Membrane Microreactors for the On‐Demand Generation, Separation, and Reaction of Gases

Abstract The use of gases as reagents in organic synthesis can be very challenging, particularly at a laboratory scale. This Concept takes into account recent studies to make the case that gases can indeed be efficiently and safely formed from relatively inexpensive commercially available reagents for use in a wide range of organic transformations. In particular, we argue that the exploitation of continuous flow membrane reactors enables the effective separation of the chemistry necessary for gas formation from the chemistry for gas consumption, with these two stages often containing incompatible chemistry. The approach outlined eliminates the need to store and transport excessive amounts of potentially toxic, reactive or explosive gases. The on‐demand generation, separation and reaction of a number of gases, including carbon monoxide, diazomethane, trifluoromethyl diazomethane, hydrogen cyanide, ammonia and formaldehyde, is discussed.


Introduction
Gas-liquid transformations are very important for organic synthesis. Whether ac hemical is widely used will dependo nt he easinesst os ource,t ransport, store and handle the chemical.I t is becoming increasingly difficult to transport dangerousa nd toxic gases due to ever growingr estrictions. [1] Furthermore, some gases are simply too reactiveo rs hort-lived to be produced, stored and transported for later use. [2] Users may be hesitant to use ag as due to safety concerns, or perhaps lack the necessary experience or infrastructure to support their use. In addition, more specialized and expensive equipmenti sr equired for accessing higherp ressures (e.g.,a utoclavea pparatus). Whilst the use of gases on an industrial scale provides little hindrance, at al aboratory scale these challenges are unfortunately responsible for the underuse of toxic and flammable gases within many organic chemistryl aboratories. [3] The majority of alternatives to the use of gases are often more expensive, atom inefficient reagents ("gas surrogates"), that are not av iable option for use in large scale manufacturing. Thus processc hemists are forced to swap these protocols with con-ventional gaseous reagents during scale-ups tudies, whicha dversely impactst he time-to-market due to the cost and time associated with the re-development.

Conventional Approaches for Handling Gases
There are an umber of approaches used for the introduction of ag as into an organic reaction. Thee xact approach used dependso nanumber of aspects, including the properties of the gas, the reaction conditions neededf or the organic transformation, the scale and the capabilities of the available equipment.
Ac ommon approach at al aboratory scale is to simply affix a pre-filled balloon to ar ound-bottom flask to provide ag as at atmosphericp ressure. This approach is commonly used, but is unsafei fthe balloon suddenly bursts and investigation of pressure effects is not possible. As yringe can also be pre-loaded with ag as and used to introduce the gas at ac ontrolled flow rate. Am ore elegant method for the introduction of ag as directly from ac ylinder is by use of am ass flow controller (MFC) to regulate flow rate. However,t he installation of gas cylinders within al aboratory can be time consuming and cause accommodation issues, such as the requirement for af ire resistant storagec abinet. For gases with al ow vapor pressure, a common method is to condense the gas into the liquid phase for use in ar eaction. [4] The condensation of ag as can be highly hazardous due to flammability issues. Gases can also be formed in situ or ex situ from solid or liquid reagents, known as gas surrogates. [5,6] Some gases are highly reactive and therefore need to be prepared on-site and only shortly before use. Dangerous purification operations (e.g.,d istillation) are often necessary for isolation of these gases with sufficient purity.T he main limitation of an in situ approach is that there are often chemicalc ompatibilityi ssues between the gas forming reaction and the organic transformation consuming the gas. In many instances, the conditions necessary for the generation of ag as uses acidic or basic aqueous conditions, therefore making it difficult to produce ag as in an anhydrous manner,w hich is critical for the performance of many organic reactions.
To overcome the compatibility issues, Skrydstrup and coworkers devised at wo-chamber batch glassware system for the ex situ generation of gas. [7] The system comprises of two separatec hambersw hich are connected to allow the passage of gas from the chamber for gas generation to the chamber for gas consumption. This approachh as the limitation that a gas can accumulate within the system if not consumed at a sufficient rate and that it can only be operated at low pressures. mensionso fc ontinuous flow reactors provide ah igh surfaceto-volumer atio, resulting in enhanced heat and mass transfer characteristics. [11] The small internal volume ensures only a small chemicali nventory is handled ata ny one time. The onsite production and consumption of ah azardous chemical within as ingle integrated unit improves the inherent safety and eliminates transportation and storage of highly reactive and hazardous reagents. [2] Furthermore, the inclusion of an inline quench within af low setup or immediately afterward avoids the accumulationo fahighly reactive chemical. Due to the merits of flow reactors, they have been widely used for performing gas-liquid reactions. [12] Single-channel microreactors are most commonly used for gas-liquid reactions (Figure 1a). Gas-liquid reactions within these systems employ ab iphasic flow regime, most commonly segmented (Taylor) flow, which facilitates rapid mixinga nd mass transfer.
Recently,m embrane microreactors have gaineds ignificant attentiona se fficient gas-liquid contactors for performing organic transformations. [13] The membrane separates two adjacent channels, typically with one containing al iquid phasea nd the other ag as phase. As emi-permeable membranew ith a very large surfacea rea allowst he selectivep assageo fg ases and low molecular weightc ompounds from one side to the other.T he gas is rapidlyc onsumed by the substratei nt he second channel. The membranes used display hardly any liquid permeability anda re selected to display broad chemical resistance. The nature of the contacting methode nsures the process is inherently safe because the liquid phase and gas phase are in differentc hannels, and the gas is fully dissolved in the liquid phase, thusf lammable organic solvents are never in the presence of agas (vapor) phase. [9,14] Kim and co-workersd eveloped ad ual-channel microreactor strategy for performingg as-liquid transformations ( Figure 1b). [15] The microreactor is fitted with ah ydrophobic poly(dimethylsiloxane) (PDMS)m embrane (45 mmt hickness) which allowsd iffusion of gases but is impermeablet ot he other reaction components. Ag as flows along one channel passing through the membrane into the second channel containing the liquid phase for the organic transformation.T he system was first reported for reactions involving O 2 . [16] Subsequently, the reactor was modified to at hree-channel microreactor so that the gas could be introduced from both sides of the liquid channel. [17] In this system,t he fabrication is simpler and the effectivei nterfacial area is doubled.
Aboutt he same time, Ley and co-workersp ioneered the tube-in-tube membrane reactor for the loading of gases for use in organicreactions (Figure 1c). [18] The inner tubing is manufactured from ag as-permeable and hydrophobic fluoropolymer,T eflon AF-2400. Teflon AF-2400 is ac opolymer of tetrafluoroethylene and perfluorodimethyldioxolane. [19] The outer tubing is either manufactured from plastic or stainlesss teel tubing depending on the system requirements. Typically,t he system is operated with the gas in the inner tube and the liquid phase in the outer tubing.T he reactor has been successfully demonstrated for an umber of gasesi ncluding CO, H 2 , CO, CO 2 ,O 2 ,O 3 ,N H 3 ,f luoroform, and ethylene. [20] Therea re two modes of operation fort he tube-in-tube reactor,e ither: (1) al iquid-phase is pre-saturated with ag as within the tubein-tube system prior to as ubsequentr eaction within as econd reactor;o r( 2) the loading of gas to the liquid channel and organic transformation are performed simultaneouslyw ithin the tube-in-tube system.An umber of versions of the tube-in-tube reactor are commercially available. [21] On-Demand Generation, Separation &R eaction of Gases In this article, we presentt he concept of the on-demand generation, separation and reactiono fg ases within continuous flow membrane systems ( Figure 2). Am embrane is necessary to ensure the gas generation and consumption occur in two separatec hannels. There are examples reported that generate ag as from reagents within as ingle-channel microreactor,b ut this approach relies on compatibilityb etween the conditions for gas generation and gas consumption, and also complicates post-reaction processing. [22] The membrane microreactorsd escribed above can also be used fort his purpose.Ag as can be generated from inexpensive and readily availabler eagents within one channel. These reagents should be safer to handle than the corresponding gas formed. The generation of agas can be carefully controlled through the cautious manipulationoft he reagent flow rates to produce the required stoichiometry for reaction. The releaseo f the gas within the system can be controlled to avoid ap otential buildup of pressure. Subsequently,t he gas selectivity diffusest hrough the membrane into an adjacentc hamber.T he membrane is generally impermeable to all other components. The second channel containst he chemistry for the main organic transformation. The use of incompatible conditions for the gas generation and consumption is possible, for example acidic conditions in one channel and basic in the second channel, or aqueous conditions in one channel and anhydrous conditions in the other channel. Thus, anhydrous gas can be prepared without dangerouspurification operations (e.g.,distillation).The gas is consumed as it is formed which minimizes the risk of accumulation, therefore the approachi sv ery safe because only as mall quantity of gas is presentw ithin the system at any one time. The generation of ag as, its separation and organic transformation are fully contained within ac losed system preventing any exposuret ot he operator. It also completely obviates the need for gas cylinders.
Herein, an umber of examples demonstratingt he use of membrane flow technologiesf or the successful continuous generation,s eparation and reaction of gases are discussed. The relative strengths andw eaknesses of the strategiesa re covered.

Carbonmonoxide (CO)
Carbon monoxide (CO) is ah ighly valuableC 1b uilding block due to the number of carbonylation reactions available to the synthetic chemist. [23] CO is ac olorless, odorless andt asteless gas. It is highly poisonous and flammable, thusi ti su nderused for organic synthesis.
Perhaps the earliest example using the tube-in-tube reactor for on-demand gas generation, separationand reactionwas reported by Ryu and co-workers (Scheme 1a). [24] In this report, CO was generated within the inner tube throught he dehydration of formic acid (HCOOH) with sulfuric acid (H 2 SO 4 ). The liberated CO then passed through the membrane to the outer tube for the main organic transformation. The main organic reaction wasapalladium-catalyzed Heck aminocarbonylation of 4-iodoanisole (1)w ith n-hexylamine (2)t of orm the amide 3. The protocol demonstrated that CO could be continuously generated and consumed with amide 3 afforded in 81 %y ield within 3h residence time. This particular example highlights the benefitofu sing membrane technology as the acidic conditions to liberate CO could be used concomitantly with the basic conditions used in the carbonylation reaction. The study was an excellent proof-of-concept, but the conditions employed are very limited by their throughput (0.042 mmol h À1 ). Scheme1.On-demand generation, separationand reaction of CO within a tube-in-tube reactorfor:a)Pd-catalyzed aminocarbonylatio and b) Pd-catalyzed alkoxycarbonylation. Pd(dba) 2 = bis(dibenzylideneacetone)palladium, Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
More recently,L ey and co-workers reporteda na lternative reactions ystem for generating CO within the tube-in-tube reactor (Scheme1b). [25] Oxalyl chloride (COCl) 2 (4)w as hydrolyzed by sodium hydroxide (NaOH)w ithin the outer channel of the tube-in-tube reactor.T he use of an Omnifitc olumn (0.68 mL) with two magnetic stirrer bars prior to the tube-intube reactorw as necessary to adequately mix the toluene phase containing COCl 2 and the aqueous NaOH phase. CO then passed through the membrane into the inner tube for the main organic transformation which was flowing counterflow to the CO generating stream. AF lowIR spectrometer was used in-line for reaction monitoring. CO 2 was observed by FTIR to pass through the membrane under certain conditions, therefore the ratio of NaOH to COCl 2 was increased to neutralize the CO 2 formed. The system was optimized on the Pd-catalyzed methoxycarbonylation of vinyl iodide 5 (Scheme 1b). The alkoxycarbonylation wasd emonstrated on an umber of vinyl and aryl iodides (eighte xamples), and aminocarbonylation (two examples). The potential scalability of the system was demonstrated with as cale-outl ong run for 320 min operation time, with athroughput of 1.43 mmol h À1 achieved.

Diazomethane (CH 2 N 2 )
Diazomethane (CH 2 N 2 )i sahighly valuabler eagent for the introduction of am ethyl or am ethylene group into am olecule. [26] Diazomethanei su sed for the preparation of methyl esters from their corresponding carboxylic acids, homologation of ketones or carboxylic acids (Arndt-Eistert reaction) and cyclopropanation reactions. However, diazomethane is ap otent carcinogen,e xtremelyt oxic, odorless yellow gas.I ng eneral, diazomethane is generated and purified by co-distillation with diethyle ther which is associated with ac ertain safe risk. It has ah igh explosive potentiala nd the vast majority of diazomethane explosions occur during the distillation process.C onsequently,d iazomethane is hardly ever used for the industrial production of chemicals duet os afety concerns. [26,27] Anhydrous diazomethane can be prepared without the need to distill through the applicationo fm embrane microreactors.
Kim and co-workers reportedt he use of the dual-channel microreactor for the in situ generation, separation andr eaction of diazomethane (Scheme2). [28] Diazomethane can be generated from the base-mediated decomposition of N-methyl-N-nitroso-p-toluenesulfonamide (Diazald, 7). In this flow configuration, 7 quickly reacts with KOH to generate diazomethane in the bottom channel, and then diffuses through the PDMS membrane to the upper channel for immediate consumption by reactionw ith the substrate. The system was successfully optimizedf or the methylation of acetic acid (8)t oa fford methyl acetate (9)w ith am oderate throughput of 0.125 mmol h À1 . The microreactor has av ery small internal volume (60 mL) which improvest he inherent safety,b ut limits throughput. The methylation of phenol (Table 1, entry 1), methylation of benzaldehyde( entry 2) and the Arndt-Eistert reactiono fb enzoic chloride( entry 3) were successfully demonstratedu sing the system.
Along similarl ines to the CO formation, CH 2 N 2 can also be generated from KOH and Diazald (7)w ithin the inner tubing of at ube-in-tube reactor, with CH 2 N 2 diffusing throught he membrane to be consumed within the substrate-carrying outer channel (Scheme 3). [29] Our group optimized the system for the methylation of benzoic acid (10)( Scheme 3a). The conditions were applied fort he methylation of an umber of nucleophiles (six examples). Subsequently,t he configurationw as also demonstrated fora[3+ +2] cycloaddition, Pd-catalyzedc yclopropanation and an Arndt-Eistert reaction( Scheme 3b). We also used the system in the context of making precursors for antiretroviral drugs in af ully telescoped flow manner. [30] Various Nprotected aminoa cids were converted into their corresponding a-halo ketones with good yields for an important step in the synthesis (eight examples). Koolman and co-workersa lso reported the synthesis of cyclopropylb oronic esters by Pd-catalyzed cyclopropanation. [31] In this case, CH 2 N 2 was generated and separated within the tube-in-tube reactor to pre-saturate the organic phase prior to the introduction of the other re-Scheme2.Dual-channel microreactor for the in situ generation, separation and reaction of diazomethane for the methylation of acetic acid.  Ad rawback of the tube-in-tube reactor is that it is limited to aC H 2 N 2 throughput of approximately 1.25 mmol h À1 .Asubsequent development was the tube-in-flaskr eactor. [32] In this configuration, the membrane is coiled inside ag lass flask, CH 2 N 2 is generated continuously within the membrane, and CH 2 N 2 diffuses through the membrane into af lask filled with substrate and solvent (Scheme 4a). The tube-in-flask reactor also allowst he organic transformation to contain solids. Al-thoughn ot yet commercially available, the tube-in-flask reactor can be assembled from commercially available parts withiñ 1h. [33] Furthermore, simplep arallelizationo ft he membranes enables am oderate throughput of materialt ob ea chieved (CH 2 N 2 at % 42.8 mmol h À1 ). However,t hroughput is still limited due to safety reasons. The implementation of PAT, such as inline FTIR (CN 2 2091 cm À1 ), is important to monitor that CH 2 N 2 does not accumulate within the flask.
Our research group,w ith co-workers from Patheon, recently described am ethodf or safe handlingo fC H 2 N 2 at potentially commercially relevant volumes. [34] Ac ontinuous stirred tank reactor (CSTR)c ascade was reported for am odified Arndt-Eistert reactiono fN-protected l-phenylalanine 15 to form diazoketone 16 (Scheme 4b). AT eflon AF-2400 membrane was fitted inside each CSTR for the introduction of CH 2 N 2 .After treatment with HCl, a-chloroketone 17 could be obtained with a throughput of 5.2 mmol h À1 .

Trifluoromethyl diazomethane (CF 3 CHN 2 )
Similar to diazomethane, trifluoromethyl diazomethane (CF 3 CHN 2 )( 19)h as both explosive and toxic properties, and is also highly volatile (b.p. 13 8C). It is ah ighly valuable reagent for the introduction of the trifluoromethyl group.C F 3 CHN 2 can be prepared from the corresponding amine 18 and aqueous sodiumn itrite (NaNO 2 )( Scheme 5). [35] In the same manner as diazomethane,C F 3 CHN 2 was observed to pass through the membrane. Ay ield of CF 3 CHN 2 with respectt ot he amineo f % 33 %c ould be achieved within the tube-in-tube reactor,c orresponding to 2.5 equiv of the diazo precursor and 5equiv of NaNO 2 .T he continuous generation of CF 3 CHN 2 was coupled with ac artridge reactor filled with polymer-supported DBU to perform ab ase-catalyzeda ldol reactiono fa ldehyde 20 with CF 3 CHN 2 to afford compound 21.T he flow protocol was successfully appliedt oc onvert an umber of aldehydes to their corresponding trifluoromethyl-functionalized diazo derivatives (nine examples).

Hydrogenc yanide (HCN)
Hydrogen cyanide(HCN) is important for anumber of chemical transformations, including the Strecker reaction for aminoa cid synthesis, chain elongation of sugars,a nd hydrocyanation. The main approach used for the preparation of anhydrous HCN is its distillationf rom aqueous solutionso fs odium cyanide (NaCN)o rp otassium cyanide( KCN) and mineral acid. The use of neat HCN for organic synthesis is limited due to its high toxicity,l ow boiling point (26 8C) and the possibility of spontaneous exothermic polymerization.
Our group reported the applicationo fatube-in-tube reactor for the in situ generation, separation and reaction of anhydrous HCN. [36] The system was optimized for the hydrocyanation of diphenylmethaneimine 22 a (Scheme 6). Aqueous solutions of sodium cyanide (NaCN)a nd H 2 SO 4 were pumped to generate HCN. A2bar back pressure was applied to prevent out-gassing of HCN. Full conversion of substrates 22 a-22 d were achieved at 110 8Cw ithin 15 minr esidence time. For slow reactions (reactiont imes > 1h), a" HCN on tap" configuration was devised whereby the generateda nd separated anhydrous HCN from the tube-in-tube reactor was added in as emi-batch manner to ar ound-bottom flask containing chemistry for the organic transformation.T his strategy was important for performing asymmetricr eactions, which involve low temperatures (< 0 8C), such as an asymmetric Steckerr eactionf or the preparation of a-aminonitriles. It also enabled organic transformations involvings olids to be conducted. This "gas on tap" strategy could also be applied to the other gases discussed in this Concept. However,f low rates should be carefully controlled to minimize the accumulation of hazardous gas.

Ammonia (NH 3 )
Ammonia (NH 3 )a th igh concentrationsi nb oth its gas and liquid forms is toxic, corrosivea nd potentially explosive. In contrast, aqueous NH 3 is as afe-to-handle and relatively inexpensive source of NH 3 .T he main limitation of aqueous NH 3 is that the presence of water which can be detrimental to the performance of many reactions.
Zhang, Wu and co-workers recently reportedt he use of at ube-in-tube reactor for the generationo f anhydrous NH 3 from an aqueous stream of NH 3 (25 %). [37] The inner tube containeda queous NH 3 , whereas the outer tube was the locationo ft he organic reaction. Karl-Fischer titration analysisd etermined that the permeation by water was negligible when operating the tube-in-tube system at temperatures below 50 8Ca nd shorter residence times.H owever,i ts hould be noted that at highero perating temperatures the permeation of water was observed. The system wasoptimized for the nucleophilic substitution on 2-chloro-8-nitroquinoline 23 by NH 3 .A ni nteresting advantage of the protocol is that the system can be operated at 20 bar pressure, which is ah igherp ressure than accessible by directly using an NH 3 gas cylinder (typically restricted to approximately 8bar). The system was successfully appliedt ot he amination of (hetero)aryl fluorides and chlorides to their corresponding primary (hetero)aryl amines (52-97 %y ields, 18 examples) over a 10 hp roduction time, including complex intermediates 25-27 (Scheme 7).

Formaldehyde (CH 2 O)
Formaldehyde is used in reactions such as the Cannizzaro reaction, hydroxymethylationa nd chloromethylation. [38] It is an adduct form of CO andH 2 so it can be used as as urrogate to syngas. However,f ormaldehyde undergoesp olymerization below 75 8C, thus its availability in pure form is highly limited. Formaldehyde is predominantly used in its hydrate form as an aqueous solution known as formalin. This solution is corrosive and is not too stable for storage at high or low temperature.
Thus, solidp araformaldehyde (HCHO) x as the polymer form is more commonly used for its ease to transport, handle, storage and use. An interesting example for in situ generation of formaldehydew as performed by Koch, Kunz and co-workers. [39] In this example they heateds olid paraformaldehyde (HCHO) x within ap ressure-resistant vessel to form gaseous formaldehyde. Paraformaldehyde is depolymerized by heating (80-100 8C). The application of av ery low back pressure prevented any out-gassing. Formaldehyde was used as ar eagent in the acid-catalyzed reactiono fF moc-alanine 28 to form oxazolidinone 29.T he tube-in-tube reactor was followed by ah eater coil to enable the reactiont og ot oc ompletiont oa fford compound 29 in 91 %y ield within less than 1h residence time (Scheme8).

Challenges and Outlook
The approach for the on-demand formation of gases from commercially availabler eagents has been demonstrated for a number of gases. We believe that this Concept can be easily expandedt oo ther gases for organic transformations. For instance,g as-liquid membrane reactors could also be used for the on-demand generation of anhydrous gases,s uch as:C O 2 , SO 2 ,C l 2 , [40] HCl and phosgene (COCl 2 ). There is an ever increasing need for the on-siteo n-demand production of chemicals, in particularg iven problemsi nsecuring supply chains for important chemicals and pharmaceuticals.
The aforementioned membrane strategies for on-demand gas generationa re appropriate options for research-scale experimentation;h owever,a ll the approaches currently suffer from limited scalability.A ll of the protocols discussed are limited by the maximum achievable throughput and by poorer performance at larger scales. Jensen and co-worker developed a quantitative model to analyze the mass transfer within at ubein-tube reactor. [41] In this study,t hey demonstrated that there are many challenges for upscaling the tube-in-tuber eactor. One possible approachfor scale-upi st hrough an umbering-up or parallelizations trategy.H owever,i nm any instances as caleup strategy restricted only to numbering-up is considered inefficient because it requires an accurate fluidd istribution which often cannota chieved. The CSTR cascade described for diazomethane is as tep toward achieving improved scale-up, but the demonstrated scale still lacked sufficientt hroughput to achieve production scale quantities. Thus, an ongoing goal of this research area should be the development of continuousflow membrane systems for the on-demand generationo fa gas at any production scale.
The membranes at larger scales become simply too cost prohibitive. Teflon (AF-2400) has the disadvantaget hat it is impractical at manufacturing scales due to its high cost ($25 000 kg À1 ). [42] Ar elativelyi nexpensive ($2-10 kg À1 )f luoropolymer poly(tetrafluoroethylene) (PTFE) membrane has recently been reported, [42] but its characteristics are not as well understood. Another limitation of Te flon AF-2400 is that it is very fragile. [43] In the case of the tube-in-tube reactort he fragile inner membrane tubing is protected by the outer tube. In case of fouling then the membrane can be washed by using an appropriate method. [32] The most common cause of breakage is when ah igh pressure gradient is applieda cross the membrane. There is ah igherl ikelihood of failure if the pressure in the outer channel is marginally highert han the inner channel. Thus, careful monitoring of the pressure on both sides of the membrane can extendt he membrane lifespan. Furthermore, the use of a2 Df lat membrane configuration is reported to extend the membrane lifespan by minimizing failure during operation. [44] An interesting potentially scalable membrane design was recently reported, whereby ap erfluorinated membrane is coated on ah ollow fiber made of at hermally and chemically resistantm aterial that provides structural integrity. [45] The identification of new,l ow cost membranes,i s critical for movingf orward. In particular,m embranem aterials that show excellent chemical compatibility,d on ot break easily, whilst at the same time allow gas diffusionb ut are water impermeable. We are currently performing membrane screening experiments within our laboratory to identify potentialm embrane systems.
Evidently,t he handlingo fh azardousg ases needs to be carefully monitored and controlled. The in-line reaction monitoring of gasg eneration and reaction should also be implemented more frequently.I nt erms of process safety,i ti si mportantt o minimize any accumulation of hazardous gas within the system.T he inclusion of process analytical technologies (PAT) will be of increasingi mportance for the monitoringa nd control of gas formation and consumption to ensure safety. [46] Conclusions We have outlined an approachfor the safe on-demandgeneration, separation and reactiono fanumber of gases from commerciallya vailabler eagents. Micro-and tubularr eactorsf acilitate the generation of small quantities of ag as at any one time. The approachd escribed avoidst he main problem associ-Scheme8.Gaseousf ormaldehyde is formed in situ from paraformaldehyde and then used for the acid-catalyzedpreparation of oxazolidinone 29 from F-moc-l-alanine 28.Fmoc = fluorenylmethoxycarbonyl, pTsOH = para-toluenesulfonic acid. ated with in situ gas formation foro rganic synthesis, whereby the chemistry necessary for the gas releasen eeds to be compatible with the chemistry of the organic transformation. The use of membrane technologiese nables the separation of the gas from the reaction conditions and chemicals used for its formation. The organic transformation can then occur within a second chamber.T he gas is subsequently consumed rapidly thus preventing the accumulationo fagas. This strategy completely avoids the storage and transportationo fh azardous gases. It also drastically improves the safety and circumvents the need for distillation in cases where the gas is generally synthesized in situ, such as diazomethane and HCN. We are convinced that the concept described herein will be embraced by the community thus increasing the use of "difficult-to-handle" gases fororganic synthesis into the future.