pubs.acs.

org/acschas Article

A Safety Guidance Document for Lithium Aluminum Hydride (LAH)

Reduction: A Resource for Developing Specific SOPs on LAH
Manipulations†
Tilak Chandra* and Jeffrey P. Zebrowski

Cite This: ACS Chem. Health Saf. 2024, 31, 162−171 Read Online
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

ACCESS Metrics & More Article Recommendations

ABSTRACT: Strong reducing agents like lithium aluminum

hydride (LiAlH4, LAH) are frequently employed by industry and
Downloaded via 177.64.157.143 on April 25, 2024 at 23:11:53 (UTC).

academic laboratories in syntheses and other research applications.

Due to LAH’s reactivity, several laboratory explosions and fires
have been documented in the literature and on various EH&S
webpages at universities. Some of the accidents were caused by
incorrect handling of LAH or by improper chemical processes, such
as weighing on regular paper, grinding, and creating friction, using
contaminated solvents and glassware, and physically scraping the
material during transfers. In many of these cases, researchers did
not have access to a guidance document or an SOP for many of
these incidents, and no thorough risk assessment was carried out.
Academic laboratories can avoid similar accidents and associated property damage by developing a safety guidance document that
identifies every facet of LAH manipulation in the experiment, including reaction setup, procedures for weighing and transferring
material to the reaction vessel, heating, and cooling during the reaction, quenching the reaction, and waste disposal. This LAH
guidance document can be used to produce a manipulation-specific SOP that covers best practices and precautions for a variety of
substrates and reaction scales.
KEYWORDS: fire, guidance document, hazards, housekeeping, lithium aluminum hydride (LiAlH4, LAH), reduction,
standard operating procedures, syringes, THF, toxic, training

1. INTRODUCTION
Lithium aluminum hydride (LAH)1 is routinely used in organic
synthesis2−11 to reduce a variety of functional groups such as
acids, epoxides, esters, ketones, lactones, and nitriles (Figure 1).
This reagent has broad reactivity, and generally, reductions are
easily carried out at ambient or elevated (reflux) temperatures,
depending on the nature of the substrates. Ethereal solvents,
such as anhydrous diethyl ether or tetrahydrofuran (THF),
which are themselves flammable are used as solvents12,13 for
LAH manipulations. Since LAH reductions are typically
exothermic requiring effective cooling of the reaction mixture
to prevent substrate degradation and unintended outcomes like
runaway reactions.14 Water and protic solvents should not be
used because LAH reacts with them.
LAH is so reactive that several fires have occurred not because
of flawed storage, but rather because of its handling during the
manipulation.15−17 For example, Merlic and co-workers
reported a fire started during grinding of LAH.18 In this report,
the cause and prevention of LAH grinding and manipulations
are precisely described. During another LAH manipulation, an
incorrect ratio of LAH and solvent resulted in excess H2 gas
production in a reaction vessel, causing overpressurization. As a
result, the reaction mixture spilled inside the chemical fume
hood and triggered a fire. Another LAH manipulation fire
occurred when a student was trying to transfer LAH from a
container using a metal spatula and normal paper.19
Environment, health, and safety divisions of universities
typically have several SOPs, or policy documents, published on
their Web sites.20−23 However, these publications are directed at
safety professionals and are less helpful for bench chemists.
Furthermore, for LAH reductions, technical and reaction-
specific information is typically left out of most SOPs, or safety
documents. Several research articles on LAH-mediated
reductions lack experimental information, despite the abun-
dance of literature on the subject.9,24−27 Thus, the goal of this
guideline for LAH reduction is to provide researchers with
Received: November 5, 2023
Revised: January 9, 2024
Accepted: January 17, 2024
Published: February 9, 2024

© 2024 American Chemical Society https://doi.org/10.1021/acs.chas.3c00102

162 ACS Chem. Health Saf. 2024, 31, 162−171
ACS Chemical Health & Safety
Figure 1. Reduction of different substrates using LAH.
guidance when developing an SOP for LAH reduction tailored
for a range of substrates and scales. When using this guidance
document for creating a structured standard operating
procedure (Figure 2) for LAH reduction, it is important to
include an overview of the technique, instructions for
assembling the reaction setup, the general procedure (heating
and cooling), identification of physical and chemical hazards,
steps for reducing or eliminating risks, emergency response
protocols for “what-if” scenarios, and waste management
protocols.
SOPs and guidance documents to handle hazardous
compounds are widely available online.28−33 Nevertheless,
since comprehensive instructions for handling LAH in the
reactions that need to be performed are not available, we are
here to provide a reasonable general guideline document for
LAH.
1.1. Hazard Identification. LAH is an air- and moisture-
sensitive solid. In contact with water, it releases hydrogen gas
that may ignite spontaneously.1,34,35 It is corrosive to the skin,
eyes, and mucous membranes (Figure 3). LAH dust can cause
injury if it encounters the skin, eyes, or mucous membranes
because it reacts with water to form hydroxides. Furthermore, a
significant quantity of LAH is likely to burn severely upon
contact with skin.
Figure 2. A structured standard operating procedure (SOP) for LAH reduction.
163
pubs.acs.org/acschas Article
LiAlH4 + 4H 2O 4H 2 + LiOH + Al(OH)3
Perform a literature search on the reagent and substrate
reactivity to complete a risk assessment on the LAH
manipulations (Figure 3 and Table 1). For LAH use, there are
several subpar or flawed literature procedures. As a result, it is
advised that you thoroughly read the published material and this
guidance document. Regardless of the results of their literature
search, a researcher working with LAH, especially for the first
time, should get feedback and assistance from the principal
investigator and senior lab members (or even talk with someone
from a different lab with experience!). Researchers may be
exposed to inherent dangers because structural changes to the
substrate and reaction conditions can greatly affect LAH
reactivity. As a result, an assessment of the substrate and
reaction conditions is essential. It has been determined that
compounds containing aluminum and perfluorophenol sub-
stituents have the potential to explode.36−45
1.2. Hazard Control. 1.2.1. Substitutions. Academic
laboratories use LAH far too often; in industry, this is not
usual. When reducing aldehyde or ketone, less reactive hydride
reagents such as sodium borohydride (NaBH4) work just as well
and do not require the use of LAH.
1.2.2. Engineering Controls. A fume hood equipped with a
vertical sash or a combination sash will serve as an effective
engineering control. The chemical fume hood should be free of
unwanted items and chemicals, especially flammable solvents.
Glove boxes are also an option for manipulating LAH and for
small scale and ambient temperature substrate reduction
purposes (Figure 4).
1.2.3. Administrative Controls. A novice should not attempt
the LAH manipulations on their own, since LAH is quite
reactive and has caused numerous fires. When a researcher uses
LAH for the first time, a more experienced lab member should
supervise and provide guidance. Follow the guideline document,
SOP, and literature exactly; do not deviate from this without first
consulting the PI. If scales exceed the guidelines’ limitations, an
updated risk assessment might be necessary.
1.2.4. PPE. Long pants, closed-toe shoes, nitrile gloves, safety
glasses, and a flame-retardant lab coat were worn for protection
during LAH manipulations.
https://doi.org/10.1021/acs.chas.3c00102
ACS Chem. Health Saf. 2024, 31, 162−171
ACS Chemical Health & Safety pubs.acs.org/acschas Article

Figure 3. THF & LAH: GHS pictograms with hazard statements.

Table 1. Hazard Assessment for LAH-Mediated Reduction (What-if Strategy)46

department: chemistry/biochemistry description of operation: use of LAH for organic syntheses review team date 11/01/2023
a
what if? answer probability consequences recommendationsb
using a rxn flask that is too small for the LAH discharge of the mixture from high fire and chemical expo- use a slightly larger flask, even for a small-scale
reduction the flask sures reaction, to contain the contents for excess heat
formationc
the rxn vessel is not moisture free creation of an explosive atmos- high fire or explosion to prevent any undesirable outcomes, make sure there
phere because of H2 formation is no moisture present in the reaction setup
the rxn mixture cannot be effectively stirred inadequate heat transfer and medium low yield to stir the rxn mixture, use a suitable oval-shaped
with the current magnetic bar insufficient rxn mass stirring magnetic bar
rxn assembly is not vented properly pressure build-up high fire and explosion properly vent the rxn mixture using a calcium chloride
guard tube or a Schlenk line port.
the substrate is added quickly to the mixture an exothermic reaction or un- high fire and explosion the substrate must be added dropwise to rxn mixture to
of LAH and THF without proper cooling controlled rxn control the rxn exothermicity
uncontrolled nitrogen flow is used during solid LAH will blow in air from high LAH spills and fires ensure that the N2 pressure is appropriately managed
LAH addition uncontrolled N2 gas using a Schlenk port or regulator
the temperature controller malfunctions or potential uncontrollable reac- high chemical exposures and consider using a redundant temperature controller
is configured incorrectly. tion; potential loss of contain- fires
ment
the condenser’s water flow either stops or inability to condense ether or high substrate and product student monitors reaction regularly
diminishes. THF-based solvents loss
N2 supply is depleted while adding LAH potential for air to enter the flask high potential for a flamma- throughout the reaction, closely monitor the N2 flow
ble environment
reflux condenser water is not cold enough failure to condenser volatiles high decomposition of the make sure the water circulated to the condenser is cold
for high temperature rxn such as ether or THF substrate and solvent
loss
LAH pellets are grinded using a ceramic friction from grinding the LAH high fire or explosion the use of LAH pallets should be avoided in favor of
pestle pellets may cause an ignition LAH powder.
a
An experienced laboratory member (a senior student or postdoctoral associate) can guide a novice through each phase of the what-if analysis for
the hazard assessment procedure. A thorough LAH manipulation reaction setup diagram and any prepared step-by-step operating instructions may
be used by the lab member. bThe following topics should be considered when posing questions regarding LAH manipulations: possible human
mistakes; equipment component failures; and deviations from the expected or scheduled critical parameters (such as temperature, pressure, time,
and flow rate). Human error occurs regardless of experience level or education. Human error factors may impact decisions about written SOPs,
engineering controls, etc. cIf the solvent volume is 200 mL, use a 500 mL three-neck round-bottom flask.

Figure 4. Use of an inert atmosphere and glovebox (right) for LAH manipulations.

164 https://doi.org/10.1021/acs.chas.3c00102
ACS Chem. Health Saf. 2024, 31, 162−171
ACS Chemical Health & Safety
Figure 5. A small-scale LAH reduction reaction setup inside a chemical fume hood, a solid addition funnel, an adapter (Merlic), and a LAH vial.
2. SUITABLE REACTION SETUP FOR LAH REDUCTION
Assemble glassware (Figure 5) inside a properly functioning
chemical fume hood or glovebox (for small-scale and ambient
temperature reactions).
2.1. For a Small-Scale Reaction (up to 5.0 g of LAH).
You can use a small round-bottom flask (RBF) with three or two
necks. Make sure the flask is clamped correctly to prevent the
reaction mixture from being spilled (Figure 5). Choose a flask
size so that, following a full reaction and the addition of all
quenching agents, it is no more than two-thirds full.
The flask should be equipped with an oval-shaped magnetic
bar, a stir plate, and an inert gas inlet, and the remaining necks of
the flask should be equipped with a condenser and an additional
funnel for the addition of substrate and quenching reagent. A
Schlenk line29 nitrogen port or a nitrogen source from a cylinder
can be used to generate an inert atmosphere. A cooling bath is
typically utilized under the reaction flask during the LAH
addition, and it is best practice to support it with a laboratory
jack so that it can easily be removed without attempting to move
the reaction flask assembly.
2.2. For a Large-Scale Reaction (>5.0 g). Reaction
glassware should consist of a 3-neck RBF equipped with a
nitrogen gas line and a reflux condenser (Figure 6). A
Figure 6. A dropping funnel for substrate addition and a mechanical
stirrer for a large-scale reaction.
165
pubs.acs.org/acschas Article
mechanical stirrer is recommended for large-scale reactions to
stir the mixture efficiently. A cooling bath is typically necessary,
and due to the limitations of heat transfer, a slow addition of
LAH is usually required. The risks posed by a large-scale LAH
reaction will not be the same as those of a small-scale reaction.
2.3. Best Practice (Glassware Cleaning and Drying).
The glassware that is utilized in the reaction must be clean and
without impurities. Use only glassware that is free of chips,
cracks, and nicks. Moisture must be removed from THF and
substrates. A large-scale assembly consisting of a large
condenser, a 1 L flask, and a dropping funnel cannot be dried
in a desiccator. These large-scale reaction assemblies are best
dried with a heat gun, a vacuum, and nitrogen. This method
works better at removing surface moisture. Stopcocks and glass
joints should not be heated over a flame. Small flasks and small
condensers, on the other hand, are typically easy to dry in an
oven and can be bought at room temperature under a calcium
chloride desiccator.47
NOTE: Stress may arise if a particular area of glass is exposed
to direct or concentrated heat from a heat source, such as a
Bunsen burner. Bunsen burner use might cause stuck joints, as
well. As a result, for LAH manipulation on large-scale glass
assemblies, the use of a heat gun is recommended.
After assembling the setup in a chemical fume hood, connect
the reaction assembly to a vacuum source and nitrogen (Figure
7). Nitrogen and a vacuum are appropriate for this drying, where
nitrogen is used as an inert gas for flushing out the residual
moisture. Carefully heat the assembly using a heat gun and
continuously evacuate it, then purge the assembly with nitrogen.
Repeat this step 3−4 times to remove all the moisture. The
Tygon tubes used for chilled water fitted to the condenser and
Keck Clips for connections should not be heated during this
process. Keck clips lose their holding capacity if they are heated
at high temperatures or used incorrectly.
2.4. Weighing LAH. Weigh out LAH just before using it in
the reaction. LAH powder can be measured into scintillation
vials, solid addition tubes (Merlic), or glass containers with a lid
(Figure 5) inside a glovebox or outside, carefully, and safely
transferred inside a chemical fume hood under an inert
atmosphere for further manipulation. In practice, especially on
a small scale, most people just weigh LAH out in the open. You
can keep a small container of LAH in the glovebox for handling
and weighing if laboratories handle the chemical frequently. Be
aware that there have been numerous reports of fires starting
when a metallic spatula is used for LAH transfer. Therefore, the
https://doi.org/10.1021/acs.chas.3c00102
ACS Chem. Health Saf. 2024, 31, 162−171
ACS Chemical Health & Safety
Figure 7. A large reaction setup for drying and a complete reaction
setup for the large-scale LAH reduction.
use of a plastic or a ceramic spatula for LAH transfer is
recommended.48 Any minor spills inside the glovebox should be
cleaned immediately to avoid contamination. Laboratories
without access to a glovebox can also transfer LAH under a
nitrogen atmosphere outside or inside a glove bag with care.
Finally, be prepared in advance by having proper training on
laboratory emergency procedures, such as how to use sand to
cover the material or using a class D fire extinguisher if the LAH
catches fire.
3. GENERAL USE/PROCEDURE
Generally, two methods are employed to transfer LAH for
reduction: (i) normal addition and (ii) inverse addition. During
a normal addition, a solution of the substrate is added to a
mixture of LAH in THF or diethyl ether under an inert
atmosphere.49 For the second method, the LAH solution is
added to the substrate in a desired solvent. The inverse addition
is used when the substrate is selectively reduced to the desired
product and to control the reaction exotherm. As an example,
cinnamaldehyde is reduced to hydrocinnamyl alcohol when
reduced with an excess of LAH (>2.0 equiv) by the normal
addition method. In this method, a solution of cinnamaldehyde
is added to the solution of LAH. With excess LAH, both the
double bond and the carbonyl group are reduced. However,
cinnamaldehyde is reduced to cinnamyl alcohol with 1.0 equiv of
LAH in the inverse addition method (Figure 8).9,50,51NOTES:
• Ensure that the reaction flask is moisture free and is under
an inert gas blanket.
• Use of a laboratory jack is recommended (prudent
practice) to replace a cooling bath with an oil bath when
the reaction is carried at an elevated temperature (Figure
9).
Figure 8. Normal and reverse addition of LAH to prepare hydrocinnamyl alcohol and cinnamyl alcohol.
166
pubs.acs.org/acschas Article
• To prevent moisture from surrounding the reaction setup,
it is advised to use an oil bath or sand bath for heating
instead of a water bath. Oil baths generally provide
homogeneous and controlled heating for LAH manipu-
lations.
• To prevent the formation of a crust above the liquid or
sediment at the bottom of a heated flask, gentle and
efficient stirring is essential.
• Add enough anhydrous solvent52 to the flask so that the
LAH is easily stirred to cool the mixture.
Most researchers usually run reactions at 0.1 to 1 M in the key
substrate. The issue with LAH reductions is that if they are too
concentrated, a gel will form during the reaction or upon
quenching. Therefore, the more diluted reaction mixture is
better.
• The low ratio of LAH to substrate (1.0 to 2.0) is
recommended to avoid workup difficulty and runaway
reactions. This is determined based on the nature of the
substrate.
During the reduction, only around two of LAH’s four hydrides
are typically used; quenching the other three poses a serious risk
if only one is utilized (nearly like LAH). However, the last
hydride, which is more parallel to sodium borohydride, is not as
reactive in quenching when three are employed. Therefore,
three hydrides will remain in a 1:1 molar ratio of substrate to
LAH if one is reducing an aldehyde, epoxide, or ketone (to the
alcohol). As a result, it is safer to use a 2:1 molar ratio of the
substrate to LAH rather than a 1:1 molar ratio. In contrast, if one
is reducing an anhydride or diester (to the diol), a 1:1 molar
ratio of substrate to LAH would result in no remaining hydrides
and most likely an incomplete reaction.
NOTE: For direct addition, LAH was added to the solvent in
the nitrogen-purged reaction setup before the other reactant.
Here, there are two safety issues. First, alcohol or water traces in
ether, or THF solvent, or even condensed water may react
strongly with LAH. One can start a fire by pouring such a solvent
onto a significant quantity (∼5 + g). Therefore, the solvent will
become dry when a small amount of LAH is introduced into an
ethereal solvent. When the ethereal solvent and LAH are
combined, there is a heat of solvation. Therefore, once more, if
one begins to pour such a solvent onto a quantity of LAH, then it
may catch fire and have disastrous effects. Therefore, once the
first portion has dried the solvent, LAH is still added, little by
little, to the solvent in the reaction flask.
• Take off the stopper or cap and use a solid addition funnel
or solid addition tube to add LAH portion-wise while
stirring. The reaction setup must be kept in an inert
atmosphere while adding LAH. Replace the stopper when
done. For dropwise (inverse) addition to the reaction
mixture, a solution of LAH in THF can also be utilized;
these solutions are sold by several suppliers. The solid
addition tube developed by the Merlic group53−55 can be
loaded with LAH in a glovebox and then attached to the
https://doi.org/10.1021/acs.chas.3c00102
ACS Chem. Health Saf. 2024, 31, 162−171
ACS Chemical Health & Safety
Figure 9. Use of a lab jack for easy replacement of a cooling bath with a heating bath and heat control.
reaction flask to avoid transferring LAH via a simple
funnel.
• Transferring LAH slurry via a syringe or cannula may clog
the syringe or cannula. An SOP should be developed for
syringe or cannula transfers to address clogs.56 The use of
a larger-diameter cannula will help to prevent buildups
and clogs from small particles of LAH. In the event of a
clog, chilled ethyl acetate would probably be best for
quenching.
• LAH has some solubility in ether solvents but tends to
form a slurry when a relatively large quantity of the
reagent is used.57 The LAH solutions in THF are also
available through various vendors and can be directly used
during the inverse addition to the reaction mixture.
• Add the substrate to the reaction vessel carefully at the
desired temperature in small portions to control the
reaction exotherm and to prevent substrate decomposi-
tion due to high heat. Just as LAH was added slowly (in
portions) to the solvent, the substrate must be added
slowly to the solvent/LAH solution. This is best done by
dissolving the substrate in the inert solvent and using an
addition funnel to slowly add the solution. The size of the
cooling bath and time for substrate addition depend on
the substrate’s reactivity and heat transfer capacity.
• Remove the reaction aliquot carefully and quench using
water or ethyl acetate to monitor the reaction progress.58
This is often problematic as the alkoxy-aluminum species
are not always hydrolyzed on silica gel. So, withdraw a
drop of the reaction mixture using a needle, add a few
drops of water in a small test tube, add a few drops of
ether, mix, and TLC the ether layer. The use of GC and
HPLC is recommended when the TLC method is not
appropriate.
• Once all the substrates have been reduced, the reaction
mixture should be cooled to 0 °C. Excess hydrides are
quenched by adding ethyl acetate. The reaction is
quenched (hydrolysis of alkoxy-aluminum species) by
water in the Fieser procedure.
• Make sure your product is stable under these conditions
and does not generate any additional product from ethyl
acetate. After the quenching is over, the product should be
167
pubs.acs.org/acschas Article
isolated by filtration or extraction using appropriate
solvents.
• To avoid any difficulty during an LAH workup (emulsion
formation, etc.), a Fieser workup is recommended.59
3.1. Fieser Workup for LAH Reduction. Once the reaction
mixture has been diluted with ether or THF, it should be allowed
to cool to 0 °C. It is best to add a small amount of water at a time.
Add the required 15% sodium hydroxide to this mixture in the
second step. After thoroughly mixing the ingredients, let them sit
for 15 min at room temperature. The needed anhydrous
magnesium sulfate should be added to this mixture in the third
stage. Stir the mixture for 15 min, then filter the mixture to
remove any salt.
3.2. Example LAH Reduction. 3.2.1. (4S,5S)-2,2-dimeth-
yl-1,3-dioxolane-4,5-diyl)dimethanol.49 A flame-dried flask
equipped with a reflux condenser containing LAH (4.058 g,
106.9 mmol) and a stir bar was flushed with nitrogen, and then
anhydrous THF (38.0 mL) was added (note: a safer method
would be to add LAH to a stirring solution of THF). The flask
was cooled to 0 °C, and then a solution of dimethyl (4R,5R)-2,2-
dimethyl-1,3-dioxolane-4,5-dicarboxylate (7.778 g, 35.6 mmol)
in THF (19.0 mL) was added dropwise. The mixture was stirred
at rt for 30 min and then at reflux temperature for 3 h. The
mixture was cooled to 0 °C and diluted with diethyl ether, and
water (4.1 mL) was added dropwise, followed by 15% aqueous
NaOH (4.1 mL), then another portion of water (12.2 mL). The
solution was warmed to room temperature, stirred for 15 min,
and then MgSO4 was added until the reaction mixture became
white. The mixture was further stirred for an additional 15 min
and then filtered through Celite. The solvent was removed in
vacuo. Column chromatography with 100% ethyl acetate gave
4.461 g (77% yield) of the known clear colorless oil.
Most accidental fires and runaway reactions occur during
quenching reactions, where excess LAH is used or the
consumption is not complete. Therefore, extreme precautions
must be used when quenching an LAH reaction. The quenching
of an unreacted LAH using water should be done with caution
during the reaction workup because it will release hydrogen gas,
which will generally result in foaming. The size of the reaction
flask should be enough to hold the solvent and quenching
material to avoid spills. The alumina salts generated during the
hydrolysis can form a paste that is challenging to separate from
https://doi.org/10.1021/acs.chas.3c00102
ACS Chem. Health Saf. 2024, 31, 162−171
ACS Chemical Health & Safety
the product and becomes difficult to stir when too much water is
added. The addition of anhydrous magnesium sulfate to the
mixture may dehydrate the hydrated alumina to provide a free-
flowing powder (Fieser Workup). Applying a thick layer of a
Celite pad to the fritted funnel to filter the rxn mixture will avoid
clogging the funnel from aluminum salts and other side
products.
4. SAFETY CONSIDERATIONS
4.1. Emergency Preparedness for Working with the
LAH Manipulations. Safety awareness and preparedness60−64
are critical components of any safety management system and
should be reviewed61,65−67 before working in the lab (Table 2).
Table 2. Laboratory Emergency Checklist Before Working
with LAH Manipulations46,68,69
items
all safety information on LAH and the substrate from a literature
search and their SDSs have been collected, reviewed, and
understood
chemical reactivity, incompatibility, and process safety issues have
been examined
all appropriate PPE is available and properly used
a flame-resistant lab coat is available
leather, closed-toe shoes are worn
an appropriately sized bottle tote safety carrier is available
a class B and D fire extinguisher and a dry sand bucket are available
eyewash and safety showers are available.
A spill involving LAH will require quick attention, because it
may ignite. When a small quantity of LAH is spilled, the material
should be covered immediately with dry sand or calcium oxide
to prevent any ignition.
Using noncompatible materials should be avoided for spills
involving LAH to prevent additional complications (Figure 10).
Figure 10. Class D fire extinguisher and sand/lime for handling LAH
and reaction mixture spill.
For the safe handling of small as well as large spills, lab-specific
training, and preplanning are critical for reducing the chemical
and physical hazards. Students and researchers should be trained
in the use of eyewashes, safety showers, fire extinguishers, and
correct adsorbent materials. Any large spills outside a chemical
fume hood that can cause a fire and other environmental impacts
should be handled by trained safety professionals. An updated
lab-specific chemical hygiene plan (LSCHP) must be available
in laboratories, including established safety policies and
procedures for handling hazardous chemicals and limiting the
storage of such chemicals inside a chemical fume hood (good
housekeeping)70,71 to minimize risk.
pubs.acs.org/acschas Article
4.2. Exposures. The exposure of skin, eyes, and mucous
membranes to LAH dust is corrosive because LAH will react
with water to form hydroxides. And any significant quantity of
LAH landing on the skin is likely to ignite and result in
significant burns.
4.2.1. Real Incident. A blob of burning LAH powder hit a
student’s neck burning the skin, then landed on the shoulder,
and burned through the FR lab coat. Burning LAH is hot! (a
reference to this information is not available)
4.3. Spills and Decontaminations. 4.3.1. Small Spills
(Less Than 0.5 g LAH). Researchers should clean up any small
spills inside a chemical fume hood if they are properly trained
and fully aware of the properties of LAH. Cover the spill with dry
sand or other noncombustible material, and whenever possible,
prevent the entry of LAH into laboratory sinks. If there is no
potential for fire or exposure, then proceed with cleaning and
decontamination. Dry powders or a class D fire extinguisher
yes no should be used for any LAH fire. Avoid using a CO2 extinguisher
x because LAH reacts with carbon dioxide72 and will spread the
fire.
x
4.3.2. Large Spills. Procedures and practices should be
implemented to prevent any large spills from occurring outside
x of containment. Prior to performing any work, however, the
x local EH&S team should be consulted on the appropriate
x procedures should a large spill occur.
x 4.4. Decontamination of Glassware and Other Items.
x Destroy residual LAH using ethyl acetate and finally with water
x before taking the glassware out of the chemical fume hood
(prudent practice). When performing manipulations inside a
glovebox, it is necessary to clean the working surfaces, the
weighing balance, and other items. This LAH decontamination
procedure applies only to small-scale LAH manipulations, and
decontamination for large-scale manipulations may differ.
5. STORAGE OF LAH
During storage, containers should be kept tightly closed in a dry
and well-ventilated place. Regularly monitor the cabinets and
containers for any deterioration. Store separately from strong
acids, alcohols, powdered metals, and water. The container’s
hazard communication label must state ″Water Reactive.″
During storage, LAH should never come into contact with water
or water-containing compounds.
6. WASTE/UNWANTED MATERIAL DISPOSAL
The large unused quantity in a reagent bottle should be disposed
of through the Environment, Health, and Safety Department.
Researchers should not quench larger quantities of unused LAH
or other pyrophoric reagents to help their EH&S. Such
quenching would violate waste laws.
LAH hydrolysis, or quenching, is generally carried out by
slowly adding ethyl acetate to a solution of LAH in an inert
ethereal solvent, followed by adding an ammonium chloride
solution to the mixture. Never pour unreacted LAH into the
solvent waste container. Large quantities of LAH should not be
quenched in the laboratory for disposal purposes due to the
potential hazards. Collect LAH was collected in a separate
container with an appropriate label for proper disposal.
7. CONCLUSIONS
Safe manipulation of lithium aluminum hydride (LAH) involves
proper experimental design, risk assessment, and emergency
preparedness. Risks are reduced or eliminated by being aware of
168 https://doi.org/10.1021/acs.chas.3c00102
ACS Chem. Health Saf. 2024, 31, 162−171
ACS Chemical Health & Safety
them before the beginning of manipulation. A risk assessment
should be completed to identify all risks associated with the
procedure and to determine how to control, reduce, or, if
possible, eliminate the risks. Based on the risk assessment,
appropriate methods and techniques for handling LAH should
be developed into a reaction-specific SOP using this guidance
document and additional resources available in the literature. If
you are not aware of the potential process risks, review the
possibilities with your PI, your chemical hygiene officer (CHO),
the university environment and health resources, or other lab
colleagues who may be familiar with similar chemistry or
processes. A superficial search for hazards posed by chemicals is
not sufficient.
While working with LAH, maintaining good laboratory
housekeeping is also key to preventing unwanted events, such
as chemical spills, exposure, and fire. The chemical fume hood
and glovebox should be kept clutter-free for good access and to
prevent unwanted events. Prudent laboratory practices should
be employed during the reaction, storage, and disposal of LAH
and LAH mixtures. You need to consider how the chemicals are
used and look for potential interactions among different
materials. Finally, use the information from your research
about the safety of the reactions to develop an SOP that
documents the precautions that must be taken. Make sure that
everyone working within the lab has been given a complete
orientation of the laboratory so that they are familiar with the
location of all emergency equipment (i.e., eyewash stations,
safety showers, and fire extinguishers) and laboratory policies.
■ AUTHOR INFORMATION
Corresponding Author
Tilak Chandra − Department of Environment, Health & Safety,
University of Wisconsin−Madison, Madison, Wisconsin
53715, United States; orcid.org/0000-0002-6118-796X;
Email: tilak.chandra@wisc.edu
Author
Jeffrey P. Zebrowski − Department of Environment, Health &
Safety, University of Wisconsin−Madison, Madison,
Wisconsin 53715, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.chas.3c00102
Author Contributions
CRediT: Jeffrey P Zebrowski formal analysis, methodology,
resources.
Notes
The views expressed in this manuscript are those of the author
and do not necessarily reflect the views of the organizations we
have worked for or are now affiliated with. We illustrated our
points using accessible literature and our experience working
with LAH. This article should not be used as the entire source of
training for any procedure, method, or task; rather, it should
only be used as a guide. Any remarks or references to
commercial goods, trade names, trademarks, producers,
distributors, or anything else are merely for illustration purposes
and do not imply a recommendation of any specific product or
service.
The authors declare no competing financial interest.
169
pubs.acs.org/acschas Article
■ ACKNOWLEDGMENTS
We sincerely thank Prof. Craig Merlic (UCLA Chemistry
Department), Neal Langerman, Rob McClain, Profs. Ive
Hermans, John Berry, Jen Schomaker, Dan Weix, and Bhaskar
C. Das for productive discussions and information for this
manuscript, and Todd A. Yanke, Chris Strang (AVC-EH&S),
and Lisa Lenertz for their support.
■
†
DEDICATION
This article is dedicated to Ralph Stuart III, past chair and
membership chair of the Division of Chemical Health and Safety
(DCHAS), for his outstanding influence on academic health and
safety.
■ REFERENCES
(1) Bretherick’s Handbook of Reactive Chemical Hazards, Eighth
Edition https://www.sciencedirect.com/book/9780081009710/
brethericks-handbook-of-reactive-chemical-hazards (accessed Dec 23,
2023).
(2) Fieser and Fieser’s Reagents for Organic Synthesis, 2006.
DOI: 10.1002/9780471264194.
(3) Encyclopedia of Reagents for Organic Synthesis, 2nd Edition,
2009. https://onlinelibrary.wiley.com/doi/10.1002/047084289X.
rl036.pub2 (accessed Jan 9, 2023).
(4) Augustine, Reduction; techniques and applications in organic
synthesis, Volume 1, 1968, p. 12.
(5) Gaylord, N. G. Reduction with complex metal hydrides. J. Chem.
Educ. 1957, 34 (8), 367−374.
(6) Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567−607.
(7) Gaylord, N. G.; Kay, D. J. Complex metal hydride reactions. I.
Lithium aluminum hydride reduction of heterocyclic nuclei. J. Am.
Chem. Soc. 1956, 78 (10), 2167−2169.
(8) Newman, M. S.; Fukunaga, T. The reduction of amides to amines
via nitriles by lithium aluminum hydride. Am. Chem. Soc. 1960, 82 (3),
693−696.
(9) Mellem, K. T.; Myers, A. G. A Simple, scalable synthetic route to
(+)- and (−)-pseudoephenamine. Org. Lett. 2013, 15 (21), 5594−
5597.
(10) Brown, W. G. Lithium aluminum hydride in organic chemistry. J.
Am. Chem. Soc. 1956, 78 (13), 3232.
(11) Denmark, S. E.; Ryabchuk, P. G. (R)-N,N’-Dimethyl-1,1′-
binaphthyldiamine. Org. Synth. 2019, 96, 382−399.
(12) Diethyl Ether SDS: https://www.sigmaaldrich.com/US/en/
sds/sial/296082 (accessed Dec 23, 2023).
(13) Tetrahydrofuran SDS: https://www.sigmaaldrich.com/US/en/
sds/sial/401757 (accessed Dec 23, 2023).
(14) A campus laboratory fire involving lithium aluminum hydride:
https://ehs.stanford.edu/reference/campus-laboratory-fire-involving-
lithium-aluminum-hydride (accessed Dec 23, 2023).
(15) Safety seminar: Handling hazardous chemicals. https://www.
chem.s.u-tokyo.ac.jp/users/safety/SafetySeminar_2017_En.pdf (ac-
cessed Dec 23, 2023).
(16) LAH Fire: https://www.jst.umn.edu/learning-experience-
reports/past-lers/lah-fire (accessed Dec 23, 2023).
(17) LAH and friction as an ignition source: http://www.ilpi.com/
dchas/2011/20110630a.html (accessed Oct 29, 2023).
(18) Merlic, C. A.; Ferber, C. J.; Schröder, I. Lessons learned − lithium
aluminum hydride fires. ACS Chem. Health Saf. 2022, 29 (4), 362−365.
(19) Lithium aluminum hydride fire: https://ehs.utexas.edu/sites/
ehs.utexas.edu/files/LAH_Fire.pdf (accessed Dec 23, 2023).
(20) LAH: https://ehs.princeton.edu/laboratory-research/chemical-
safety/chemical-specific-protocols/lithium-aluminum-hydride (ac-
cessed Dec 23, 2023).
(21) Procedures for safe use of pyrophoric solids https://ehs.ucsc.
edu/programs/research-safety/documents/ucla-pyrophoric-solid.pdf
(accessed Dec 23, 2023).
https://doi.org/10.1021/acs.chas.3c00102
ACS Chem. Health Saf. 2024, 31, 162−171
ACS Chemical Health & Safety
(22) https://studylib.net/doc/7595021/lithium-aluminum-hydride-
cas-no.16853-85-3 (accessed Dec 23, 2023).
(23) Safe use of pyrophoric reagents: https://research.columbia.edu/
sites/default/files/content/EHS/Homepage/pyrophorics.pdf (ac-
cessed Dec 23, 2023).
(24) Donners, M. P. J.; Hersmis, M. C.; Custers, J. P. A.; Meuldijk, J.;
Vekemans, J. A. J. M.; Hulshof, L. A. Hydride reduction of a lactate
ester: Optimization and scale-up. Org. Proc. Res. Dev. 2002, 6, 606−610.
(25) Sabater Lüntzel, C.; Widder, S.; Tobias, V.; Pickenhagen, W.
Enantioselective Syntheses and Sensory Properties of the 3-Mercapto-
2-methylpentanols. J. Agric. Food Chem. 2000, 48, 424−427.
(26) Johnson, T. A.; Michael D Curtis, M. D.; Beak, P. Highly
diastereoselective and enantioselective carbon bond formations in
conjugate additions of lithiated N-Boc allylamines to nitroalkenes:
Enantioselective synthesis of 3,4- and 3,4,5-substituted piperidines,
including (−)-Paroxetine. J. Am. Chem. Soc. 2001, 123 (5), 1004−1005.
(27) Heathcock, C. H.; Ruggeri, R. B.; McClure, K. F. Daphniphyllum
alkaloids. 15. Total syntheses of (.+-.)-methyl homodaphniphyllate and
(.+-.)-daphnilactone A. J. Org. Chem. 1992, 57, 2585−2599.
(28) Chandra, T.; Zebrowski, J. P.; McClain, R.; Lenertz, L. Y.
Generating standard operating procedures for the manipulation of
hazardous chemicals in academic laboratories. ACS Chem. Health Saf.
2021, 28 (1), 19−24.
(29) Chandra, T.; Zebrowski, J. P. Reactivity control using a Schlenk
line. J. Chem. Health Saf. 2014, 21 (3), 22−28.
(30) Tips and tricks for the lab: Air-sensitive techniques (1) https://
www.chemistryviews.org/details/education/3728881/Tips_and_
Tricks_for_the_Lab_Air-Sensitive_Techniques_1/ (accessed Dec 23,
2023).
(31) The Stahl group safety resources, University of Wisconsin-
Chemistry links: https://stahl.chem.wisc.edu/links/ (accessed Dec 23,
2023).
(32) The Berry group SOPs and safety resources, University of
Wisconsin- Chemistry links: https://berry.chem.wisc.edu/content/
safety-0 (accessed Dec 23, 2023).
(33) SOP documents: https://sarponggroup.com/sops/ (accessed
Dec 23, 2023).
(34) Lithium aluminum hydride SDS: https://www.sigmaaldrich.
com/US/en/sds/aldrich/686034?userType=anonymous (solid, ac-
cessed Dec 23, 2023).
(35) Lithium aluminum hydride SDS: https://www.sigmaaldrich.
com/US/en/sds/aldrich/703508?userType=anonymous (solution, ac-
cessed Dec 15, 2023).
(36) Lee, C. H.; Lee, S. J.; Park, J. W.; Kim, K. H.; Lee, B. Y.; Oh, J. S.
Preparation of Al(C6 F5)3 and its use for the modification of
methylalumoxane. J. Mol. Catal. Chemical 1998, 132, 231−239.
(37) Safety Alert: explosion during prep of (C6F5)PH2 https://cen.
acs.org/articles/90/i21/Safety-alert-explosion-during-prep.html (ac-
cessed Dec 23, 2023).
(38) Safety forum: explosion of perfluorosuccinamide and lithium
aluminum hydride. Chem. Eng. News 1951, 29, 30, 3042.
(39) Taydakov, I. V. Serious explosion during large-scale preparation
of an amine by alane (AlH3) reduction of a nitrile bearing a CF3 group.
ACS Chem. Health Saf. 2020, 27 (4), 235−239.
(40) Karo, W. Reducing fluorinated compounds with LiAIH4 causes
explosion. Chem. Eng. News 1955, 33 (13), 1368−1370.
(41) Lithium aluminum hydride not safe for drying methyl ethers;
Chem. Eng. News 1953, 31, 22, 2334.
(42) Garner, W. E.; Haycock, E. W. The thermal decomposition of
lithium aluminum hydride. Proc. Royal Soc. London. Series A 1952, 221,
335 DOI: 10.1098/rspa.1952.0046.
(43) Pohlman, J. L. W.; Brinckmann, T. E.Z. Z. Naturforsch., B: Anorg.
Chem., Org. Chem. 1965; Vol. 20, p 5.
(44) Richardson, P. F.; Steven, A.; Kargbo, R. B.; Mateos, C.; Zlota, A.
A.; Nawrat, C. C.; Ramirez, A.; Knight, J. Some Items of Interest to
Process R&D Chemists and Engineers. Org. Process Res. Dev. 2022, 26,
1−9.
(45) Chemical safety: LiAlH4 reduction of SiCl4. Chem. Eng. News
2005, 83, 51, 4−7.
170
pubs.acs.org/acschas Article
(46) American Chemical Society. Identifying and evaluating hazards
in research laboratories. https://www.acs.org/content/acs/en/
chemical-safety/teachand-learn/university.html (accessed Oct 29,
2023).
(47) UW-Chemistry pyrophoric SOP: https://uwmadison.app.box.
com/s/3zzzi5kfdfh57slx1a87emx481z2zjvn (accessed Dec 23, 2023).
(48) Lithium aluminum hydride fire: https://h2tools.org/lessons/
lithium-aluminum-hydride-laboratory-fire (accessed Dec 23, 2023).
(49) Boon, B. A. Thesis Dissertation; Merlic Lab, the University of
California: Los Angeles, 2017, p 192. https://escholarship.org/uc/
item/95h074r0 (accessed Dec 23, 2023).
(50) Krishnamurthy, S.; Brown, H. C. Selective reductions. 28. The
fast reaction of lithium aluminum hydride with alkyl halides in
tetrahydrofuran. A reappraisal of the scope of the reaction. J. Org. Chem.
1982, 47 (2), 276−280.
(51) Nystrom, R. F.; Brown, W. G. Reduction of organic compounds
by lithium aluminum hydride. I. aldehydes, ketones, esters, acid
chlorides, and acid anhydrides. J. Am. Chem. Soc. 1947, 69 (5), 1197−
1199.
(52) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Safe and convenient procedure for solvent purification.
Organometallics 1996, 15 (5), 1518−1520.
(53) Adapters-solid addition. https://chemglass.com/adapters-solid-
addition-merlic-airfree-schlenk (accessed Dec 23, 2023).
(54) https://www.fishersci.com/shop/products/adapter-solid-
addition-24-40/AF050302 (accessed Dec 23, 2023).
(55) https://www.labdepotinc.com/p-63931-adapters-solid-
addition-merlic-airfree-schlenk (accessed Dec 23, 2023).
(56) Chandra, T.; Zebrowski, J. P.; Lenertz, L. Y. Safe handling of
cannulas and needles in chemistry laboratories. ACS Chemical Health &
Safety 2022, 29 (2), 175−183.
(57) Lithium aluminum hydride: https://www.chemicalbook.com/
ProductChemicalPropertiesCB7318252_EN.htm (accessed Dec 23,
2023).
(58) Lewis, H. W.; Moody, C. J. Experimental Organic Chemistry:
Principles and Practice (Illustrated ed.).; Wiley-Blackwell, June 13, 1989;
pp 159−173. ISBN 9780632020171.
(59) Fieser work-up: http://www.chem.rochester.edu/notvoodoo/
pages/magic_formulas.php?page=aluminum_hydride_reduction (ac-
cessed Dec 23, 2023).
(60) Employee suffers burns in chemical explosion: https://www.
osha.gov/ords/imis/accidentsearch.accident_detail?id=170710511
(accessed Dec 23, 2023).
(61) Merlic, C. A.; Ngai, E.; Schroeder, I.; Smith, K. Report of the
University of Hawaii at Manoa on the hydrogen/oxygen explosion of
March 16, 2016. In Technical Analysis of Accidents; U.C. Center for
Laboratory Safety: Los Angeles, CA, 2016 https://cls.ucla.edu/images/
document/Report%201%20UH.pdf (accessed Dec 23, 2023)..
(62) Lithium aluminum hydride: Princeton University: https://ehs.
princeton.edu/laboratory-research/chemical-safety/chemical-specific-
protocols/lithium-aluminum-hydride#:~:text=
Fire%3A%20Use%20Class%20D%20extinguisher,cover%20the%20s
pill%20with%20sand (accessed Dec 23, 2023).
(63) Kemsley, J. Texas Tech lessons. Chem. Eng. News 2010, 88 (34),
34−37.
(64) Ménard, A. D.; Trant, J. F. A review and critique of academic lab
safety research. Nat. Chem. 2020, 12, 17−25.
(65) Langerman, N. Management of change for laboratories and pilot
plants. Org. Process Res. Dev. 2008, 12, 1305−1306.
(66) Cadwallader, L. C.; Pawelko, R. J. Elements of experiment safety
in the laboratory. J. Chem. Health Saf. 2019, 26 (4−5), 20−25.
(67) National Research Council. Safe Science: Promoting A Culture of
Safety in Academic Chemical Research; The National Academies Press:
Washington, D.C., 2014.
(68) Reductions with lithium aluminum hydride reduction: https://
www.ch.ic.ac.uk/local/organic/0405Expt5.pdf (accessed Dec 23,
2023).
(69) Reductions: https://hwpi.harvard.edu/files/myers/files/5-
reduction.pdf (accessed Dec 23, 2023).
https://doi.org/10.1021/acs.chas.3c00102
ACS Chem. Health Saf. 2024, 31, 162−171
ACS Chemical Health & Safety pubs.acs.org/acschas Article

(70) Laboratory housekeeping: https://www.labmanager.com/lab-

health-and-safety/laboratory-housekeeping-21269 (accessed Dec 23,
2023).
(71) Housekeeping: https://www.acs.org/industry/industry-
matters/on-the-safe-side/ken-fivizzani-housekeeping.html (accessed
Dec 23, 2023).
(72) Thompson, B. T.; Gallaher, T. N.; DeVore, T. C. The Reaction of
lithium aluminum hydride with carbon dioxide or sodium bicarbonate.
Polyhedron 1983, 2 (7), 619−621.

171 https://doi.org/10.1021/acs.chas.3c00102
ACS Chem. Health Saf. 2024, 31, 162−171