid and/or exothermic chemistries, the incorporation of a static mixing chip can be very beneficial.
This is a passive mixing device that typically incorporates special microscale geometric features to promote mixing, but can operate at ml/min flowrates and thereby deliver more useful throughputs. The microscale features lead to efficient heat exchange.

The benefits are that both rapid, reproducible mixing and excellent temperature control can be simultaneously achieved. This in turn leads to more robust chemistry and hence reliable and straightforward scaleability.

Uniqsis offers glass static mixers that may be easily fitted to the FlowSyn and can withstand operating pressures up to 40 bar. In addition these devices have special ports that accept the standard HPLC fittings used on the FlowSyn, thereby making tubing connections to the glass straightforward to achieve.

What about using air or moisture sensitive reagents with FlowSyn?
Yes, with a few simple precautions, this is possible.

Since flow reactors have no reactor 'head space', they are well suited for handling air sensitive reagents.

Reagent and solvent stock bottles can be inerted by connection to the inert gas manifold found in most fume cupboards (Uniqsis can supply an alternative independent manifold which attaches directly to the FlowSyn if required). The reagent bottle tops have Luer fittings for this purpose. In addition the inlet lines are available with rigid tails (either stainless steel or PEEK) that can be inserted directly through a Sure-Seal reagent bottle cap.

It is essential to thoroughly flush the flow path with a dry solvent to remove any moisture first. An anhydrous water miscible solvent, typically THF, (ideally from a solvent still) is preferred for this purpose.

Finally, it is very important to fit a piston back-wash system to the pump heads (Uniqsis can supply a kit specially designed for this purpose). It is preferable to continuously flush the pump heads in this way - often at quite a high flow rate. However, in some cases, periodically using a syringe charged with a suitable solvent is usually adequate.

Uniqsis recommend that nBuLi is diluted to 0.8M when used under flow-through conditions.

Looking after pump head check valves
Proper operation of the check valves fitted to the high pressure pump heads is critical for accurate and reliable pumping.
FlowSyn is fitted as standard with high quality, chemically inert check valves. These should give many hours reliable use - provided some simple precautions are followed:

• Use inlet filters – particulates can damage the pump heads and may cause the check valves to fail open.
• Do not allow reagents to remain stagnant in the pump heads for long periods.

Check valves can be cleaned either by sonication or by flushing using a suitable cleaning solvent. Uniqsis recommends a [1:1:1] mixture of THF:AcOH:water or DMF:AcOH:water.
Flushing the check valves can be conveniently done by using the Uniqsis Check Valve Cleaning Kit (UQ7035).

What is the maximum usable pressure of the standard FlowSyn?
All new standard FlowSyn units are rated to 1400psi (or 100bar). However this maximum is only possible when using Stainless Steel or Hastelloy® coil reactors.
When using Teflon or PFA coil reactors the pressure is automatically limited to 300psi (or 21bar) for safety.

What is the maximum temperature the standard FlowSyn can reach?
The standard FlowSyn includes two separate heating modules. The coil reactor unit (homogeneous) can be heated to 260°C and the column reactor unit (heterogeneous) can be heated to 150°C. The temperature of each reactor has been calibrated so that the temperature of the solution is accurate to ±1°C. The maximum temperatures are achievable using the stainless steel coil reactor (260°C). For Teflon and PFA coil reactors the system limits the maximum temperature to 150°C.This ensures that the tubing is not damaged by over-heating.

What safety features are incorporated within FlowSyn
The FlowSyn system has been designed with a number of safety features to protect you and your working environment in the event of a failure: There are four main safety features.

• Constant alarm-linked pressure monitoring for under- and over-pressure. If a leak or pressurisation above the safe limit is detected, the pumps stop.
• All pressure-critical parts are pressure tested and rated; pressure limits are automatically set by FlowSyn according to the reactor material.
• Unique to FlowSyn is that all pressurised parts are contained within the Plexiglass safety cover which has an alarmed safety interlock to warn the user not to open it during operation.
• An over-temperature alarm/cut-out protects the system from over-heating. In addition to a mechanical/thermal fuse, when powered on, the FlowSyn firmware constantly monitors the reactor temperatures and will independently disable the heaters if an over-temperature condition of more than 10C is detected.

How chemically resistant is FlowSyn?
We fit all FlowSyns with modified high pressure pumps that do not contain PEEK (PEEK is an excellent engineering polymer but has poor compatibility with concentrated mineral and organic acids and very strong organic bases). Wetted parts are fabricated from sapphire, ruby, Kel F, Hastelloy® and carbon filled PTFE. For many scientists, the standard PEEK and PTFE flow path will be more than adequate.

You can specify different materials for the FlowSyn flow path so that the system best meets the chemical requirements of your application. You will need to consider the following factors:

• A full PTFE flow path offers the broadest chemical resistance, particularly to concentrated mineral acids – but lacks the physical strength to operate safely at very high pressures.
• Stainless steel offers a good compromise with the strength to safely operate at high pressures with permanently swaged 316SS tubing. It has broad chemical resistance so long as it is not exposed to high concentrations of HCl.
• Hastelloy® offers the best combination of chemical resistance and high pressure capability – but is the most expensive.

If you need more information or assistance in making your choice, please contact us directly.

What pressure and temperature can the FlowSyn mixer block withstand?
Each individual block is pressure tested to 40 bar and can be used at -70°C to +150°C.

Can FlowSyn coils be used for sub-ambient reactions?
Yes – All coils can be used with FlowSyn Cold down to at least -90°C. The same coil reactors may also be used with the Polar Bear Plus Flow reactor module.

Can I rewind my FlowSyn coil reactor?
Yes. The coil reactors have been made so that the tubing can be quickly and easily replaced by the user. This is both pragmatic and cost-effective.

Other suppliers insist that you repeatedly purchase expensive new coil reactors each time the tubing becomes blocked or worn out. We recognise that blockages do occur from time to time, and PTFE tubing should be replaced periodically to reduce the risk of potential rupture (- after every 10 - 20 uses is recommended, particularly as repeated pressure and heat cycling of thermoplastic materials causes fatigue), so we make it as easy as possible for you to re-wind your own. It only takes a matter of minutes! We can even provide tubing in bulk quantities to reduce the cost as much as possible.

Of course, we are more than happy to re-wind your coil reactors for you, but this is only really worth considering where the coils are made of metal (stainless steel or Hastelloy®).

Can I do multiple step chemistries with FlowSyn?
Yes – up to 3 temperature zones and 4 reagent inputs are possible with the FlowSyn + external pump(s).

Whilst FlowSyn is compatible with up to 2 individual standalone high pressure pumps (10P or 20P), a more attractive option is to upgrade FlowSyn by the addition of a Binary Pump Module (BPM). This device is essentially a replica of the FlowSyn itself, but is devoid of the reactor modules.

Can FlowSyn be used to produce compound libraries or handle multiple reagent sets for, say, reaction profiling?
Yes. Generally for compound library preparation, the individual monomers are introduced into the flow stream using sample loops. This has the added advantage that because only solvent and not reagent solutions are pumped through the pump heads, the pump heads need less maintenance and cleaning. If you are using FlowSyn Auto-LF, the system will automatically wash and refill the sample loops from a pre-determined set of reagents. Otherwise the sample loops need to be filled by hand with a syringe, which means that you need to keep going back to the machine.

With the FlowSyn Auto-LF package you can design your combinatorial array upfront and the flow reactor will automatically run the chemistry and prepare the compound library completely unattended. In a similar way, this set up can be used for reaction profiling using a set of different reagents (say bases or coupling reagents, for example).

Also, because the sample loop refilling and product collection and/or fractionation are handled separately, the system will typically start to fill the sample loops for the next experiment before the current experiment has finished. As loop loading is a relatively slow process, this saves a considerable amount of time when experiments are processed serially using a single flow reactor.

Why is it important to collect the steady state?
Generally, only the material at the steady state has a product distribution that is truly representative of a scale up result.

What is the difference between HT and LT PTFE coil reactors?
Perfluoroelastomers such as PTFE and PFA soften considerably at elevated temperatures and this leads to stretching of the tubing when pressurised. Consequently, the tubing can expand and lose intimate contact with the metal mandrel of the coil reactor which compromises heat transfer and therefore temperature stability. This in effect limits the maximum temperature to approximately 100°C for LT (low temperature) coil reactors.

The HT (high temperature) coil reactor design, however, incorporates deeper channels (grooves) such that the tubing locates in a ‘micro oven’ environment. This allows more movement of the tubing before a stable temperature environment is compromised. HT coil reactors can therefore be heated up to a maximum of 150°C.

An additional, and important, benefit of the FlowSyn coil reactor design is that the reactor contents are safely contained within the glass cover in the event of a coil reactor rupture under pressure. The pumps will stop immediately to minimise any spillage, and any liquid escaping from the reactor (the largest coils we offer contain 50 ml) will simply drain into the PTFE coated reactor containment tray.

In the event of a rupture and spillage, replacement or repair of the coil is straightforward, and clean up of the instrument is quick and easy. This is NOT the case with hot air (convector) heating systems where not only can the coil reactor not be repaired, but the inside of the instrument becomes contaminated and the unit has to be dissembled and decontaminated. A major undertaking!

I'm a bit confused about check valves ...
Check valves are critical to the proper operation of the high pressure pumps used by Uniqsis. For optimal chemical compatibility, the check valves are made from perfluoropolymer with a Titanium outer casing and a ruby ball. There is no spring fitted, the CV's are gravity seated.
The latest design of CV's are used that do not have a compressible top and base - which can lead to problems.

It is also possible to fit CV's with a PEEK outer casing, however, these are generally less chemically resistant, in particular to concentrated mineral acids; but issues may also sometimes be encountered with some solvents such as THF and dichloromethane.

When changing between water and dichloromethane I see large pressure oscillations and can't seem to get the pumps to stabilise and pump properly?
Uniqsis recommend when switching between 2 immiscible solvents that the pumps are flushed with an intermediate solvent in which both solvents are miscible.

Acetone is the most convenient (and benign) intermediate solvent to use, and usually works to effectively flush the check valves and stabilise the pumps. Alternatively, we have found dimethylformamide (DMF) to also be very effective.

Fluorous solvents can be a particular problem, although MeOH is often effective in these cases.

This process should only take a few minutes to complete.

Can I pump dichloromethane (DCM) using FlowSyn
Yes, however there are a couple of things to consider upfront.

Firstly, DCM has a boiling point close to RT and is therefore prone to out-gassing in the pump feed lines because a partial vacuum is applied each time the pump heads refill. The resulting gas bubbles can cause pressure pulsation at the pump heads resulting in inconsistent flow.
This can largely be alleviated by using fresh bottles of DCM (which typically contain minimal dissolved gases) or degassing the DCM prior to use. Applying a mild positive pressure to the solvent containers using a gas manifold or nitrogen balloon also helps.

Secondly, the pump inlet selection valves can become warm in continued use and this may lead to gas bubbles in the inlet lines. Uniqsis can make an electrical modification to the FlowSyn (or BPM) to largely alleviate this problem if required. Please contact Uniqsis for more details.

Finally, please bear in mind that DCM decomposes at elevated temperatures (above 180C). The HCl liberated is corrosive to stainless steel reactors.

My coil reactor is blocked! What can I do?
All Uniqsis coil reactors can be re-wound and the tubing replaced by the end-user. However, there are a couple of things worth trying first:
1. Coil reactors made from metal tubing are terminated with swaged fittings. That is to say, the ferrule is held in place by crimping the tubing slightly. Blockages can happen at occlusions like this. Try cutting off a short length of tubing at the inlet and outlet and replace the fittings.
2. Try back-flushing the coil reactor (reverse the flow).
3. Try sonicating the coil reactor whilst maintaining back pressure (low flow rate) in an ultrasound bath.
Good luck!

What is the maximum temperature the standard Uniqsis FlowSyn can reach?
The standard FlowSyn includes two separate heating modules. The coil reactor unit (homogeneous) can be heated to 260°C and the column reactor unit (heterogeneous) can be heated to 150°C. The temperature of each reactor has been calibrated so that the temperature of the solution is accurate to ±1°C. The maximum temperatures are achievable using the stainless steel coil reactor (260°C). For Teflon and PFA coil reactors the system limits the maximum temperature to 150°C.This ensures that the tubing is not damaged by over-heating.

Please Note: The coil reactor heating module (FlowSyn, HotCoil) can be upgraded to operate at up to 300°C, if required.

Can I pump organometallic bases such as LiHMDS and BuLi using FlowSyn?
Yes. However, we recommend that you adhere to the following guidelines:

• The organometallic should not contain precipitate. If so, it is advisable to use an in-line filter.
• All solvents should be anhydrous, and the stock bottles inserted under a N2 or Ar blanket (tubing from a low pressure gas manifold can be terminated with the ends of disposable syringes and these can be inserted directly into our recommended bottle tops). A short length of wide-bore SS tubing can be inserted directly through Sure-Seals and connected directly to the FlowSyn using standard fittings.
• The flow path should be thoroughly flushed through with an anhydrous solvent (e.g. THF) before any moisture sensitive or air sensitive reagents are pumped.
• We recommend that you fit a Backflush Kit (UQ-7210) to the pump heads. Salts (amongst other things!) derived from hydrolysis of organometallic reagents tend to accumulate between the high and low pressure pump seals. These should be removed periodically by either dissembling the two halves of the pump heads, or more conveniently, by flushing with a suitable cleaning solvent using the Backflush Kit (e.g. 1:1:1 [AcOH:THF:H2O] or [AcOH:THF:DMF]).
• The FlowSyn should be flushed with a cleaning solvent after use (1:1:1 [AcOH:THF:H2O] works well), and then stored in iPrOH.

Finally, please remember that using the sample loops to deliver corrosive or moisture sensitive reagent solutions avoids the need to pass the solutions through the pump heads and therefore, certainly for small voumes, this is the recommended procedure when working with such reagents (sample loops are available in sizes up to 50ml).

This protocol should ensure that your FlowSyn performs reliably.

Is it always necessary to store the FlowSyn in iPrOH after use?
It is very important, particularly if you pump reagent solutions through the pump heads, to clean them out thoroughly after use and then store them in a benign solvent. iPrOH is particularly good because it helps to ensure that the check valves in the pump heads are conditioned properly. Other clean solvents are also suitable overnight, however, we recommend iPrOH for prolonged storage of the FlowSyn.

If you are using a fluorous system solvent (for plug flow work), we recommend that you do not routinely switch back to IPrOH to store the system in overnight. Leave it primed with the fluorous solvent. Conditioning the check valves to give stable flow can be particularly problematic and require prolonged flushing in these cases.